HK1172024A

HK1172024A - Inhibitors of pi3 kinase and/or mtor

Info

Publication number: HK1172024A
Application number: HK12112860.8A
Authority: HK
Inventors: Kristin Andrews; Yunxin Y. Bo; Shon Booker; Victor J. Cee; Noel D'angelo; Bradley J. Herberich; Fang-Tsao Hong; Claire L. M. Jackson; Brian A. Lanman; Hongyu Liao; Longbin Liu; Nobuko Nishimura; Mark H. Norman; Liping H. Pettus; Anthony B. Reed; Adrian L. Smith; Seifu Tadesse; Nuria A. Tamayo; Bin Wu; Ryan Wurz
Original assignee: Amgen Inc.
Priority date: 2009-04-28
Filing date: 2010-04-27
Publication date: 2013-04-12

Description

Inhibitors of PI3 kinase and/or MTOR

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application No.61/173,520 filed on 28/4/2009 and U.S. provisional application No.61/258,532 filed on 5/11/2009, which are hereby incorporated by reference.

Technical Field

The present invention relates to compounds that inhibit phosphoinositide 3-kinase (PI 3K) and/or the mammalian target of rapamycin (mTOR); methods of using the compounds to treat diseases or conditions such as cancer; and pharmaceutical compositions containing said compounds.

Background

PI3 kinases are a family of lipid kinases that have been found to play a key role in the regulation of many cellular processes including proliferation, survival, carbohydrate metabolism and motility. PI3K is thought to play an important role in intracellular signal transduction. In particular, PI3K produces and conveys signals that have an important role in cancer. PI3K is ubiquitously expressed, activated by a high proportion of cell surface receptors (particularly those associated with tyrosine kinases), and affects a variety of cellular functions and events. While some PI3K activity may be essential for cell health, PI3K is a diverse group of enzymes, with growing evidence of functional specialization. This opens up the possibility to develop subtype-selective inhibitors that can be used to treat cancer.

The main enzymatic activity of PI3K is the phosphorylation of inositol lipids (phosphoinositides) at position 3 of the inositol head group. PI3 kinase catalyzes the addition of phosphate to the 3' -OH position of the inositol ring of inositol lipids, producing phosphatidylinositol monophosphates, phosphatidylinositol diphosphates, and phosphatidylinositol triphosphates.

There are a total of eight mammalian species PI3K, which are classified into three major classes based on sequence homology, in vivo outsole preference, and methods of activation and regulation. The first class (class I) of enzymes have broad substrate specificity and confer phosphatidylinositol (PtdIns), PtdIns (4) P and PtdIns (4, 5) P ₂And (4) phosphorylation. Class I PI3 kinases include mammalian p110 α, p110 β, p110 δ, and p110 γ. Different members of the PI3 kinase family produce different lipid products. To date, four 3-phosphorylated inositol lipids have been identified in vivo. These lipids are bound by proteins that contain a suitable lipid recognition module and act as effectors or forward PI3K signals. The most familiar form of PI3K is a heterodimeric complex consisting of a catalytic subunit of 110kDa (now known as p 110. alpha.) and a formulated subunit of 85kDa (p 85. alpha.).

Phosphatidylinositol 3-kinase-alpha (PI3K alpha), a dual specific lipid and protein kinase, comprises an 85kDa regulatory subunit and a 110kDa catalytic subunit. The proteins include PtdIns, PtdIns (4) P and PtdIns (4, 5) P using ATP₂Phosphorylated catalytic subunits. PTEN is a tumor suppressor that dephosphorylates phosphatidylinositol (3, 4, 5) -triphosphate (PIP3, the major product of class I PI3 kinase). Translocation of protein kinase B (AKT1, PKB) to the cell membrane requires PIP3, PIP3 is phosphorylated on the cell membrane and activated by upstream kinases. The effect of PTEN on cell death is mediated by the PI3K α/AKT1 pathway.

PI3K a has been implicated in cytoskeletal remodeling, apoptosis, vesicle trafficking, and control during proliferation and differentiation. Increased copy number and expression of the p110 a gene (PIK3CA) is associated with a number of cancers, such as ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, thyroid cancer, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), and glioblastoma. In view of the important role of PI3K α in biological processes and disease conditions, inhibitors of this protein kinase are desirable. The present invention provides PI3K inhibitors, particularly PI3K α inhibitors, useful for treating PI3K α -mediated diseases and conditions.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is approximately 289kDa in size and is a member of the evolutionarily conserved eukaryotic TOR kinases. mTOR proteins are members of the PI3 kinase-like kinase (PIKK) family of proteins due to their C-terminal homology (catalytic domain) to PI3 kinase and other family members, such as DNA-dependent protein kinase (DNA-PKcs), ataxia telangiectasia mutated protein (ATM).

mTOR kinase has been shown to be a central regulator of cell growth and survival by mediating a variety of important cellular functions including translation, cell cycle regulation, cytoskeletal remodeling, apoptosis, and autophagy. mTOR resides in two distinct complexes of biochemical properties and functions that are conserved from yeast to humans. The rapamycin-sensitive mTOR-Raptor complex (mTORC1) regulates translation by activating p70S6 kinase through phosphorylation and inhibiting eIF4E binding protein 4EBP1, the physiological function that is described as the most well-established mTOR signaling. mTORC1 activity is regulated by extracellular signals (growth factors and hormones) via PI3K/AKT pathway and by nutrient availability, intracellular energy status and oxygen via regulatory factors like LKB1 and AMPK. Rapamycin and its analogs inhibit mTORC1 activity by interrupting the interaction between mTOR and raptor. The rapamycin insensitive complex mTORC2 was not discovered until recently. Unlike mTORC1, which contains raptor, mTORC2 complex contains other proteins including Rictor and mSin 1. mTORC2 phosphorylated AKT at the hydrophobic Ser473 site and appeared to be essential for AKT activity. Other substrates of mTORC2 include PKC α and SGK 1. It is not fully understood how mTORC2 activity is modulated.

The mTORC1 pathway can be activated by an increase in PI3K/AKT signaling or mutations in the tumor suppressor PTEN or TSC2, providing favorable conditions for cell growth by promoting protein synthesis. Cancer cells treated with the mTORC1 inhibitor rapamycin showed growth inhibition and in some cases apoptosis. In clinical trials for the treatment of cancer, there are three rapamycin analogues, CCI-779(Wyeth), RAD001(Novartis) and AP23573 (Ariad). However, response rates vary with different cancer types, with low response rates below 10% in glioblastoma and breast cancer patients and high response rates around 40% in mantle cell lymphoma patients. Recent studies have demonstrated that rapamycin can actually induce strong AKT phosphorylation in tumors by attenuating the feedback inhibition of receptor tyrosine kinases mediated by p70S6K (one of the downstream effectors of mTORC 1). For example, in phase I clinical trials of RAD001, an increase in pAKT was observed after dosing (+ 22.2% to 63.1% of initial values). If mTORC1 inhibition of induced phospho-AKT leads to an increase in cancer cell survival and acquires additional foci, this could counteract the growth inhibitory effect of rapamycin analogues and explain the altered response rate. Therefore, the identification and development of small molecules targeting mTOR catalytic activity (inhibiting mTORC1 and mTORC2) would lead to more effective therapies for treating cancer patients that prevent AKT activation by mTORC 1-specific inhibitors like rapamycin and its analogs. Deregulated mTOR activity has been shown to be associated with a variety of human cancers, such as breast, lung, kidney, brain, ovary, colon, cervix, endometrium, prostate, liver, thyroid, gastrointestinal, blood and lymph cancers, as well as other diseases such as hamartoma syndrome, rheumatoid arthritis, multiple sclerosis. In view of the important role of mTOR in biological processes and disease conditions, catalytic inhibitors of this protein kinase are desirable. The present invention provides kinase inhibitors, in particular PIK kinase inhibitors, more in particular mTOR inhibitors, which are useful in the treatment of diseases mediated by kinases, in particular PIK kinases, more in particular mTOR.

Summary of The Invention

In aspect 1, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof,

wherein Ar is¹Is a 5 to 10 membered monocyclic or bicyclic ring which can contain 0 to 4 heteroatoms independently selected from O, N or S, and said ring can be unsubstituted or substituted with a group independently selected from: c_1-4Haloalkyl, halo, oxo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b 、-N(R^a)C(＝O)OR^b 、-N(R^a)C(＝O)NR^aR^a 、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、 -C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Y is a saturated, partially saturated or unsaturated 5, 6 or 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, substituted with 0, 1 or 2 substituents independently selected from: c_1-8Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^aor-NR^aC_2-6Alkyl OR^a；

Each R^aIndependently is hydrogen or R^b；

Each R^bIndependently is phenyl, benzyl, C_1-6Alkyl radical, C _4-8Heterocycloalkyl or C_3-8Cycloalkyl radicals in which phenyl, benzyl, C_1-6Alkyl radical, C_4-8Heterocycloalkyl or C_3-8Cycloalkyl is substituted with 0, 1, 2, or 3 substituents independently selected from: halo, -OH, -S (═ O)₂R^b、-OC_2-6Alkyl OR^a、C_1-4Alkyl radical, C_1-3Haloalkyl, -OC_1-4Alkyl, -NH₂-CN or-NR^aR^a；

Each R^cIndependently hydrogen, -OR^a、-NR^aR^a、C_1-6Alkyl radicals or radicals CR^cR^cCan form C_3-8A cycloalkyl ring;

each n is independently 0, 1, 2 or 3;

each Z¹、Z²、Z³Or Z⁴Independently selected from N, NR or CR; or Z¹And Z²、Z²And Z³Or Z³And Z⁴In the case of NR or CR, may beThe two R taken together with the carbon or nitrogen atom to which they are attached form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)²N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CH)₂)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c _1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R is independently selected from hydrogen, oxo, C_1-4Haloalkyl, halo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、 -OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8 aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_3-8Cycloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cCR^c)_nO(CR^cCR^c)_nCF₃、-(CR^cCR^c)_nN(CR^cR^c)nOR^a、-(CR^cR^c)ⁿN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-8Aryl radical, C_4-8Heterocycloalkyl radical, C_3-8Cycloalkyl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, oxo, C_1-6Alkyl, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY、-(CR^aR^a)nC_3-8Cycloalkyl or- (CR)^aR^a)_nOR^a；

Q is

R²Is methyl or ethyl;

Z⁵is N or CR^c；

Z⁹Is N, NR or CR;

Z¹⁰is N, NR or CR, or Z⁹And Z¹⁰The two R groups, when taken together with the carbon or nitrogen atom to which they are attached, may form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c _1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)ⁿN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a(ii) a And the group NR^aR^aMay be a 4 to 6 membered heterocyclic ring, either alone or as part of a larger group, wherein the two R' s^aTaken together with the nitrogen atom to which they are attached, form a ring which may have from 0 to 1 additional heteroatoms selected from N, O or S, and which ring may be substituted or unsubstituted with from 1 to 3 substituents independently selected from: oxo, halo, -CN, nitro, -C (═ O) R^c、-C(＝O)OR^c、-OR^c、-OC(＝O)R^c、-SR^c、-S(＝O)R^c、-S(＝O)₂R^c、-S(＝O)₂NR^cR^c、-NR^cR^c、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl.

In aspect 1a, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof,

wherein Ar is¹Is a 5 to 10 membered monocyclic or bicyclic ring which can contain 0 to 4 heteroatoms independently selected from O, N or S, and said ring can be unsubstituted or substituted with a group independently selected from: c _1-4Haloalkyl, halo, oxo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)²N(R^a)C(＝O)OR^b、-S(＝O)²N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、 -S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R^aIndependently is hydrogen or R^b；

Each R^bIndependently is phenyl, benzyl, C_1-6Alkyl radical, C_4-8Heterocycloalkyl or C_3-8Cycloalkyl radicals in which phenyl, benzyl, C_1-6Alkyl radical, C_4-8Heterocycloalkyl or C_3-8Cycloalkyl is substituted with 0, 1, 2, or 3 substituents independently selected from: halo, -OH, -S (═ O)₂R^b、-OC_2-6Alkyl OR^a、C_1-4Alkyl radical, C_1-3Haloalkyl, -OC_1-4Alkyl, -NH₂-CN or-NR^aR^a；

Each R^cIndependently hydrogen, -OR ^a、-NR^aR^a、-CF₃、C_1-6Alkyl radicals or radicals CR^cR^cCan form C_3-8A cycloalkyl ring;

each n is independently 0, 1, 2 or 3;

each Z¹、Z²、Z³Or Z⁴Independently selected from N, NR or CR; or Z¹And Z²、Z²And Z³Or Z³And Z⁴In the case of NR or CR, the two R may, when taken together with the carbon or nitrogen atom to which they are attached, form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CH)₂)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R is independently selected from hydrogen, oxo, C_1-4Haloalkyl, halo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-(CR^aR^a)_nOR^a、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)²N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、 -N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR ^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_3-8Cycloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cCR^c)_nO(CR^cCR^c)_nCF₃、-(CR^cCR^c)_nN(CR^cR^c)_nOR^a、-(CR^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-8Aryl radical, C_4-8Heterocycloalkyl radical, C_3-8Cycloalkyl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, oxo,C_1-6Alkyl, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY、-(CR^aR^a)nC_3-8Cycloalkyl or- (CR)^aR^a)_nOR^a；

O is

R²Is methyl or ethyl;

Z⁵is N or CR^c；

Z⁹Is N, NR or CR;

Z¹⁰is N, NR or CR, or Z⁹And Z¹⁰The two R groups, when taken together with the carbon or nitrogen atom to which they are attached, may form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C _2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a(ii) a And the group NR^aR^aAlone or as part of a larger group, may be a 4-to 6-membered heterocyclic ringWherein the two R are^aTaken together with the nitrogen atom to which they are attached, form a ring which may have from 0 to 1 additional heteroatoms selected from N, O or S, and which ring may be substituted or unsubstituted with from 1 to 3 substituents independently selected from: oxo, halo, -CN, nitro, -C (═ O) R^c、-C(＝O)OR^c、-OR^c、-OC(＝O)R^c、-SR^c、 -S(＝O)R^c、-S(＝O)₂R^c、-S(＝O)₂NR^cR^c、-NR^cR^c、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl.

In aspect 2, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof,

wherein Ar is¹Is a 5 to 10 membered monocyclic or bicyclic ring which can contain 0 to 4 heteroatoms independently selected from O, N or S, and said ring can be unsubstituted or substituted with a group independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C _2-6Alkenyl or C_2-6Alkynyl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Y is a saturated, partially saturated or unsaturated 5, 6 or 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, substituted with 0, 1 or 2 substituents independently selected from: c_1-8Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NRaR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^aor-NR^aC_2-6Alkyl OR^a；

Each R^aIndependently is hydrogen or R^b；

Each R^bIndependently is phenyl, benzyl, C_1-6Alkyl or C_3-8Cycloalkyl radicals in which phenyl, benzyl, C_1-6Alkyl or C_3-8Cycloalkyl is substituted with 0, 1, 2, or 3 substituents independently selected from: halogen radical, C_1-4Alkyl radical, C_1-3Haloalkyl, -OC_1-4Alkyl, -NH₂-CN or-NR^aR^a；

Each R^cIndependently is hydrogen or C_1-6An alkyl group;

each n is independently 0, 1, 2 or 3;

each Z¹、Z²、Z³Or Z⁴Independently selected from N, NR or CR; or Z¹And Z²、Z²And Z³Or Z³And Z⁴In the case of NR or CR, the two R may, when taken together with the carbon or nitrogen atom to which they are attached, form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c _1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、 -N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CH)₂)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6 alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R is independently selected from hydrogen and C_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Q is

R²Is methyl or ethyl;

Z⁵is N or CR ^c；

Z⁹Is N, NR or CR;

Z¹⁰is N, NR or CR, or Z⁹And Z¹⁰The two R groups, when taken together with the carbon or nitrogen atom to which they are attached, may form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Cycloalkyl, - (CR)^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)ⁿN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b 、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a(ii) a And

group NR^aR^aMay be a 4 to 6 membered heterocyclic ring, either alone or as part of a larger group, wherein the two R' s^aTaken together with the nitrogen atom to which they are attached, form a ring which may have from 0 to 1 additional heteroatoms selected from N, O or S, and which ring may be substituted or unsubstituted with from 1 to 3 substituents independently selected from: oxo, halo, -CN, nitro, -C (═ O) R ^c、-C(＝O)OR^c、-OR^c、-OC(＝O)R^c、-SR^c、-S(＝O)R^c、-S(＝O)₂R^c、-S(＝O)₂NR^cR^c、-NR^cR^c、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl.

In aspect 3, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

In aspect 4, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

In aspect 5, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is¹Is N; and Z is²、Z³And Z⁴Is CR.

In aspect 6, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is¹Is N; and Z is²、Z³And Z⁴Is CH.

In aspect 7, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is¹、Z²And Z⁴Is CR; and Z is³Is N.

In aspect 8, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is¹Is N; z²And Z³Is CR; and Z is⁴Is N.

In aspect 9, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is¹Is N; z²And Z⁴Is CH; and Z is³Is CR.

In aspect 10, the present invention provides a compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is ¹Is N; z²And Z⁴Is CH; z³Is CR; and R is selected from hydrogen, C_1-6Alkyl radical, C_1-6Substituted alkyl, halo, C_1-4Haloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nSubstituted C_4-8Heterocycloalkyl, - (CR)^cR^c)_nO(CR^cR^c)_nSubstituted C_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nSubstituted C_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nSubstituted C_5-8Heteroaryl group, C_2-6Alkenyl or- (CR)^cR^c)_nNR^aR^a. In a particular embodiment of aspect 10, Z³Is CR and R is represented by-OR^aSubstituted C_1-6An alkyl group.

In aspect 11, the present invention provides a compound according to any one of aspects 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl or indazolyl, which groups may be unsubstituted or substituted.

In aspect 12, the present invention provides a compound according to any one of aspects 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzo(ii) an oxazolyl or indazolyl group, which groups may be unsubstituted or substituted with a group selected from: -OR^aHalogen, -NR^aR^a、C_1-4Haloalkyl, -N (R)^a)C(＝O)R^bor-N (R)^a)C(＝O)NR^aR^a。

In aspect 13, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

Ar¹selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl or indazolyl, which groups may be unsubstituted or substituted.

In aspect 14, the present invention provides a compound of formula I according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CH; and

In aspect 15, the present invention provides a compound according to any one of aspects 1, 2 or 5 to 12, or a pharmaceutically acceptable salt thereof, wherein R is²Is methyl.

In aspect 16, the invention provides a compound according to any one of aspects 1, 2 or 5 to 12, or a pharmaceutically acceptable salt thereof, wherein Q is

In aspect 17, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

In aspect 18, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N;

Z²and Z⁴Is CH;

Ar¹is a substituted pyridyl group; and

Z³is CR.

In aspect 19, the present invention provides a compound according to any one of aspects 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiadiazolyl, which groups may be unsubstituted or substituted.

In aspect 20, the present invention provides a compound according to any one of aspects 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzo(ii) an oxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiadiazolyl group, which may be unsubstituted or substituted by a group selected from: -OR^aHalogen, -NR^aR^a、C_1-4Haloalkyl, -N (R)^a)C(＝O)R^b、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^aor-N (R)^a)C(＝O)NR^aR^a。

In aspect 21, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

Ar¹selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzo Oxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiadiazolyl.

In aspect 22, the present invention provides a compound of formula I according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z2, Z3 and Z⁴Is CH; and

Ar¹selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiadiazolyl.

In aspect 23, the present invention provides a compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

Ar¹selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiadiazolyl, which groups may be unsubstituted or substituted.

In aspect 24, the present invention provides a compound selected from:

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indol-4-amine;

3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) phenol;

N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indazol-4-amine;

4- (2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

3- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) phenol;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (3- (6-amino-5-fluoro-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine;

3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol;

4- (2- (6-methoxypyridin-3-ylamino) -5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

methyl-6- (5-methyl-2- (pyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine;

4- (5-methoxy-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (6-methoxypyridin-3-yl) -3- (4-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine;

4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-indazol-4-amine;

4-methyl-6- (5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (6- (trifluoromethyl) pyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine;

4-methyl-6- (5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyrimidin-5-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d] Oxazol-6-amine;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methylpyridin-2-yl) -1H-indol-4-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methylpyridin-2-yl) -1H-indazol-4-amine;

4- (5-bromo-2- (4-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (6-ethoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine;

4- (2- (6-chloropyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (6-methyl-1H-pyrazolo [3, 4-d ] pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

n- (5-chloro-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (5-bromo-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) -5- (trifluoromethyl) pyridin-2-yl) -1H-indazol-4-amine;

2-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) pyrimidin-5-amine;

n- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine;

(6- (1H-indazol-4-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5-vinylpyridin-2-amine;

5-ethyl-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) ethanol;

(6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol;

5- ((4-methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

5- ((3-methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-3-ylamino) methyl) pyridin-2-amine;

n- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) pyridazin-3-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-4-ylamino) methyl) pyridin-2-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-2-ylamino) methyl) pyridin-2-amine;

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((phenylamino) methyl) pyridin-2-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine;

4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid methyl ester;

4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide;

4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-sulfonamide;

1- (4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethanone;

n5- (4-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

N5-benzyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

n2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -N5-phenylpyridine-2, 5-diamine;

N5- (2-methoxyethyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

N5-ethyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

n5- (4-methoxybenzyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

n5- (3-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine;

n- (3- (2-methyl-9H-purin-6-yl) -5-morpholinopyridin-2-yl) -1H-indazol-4-amine;

1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-3-ol;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) piperazin-1-yl) pyridin-2-amine;

((2S) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-2-yl) methanol;

((2R) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-2-yl) methanol;

n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine;

N- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) -1H-indazol-4-amine;

n- (5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide;

n5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) pyridine-2, 5-diamine;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indazol-4-amine;

n- (6- (4- (1H-indol-4-ylamino) pyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) -1H-indazol-4-amine;

6-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) pyridin-3-amine;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine; or

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) quinolin-2-amine.

In aspect 25, the present invention provides a compound selected from:

4- (3- ((6-methoxy-3-pyridinyl) amino) -2-pyrazinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (3- ((6-methoxy-3-pyridinyl) amino) -4-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

6- (3- ((6-methoxy-3-pyridinyl) amino) -2-pyrazinyl) -2-methyl-4-pyrimidinamine;

4- (4- ((6-methoxy-3-pyridinyl) amino) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxy-3-pyridinyl) -2, 4-pyrimidinediamine;

4- (2-methoxy-4- ((6-methoxy-3-pyridinyl) amino) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (4- ((6-methoxy-3-pyridinyl) amino) -2- (4-morpholinyl) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxy-3-pyridinyl) -N2, N2-dimethyl-2, 4-pyrimidinediamine;

4- (4- ((6-methoxy-3-pyridinyl) amino) -2- (1-pyrrolidinyl) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (4- ((6-methoxy-3-pyridinyl) amino) -2- (1-piperidinyl) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (4- ((6-methoxy-3-pyridinyl) amino) -2- (4-pyridinyl) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (4-fluorophenyl) -4- ((6-methoxy-3-pyridyl) amino) -5-pyrimidinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N2-cyclopentyl-N4- (6-methoxy-3-pyridyl) -2, 4-pyrimidinediamine;

5-chloro-N- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -1, 3-benzoOxazol-5-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (4-morpholinomethyl) -2-pyridyl) -1, 3-benzothiazol-5-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylmethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -2, 2-dimethyl-1-propanol;

(1S) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -2, 2-dimethyl-1-propanol;

(1R) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -2, 2-dimethyl-1-propanol;

5- ((tert-butylamino) methyl) -N- (6-methoxy-3-pyridinyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

n- (6-methoxy-3-pyridyl) -5- (((1-methylethyl) amino) methyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

n- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -5- (((2-pyridylmethyl) amino) methyl) -2-pyridylamine;

N- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -5- (((4-pyridylmethyl) amino) methyl) -2-pyridylamine;

n- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -5- (((3-pyridylmethyl) amino) methyl) -2-pyridylamine;

(6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) (4- (methylsulfonyl) phenyl) methanol;

n- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -2-pyridylamine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4- (methylsulfonyl) benzyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (4- (methylsulfonyl) benzyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) carbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (2-methoxyethyl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinecarboxamide;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((1- (methylsulfonyl) -4-piperidinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5-benzyl-2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((4-methyl-1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (((2R) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethyl-1-piperazinecarboxamide;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-hydroxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethyl-1-piperazinecarboxamide;

5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) amino) -3-fluoro-2-pyridinol;

4- (2- ((5-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -N, 6-dimethyl-1, 3, 5-triazin-2-amine;

4- (2- ((3- (difluoromethoxy) phenyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridyl) -2-methyl-1, 3-benzoOxazol-5-amine;

4- (2- ((3-fluoro-4-methoxyphenyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((4-fluoro-3-methoxyphenyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((2, 2-difluoro-1, 3-benzodioxol-5-yl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxy-3-pyridinyl) -3, 3' -bipyridin-6-amine;

4- (2- ((3, 4-dimethoxyphenyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridyl) -2-methyl-6-quinolinamine;

5 ' - (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxy-3-pyridyl) -2, 3 ' -bipyridin-6 ' -amine;

4- (2- ((5-chloro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4-methyl-6- (2- ((5-methyl-3-pyridinyl) amino) -3-pyridinyl) -1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxy-3-pyridinyl) -2, 4' -bipyridin-6-amine;

1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) carbonyl) -4-piperidinol;

6- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine;

(5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methanol;

3- (6-amino-2-methyl-4-pyrimidinyl) -N-1H-indazol-4-yl-2-quinoxalinamine;

n- (2-chloro-4- ((3- (2-methyl-9H-purin-6-yl) -2-pyridinyl) amino) phenyl) acetamide;

n- (4- ((3- (2-methyl-9H-purin-6-yl) -2-pyridinyl) amino) phenyl) cyclopropanecarboxamide;

n- (5-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

4- (5-chloro-2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5-fluoro-2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5-fluoro-2- ((5-fluoro-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinecarboxaldehyde;

4- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) -3-pyridyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5-chloro-2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine;

1- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridinyl) amino) -2-pyridinyl) -3-phenylurea;

1- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridinyl) amino) -2-pyridinyl) -3- (3-fluorophenyl) urea;

1- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridinyl) amino) -2-pyridinyl) -3- (1-methylethyl) urea;

n- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-pyridinyl) acetamide;

(5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-pyridinyl) carbamic acid methyl ester;

1- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-pyridinyl) -3- (4- (2-methoxyethoxy) phenyl) urea;

n- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) amino) -2-pyridinyl) acetamide;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -6-methyl-3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -6- (4-morpholinylmethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -6- ((2, 2, 2-trifluoroethoxy) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-3-pyridinyl) amino) -6-methyl-3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-thiomorpholinylmethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((1-oxy (oxido) -4-thiomorpholinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -3-methyl-3H-imidazo [4, 5-b ] pyridin-6-amine;

((3S) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinyl) methanol;

(3S) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinol;

(3R) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinol;

4- (2- ((2-methoxy-5-pyrimidinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethyl-1-piperazinesulfonamide;

1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -4-piperidinol;

((3R) -1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-pyrrolidinyl) methanol;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (((3S) -3-methyl-4-morpholinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5- (1-azetidinylmethyl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1-pyrrolidinylmethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1-piperidinylmethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((3- (methylsulfonyl) -1-azetidinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperidinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

2- (((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) amino) ethanol;

(2R) -2- (((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) amino) -1-propanol;

4- (5- (((2-methoxyethyl) amino) methyl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (((3R, S) -3- (methylsulfonyl) -1-pyrrolidinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-azetidinol;

2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -2, 5, 7-triazaspiro [3.4] octane-6, 8-dione;

4- (5- ((3-amino-1-azetidinyl) methyl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-azetidinyl) methanesulfonamide;

4- (5- (5, 6-dihydro [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -ylmethyl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide;

4- (amino (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethylbenzenesulfonamide;

3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxy-3-pyridinyl) -2-quinolinamine;

4- (2- ((6-methoxy-3-pyridinyl) amino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -1, 3-benzothiazol-5-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -1, 3-benzothiazol-6-amine;

4- (2- ((5-fluoro-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4-methyl-6- (5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2- (1H-pyrazol-4-ylamino) -3-pyridinyl) -1, 3, 5-triazin-2-amine;

4-methyl-6- (5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2- (1H-pyrazol-3-ylamino) -3-pyridinyl) -1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -6-fluoro-1H-indazol-4-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1-methyl-1H-pyrazol-4-yl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((3, 4-difluorophenyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxy-3-pyridyl) -1 ', 2 ', 3 ', 6 ' -tetrahydro-3, 4 ' -bipyridin-6-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1H-pyrazol-4-yl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxy-3-pyridyl) -6 '-methyl-3, 3' -bipyridin-6-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-pyridazinyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5 '-fluoro-N- (6-methoxy-3-pyridinyl) -3, 3' -bipyridin-6-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxy-3-pyridinyl) -2, 3' -bipyridin-6-amine;

5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxy-3-pyridinyl) -2, 3' -bipyridin-6-amine;

4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5-chloro-2- ((5-fluoro-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-3-pyridinyl) amino) -5- (1-methyl-1H-pyrazol-4-yl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -6- (2-methoxyethoxy) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) -1H-benzimidazol-5-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-piperazinylmeth-yl) -2-pyridyl) -1H-benzimidazol-5-amine;

4- (5- (difluoromethoxy) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridinyl) amino) -2(1H) -pyridone;

n- (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) -4-fluorobenzenesulfonamide;

n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -2-pyridyl) -2-chloro-3, 5-pyridinediamine;

n- (4- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-fluorophenyl) acetamide;

N- (4- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) amino) -2-fluorophenyl) acetamide;

n- (4- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) -1-piperazinyl) methyl) -2-pyridinyl) amino) phenyl) acetamide;

(1R, S) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -2, 2, 2-trifluoroethanol;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -2-propanol;

6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine;

6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine;

4- (5- (1-amino-1-methylethyl) -2- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5- (1-amino-1-methylethyl) -2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1-methyl-1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1-methyl-1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1-methyl-1- (4-morpholinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (1- (4- (methylsulfonyl) -1-piperazinyl) cyclopropyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine; (s) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine; or

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

In aspect 26, the invention provides a compound selected from:

6- (3- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine;

2- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) propan-2-ol;

1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone;

6- (3- (6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine;

(R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine;

4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (benzo [ d ] thiazol-5-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine;

(R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine;

4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide;

n- (5-fluoro-6-methoxypyridin-3-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

n- (5-fluoro-6-methoxypyridin-3-yl) -5- ((S) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

(R) -N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine;

1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) cyclopropanol;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (isopropylamino) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5- (1-aminocyclopropyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5- (3-aminopentan-3-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide;

6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine;

6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine;

n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyrazinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide;

4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine 2, 2, 2-trifluoroacetate;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropan-1-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol;

(S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (6-chloropyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(S) -4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -1, 1, 1-trifluoropropan-2-ol;

4- (2- (6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol;

(S) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol;

4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine;

4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (tetrahydro-2H-pyran-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxy-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (4-morpholinylmethyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide;

N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide;

n- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide;

n- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide;

n' - (2-chloro-5- ((3- (2-methyl-9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide;

(R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

2- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropionic acid;

1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropane-1, 2-diol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxy-5- (trifluoromethyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5, 6-dimethoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

3-chlorobenzoic acid 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-hydroxy-2-methylpropyl ester;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoropyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxy-5-methylpyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (methylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (phenylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-isopropyl-N-methylpiperazine-1-carboxamide;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-methyl-N- (2, 2, 2-trifluoroethyl) piperazine-1-carboxamide;

4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-cyclopropyl-N-methylpiperazine-1-carboxamide;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((S) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

4- (2- (6-chloropyridin-3-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

(R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) cyclopropanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide;

N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-yl) -2-chloropyridine-3, 5-diamine;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide;

(R) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

(S) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

(R) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide;

(S) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide;

n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide;

N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide;

n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide;

n- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide;

n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) -5-vinylpyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide;

(R) -N- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide;

(S) -N- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide;

4- (5- ((1, 1-hexahydro-5 h-isothiazolo [2, 3-a ] pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine; or

N' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide.

In aspect 27, the invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof,

wherein X¹Is fluorine or hydrogen;

Y¹is hydrogen or methyl; and

Z¹is hydrogen or methyl.

In aspect 28, the present invention provides a compound according to aspect 27, or a pharmaceutically acceptable salt thereof, wherein X1 is fluoro; y1 is hydrogen or methyl; and Z1 is hydrogen or methyl.

In aspect 29, the invention provides a compound of formula IIa or a pharmaceutically acceptable salt thereof,

wherein X¹Is fluorine or hydrogen;

Y¹is hydrogen or methyl; and

Z¹is hydrogen or methyl.

In aspect 30, the present invention provides a compound according to aspect 29, or a pharmaceutically acceptable salt thereof, wherein X¹Is fluorine; y is¹Is hydrogen or methyl; and Z is¹Is hydrogen or methyl.

In aspect 31, the present invention provides a pharmaceutical composition comprising: a compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

In aspect 32, the invention provides methods of treating: melanoma, ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, pancreatic cancer, lung cancer, gastric cancer, glioblastoma, liver cancer, prostate cancer, acute myelogenous leukemia (acute myelogenous leukemia), chronic myelogenous leukemia (chronic myelogenous leukemia), or thyroid cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof.

Detailed Description

The present invention provides a compound of formula I (as defined above) or a pharmaceutically acceptable salt thereof. The invention also provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and methods of using a compound of formula I, or a pharmaceutically acceptable salt thereof, to treat diseases or conditions such as cancer.

The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl. Typical alkyl groups are those having 1 to 8 carbon atoms, which groups are generally represented by C_1-8An alkyl group.

The term "alkoxy" means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tertiaryButoxy, propoxy, and isobutoxy. A common alkoxy group is C_1-8An alkoxy group.

The term "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

The term "alkenyl" means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds. Representative examples of alkenyl groups include ethenyl, propenyl, allyl, butenyl, and 4-methylbutenyl. A common alkenyl group is C_2-8An alkenyl group.

The term "alkynyl" means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds. Representative examples of alkynyl groups include ethynyl, propynyl (propargyl), and butynyl. A common alkynyl group is C _2-8Alkynyl.

The term "cycloalkyl" means a cyclic, non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may contain one or more double bonds. Examples of the cycloalkyl group having a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. A common cycloalkyl group is C_3-8A cycloalkyl group.

The term "perfluoroalkyl" means an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms. A common perfluoroalkyl group is C_1-8A perfluoroalkyl group. An example of a common perfluoroalkyl group is-CF₃。

The term "acyl" means a group derived from an organic acid by removal of a hydroxyl group (-OH). For example, acyl CH₃C (═ O) -prepared from CH₃C (═ O) OH is formed by removal of the hydroxyl group.

The term "aryl" means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are 6 to 13 membered rings.

The term "heteroatom" as used herein means an oxygen, nitrogen or sulfur atom.

The term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms of the aryl group have been replaced by a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxaline, isothiazolyl, and benzo [ b ] thienyl. Typical heteroaryl groups are 5-to 13-membered rings containing 1 to 4 heteroatoms. Heteroaryl groups with 5-and 6-membered rings containing 1 to 3 heteroatoms are particularly prevalent.

The term "heterocycloalkyl" means a cycloalkyl group in which one or more carbon atoms are replaced by a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuranyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups may also have one or more double bonds, but are not aromatic groups. Examples of the heterocycloalkyl group having a double bond include dihydrofuran. Common heterocycloalkyl groups are 3 to 10 membered rings containing 1 to 4 heteroatoms. Heterocycloalkyl groups which are 5-and 6-membered rings containing 1 to 3 heteroatoms are particularly common.

It is also noted that cyclic groups, i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can contain more than one ring. For example, naphthyl is a fused bicyclic ring system. The invention is also intended to include cyclic groups having bridging atoms, or cyclic groups having a helical orientation.

Representative examples of 5-to 6-membered aromatic rings optionally having one or two heteroatoms are phenyl, furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, imidazolyl, pyrazolyl, isopyrazolylOxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Representative examples of partially saturated, fully saturated or fully unsaturated 5-to 8-membered rings optionally having 1 to 3 heteroatoms are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other exemplary 5-membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-dioxolanyl,azolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isopyrazolylAzolyl, isothiazolyl, 1, 2-dithiol, 1, 3-dithiol, 3H-1, 2-Thiol group, 1, 2, 3-Oxadiazolyl, 1, 2, 4-Diazolyl, 1, 2, 5-Oxadiazolyl, 1, 3, 4-Oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-thiadiazolyl, 3H-1, 2, 3-diazolylAzolyl, 1, 2, 4-bisAzolyl, 1, 3, 2-bisAzolyl, 1, 3, 4-bisAzolyl, 5H-1, 2, 5-Thiazolyl and 1, 3-A thiol group.

Other exemplary 6-membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1, 2-biEnglish radical, 1, 3-twoEnglish radical, 1, 4-twoAlkyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3, 5-triazinyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-trithianyl, 4H-1, 2- Oxazinyl, 2H-1, 3-Oxazinyl, 6H-1, 3-Oxazinyl, 6H-1, 2-Oxazinyl, 1, 4-Oxazinyl, 2H-1, 2-Oxazinyl, 4H-1, 4-Oxazinyl, 1, 2, 5-Thiazinyl, 1, 4-Oxazine group, ortho-isoOxazine radical, para-isoOxazinyl, 1, 2, 5-Thiazinyl radical, 1, 2, 6- (3)Thiazinyl) and 1, 4, 2-A diazinyl group.

Other exemplary 7-membered rings are azepinyl, oxapinyl, thiapinyl, and 1, 2, 4-triazo.

Other exemplary eight-membered rings are cyclooctyl, cyclooctenyl, and cyclooctadienyl.

Exemplary bicyclic rings optionally having 1 to 4 heteroatoms consisting of two fused partially saturated, fully saturated or fully unsaturated 5-and/or 6-membered rings are: indolizinyl, indolyl, isoindolyl, indolinyl, cyclopentyl (b) pyridinyl, pyrano (3, 4-b) pyrrolyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indazolinyl, benzoxazinylOxazolyl, anthranoylyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxaline, 1, 8-naphthyridinyl, pteridinyl, indenyl, isoindolyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, 2H-1-benzopyranyl, pyrido (3, 4-b) pyridyl, pyrido (3, 2-b) pyridyl, pyrido (4, 3-b) -pyridyl, 2H-1, 3-benzopyrido (4, 3-b) -pyridyl Azinyl, 2H-1, 4-benzoAzinyl, 1H-2, 3-benzoAzinyl, 4H-3, 1-benzoAzinyl, 2H-1, 2-benzoOxazine radical and 4H-1, 4-benzoAn oxazine group.

The cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, all possible arrangements are meant. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl" includes 2-or 3-thienyl.

The term "substituted" means that a hydrogen atom on a molecule or group is replaced by a group or atom. Typical substituents include: halogen, C_1-8Alkyl, hydroxy, C_1-8Alkoxy, -NR^xR^xNitro, cyano, halo or perhalo C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, -SR^x、-S(＝O)₂R^x、-C(＝O)OR^x、-C(＝O)R^xWherein each R^xIndependently is hydrogen or C₁-C₈An alkyl group. It should be noted that when the substituent is-NR^xR^xWhen R is^xThe group may be joined together with the nitrogen atom to form a ring.

When used as a substituent, the term "oxo" means an ═ O group, typically bonded to a carbon atom.

The group or atom replacing a hydrogen atom is also referred to as a substituent.

Any particular molecule or group may have one or more substituents, depending on the number of hydrogen atoms that may be replaced.

The symbol "-" represents a covalent bond, and may also be used in a group to indicate the point of attachment of another group. In chemical structure, the symbol is often used to represent a methyl group in a molecule.

The term "therapeutically effective amount" means an amount of a compound that ameliorates, reduces or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one of more symptoms of a particular disease or condition.

The term "patient" means an animal such as a dog, cat, cow, horse, sheep, and a human. A particular patient is a mammal. The term patient includes males and females.

The term "pharmaceutically acceptable" means that the substance in question, such as a compound of formula I, or a salt of a compound of formula I, or a formulation containing a compound of formula I, or a specific excipient, is suitable for administration to a patient.

The term "treatment" includes prophylactic (e.g., prophylactic) and palliative treatments.

The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than the Active Pharmaceutical Ingredient (API), which is typically included for formulation and/or administration to a patient.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compound or composition may be administered all at once, e.g., by a single injection, multiple administrations, e.g., by a series of tablets, or substantially uniformly over a period of time, e.g., using transdermal delivery. It should also be noted that the dosage of the compound may vary over time.

Furthermore, the compounds of the present invention may be administered alone, in combination with other compounds of the present invention, or in combination with other pharmaceutically active compounds. The other pharmaceutically active compounds may be used to treat the same disease or condition as the compounds of the invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds may be administered simultaneously or sequentially. For example, in the case of tablets, the active compound may be contained in one tablet or in separate tablets which may be administered at once or sequentially in any order. Furthermore, it is recognized that the compositions may be in different forms. For example, one or more compounds may be delivered by tablet, while another may be administered by injection or orally as a syrup. The present invention encompasses all combinations, methods of delivery, and orders of administration.

As one aspect of the invention encompasses the treatment of a disease/condition with a combination of pharmaceutically active agents that can be administered independently, the invention further relates to combining the independent pharmaceutical compositions in a kit form. The kit comprises two separate pharmaceutical compositions: a compound of the invention and a second pharmaceutical compound. The kit comprises containers, such as separate bottles or separate foil packets, for containing the individual compositions. Other examples of containers include syringes, boxes, and bags. Typically, the kit comprises instructions for the use of the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosage intervals, or when the prescribing physician or veterinarian desires a titration scheme for the individual components of the combination.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of preferably transparent plastic material. During the packaging process, the grooves are formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. Next, a tablet or capsule is placed in the recess and a sheet of relatively hard material is sealed against the plastic foil on the surface of the foil opposite the direction in which the recess is formed. Thus, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. The preferred sheet strength is such that the tablet or capsule can be removed from the blister pack by manual pressure on the grooves to create an opening at the location of the groove in the material. The tablet or capsule can then be removed through the opening.

It may be desirable to provide a memory aid on the kit, for example in the form of a number next to the tablet or capsule corresponding to the date of the course of treatment that the specified tablet or capsule should be ingested. Another example of such a memory aid is a calendar printed on a card, for example, "first week, monday, tuesday,... et al. Other variations of the memory aid will be apparent. A "daily dose" may be a single tablet or capsule, or several pills or capsules, to be taken on a given day. Likewise, the daily dose of the compound of the invention may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, or vice versa. The memory aid should reflect this daily dosage and aid in the correct administration of the active agent.

In another particular embodiment of the invention, a dispenser is provided which is designed to dispense one daily dose at a time in the order of intended use of the daily doses. The dispenser is preferably equipped with memory aids to further facilitate compliance with the procedure. One example of such a memory aid is a mechanical counter, which indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled with liquid crystal readings or audible cues (e.g., to read the date the last daily dose has been taken and/or to remind the user when to take the next dose).

If desired, the compounds of the present invention and other pharmaceutically active agents can be administered to a patient orally, rectally, parenterally (e.g., intravenous, intramuscular, or subcutaneous injection), intracisternally, intravaginally, intraperitoneally, intravesically, topically (e.g., powders, ointments, or drops), or by oral or nasal spray. The present invention encompasses all methods used by those skilled in the art to administer pharmaceutically active agents.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and similar alcohols), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microbial contamination can be prevented by the addition of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical composition can be brought about by the use of agents which delay absorption such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders and granules. In these solid dosage forms, the active compound is mixed with at least one of the following inert conventional excipients (or carriers): such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, such as starches, lactose, sucrose, mannitol, and silicic acid; (b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicate complexes and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also contain buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. They may also contain opacifying agents and may also be of such a type that they release the active compound in a delayed manner in a particular part of the intestinal tract. Examples of embedding compositions which can be used are polymers and paraffin waxes. The active compound may also be in microencapsulated form, where appropriate with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and black sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and similar diluents.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum perhydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active compound or suitable compound is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required. Ophthalmic dosage forms, eye ointments, powders, and solutions are also contemplated as being within the scope of the present invention.

The compounds of the present invention may be administered to a patient at dosage levels ranging from about 0.1 to about 3,000mg per day. For a normal adult human weighing about 70kg, a dosage in the range of about 0.01 to about 100mg per kg body weight is generally sufficient. The particular dose and dose range that can be used depends on several factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the administered compound. Determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.

The compounds of the present invention may be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salt" refers to both inorganic and organic salts of the compounds of the present invention. The salts may be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compounds in free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, gluconate, lactobionate and dodecylsulfonate, and the like. The salts may include cations of alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., s.m. berge et al, "Pharmaceutical Salts," J Pharm Sci, 66: 1-19(1977).

Examples of pharmaceutically acceptable esters of the compounds of the present invention include C₁-C₈An alkyl ester. Useful esters also include C₅-C₇Cycloalkyl esters, and aralkyl esters such as phenyl. C₁-C₄Alkyl esters are commonly used. Esters of the compounds of the invention may be prepared according to methods well known in the art.

Examples of pharmaceutically acceptable amides of the compounds of the invention include those derived from ammonia, C₁-C₈Alkyl primary amines and C₁-C₈Amides derived from secondary dialkylamines. In the case of secondary amines, the amines may also be in the form of 5-or 6-membered heterocycloalkyl groups containing at least one nitrogen atom.Commonly used ammonia and C₁-C₃Alkyl primary amines and C₁-C₂Amides derived from secondary dialkylamines. Amides of the compounds of the invention may be prepared according to methods well known to those skilled in the art.

The term "prodrug" means a compound that is converted in vivo to yield a compound of the invention. The conversion may occur by various mechanisms, such as by hydrolysis in blood. A discussion of the use of prodrugs is provided by t.higuchi and w.stella, "Pro-drugs as Novel Delivery Systems," a.c.s.symposium Series, volume 14, and Bioreversible Carriers in Drug Design, authored by Edward b.roche, American Pharmaceutical Association and Pergamon Press, 1987.

To illustrate, if a compound of the invention contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as: (C)₁-C₈Alkyl radical (C)₂-C₁₂) Alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) aminomethyl having 4 to 10 carbon atoms, 3-phthalyl, 4-crotonolacton, γ -butyrolactone-4-yl, di-N, N- (C)₁-C₂) Alkylamino radical (C)₂-C₃) Alkyl (such as beta-dimethylaminoethyl), carbamoyl- (C)₁-C₂) Alkyl, N-di (C)₁-C₂) Alkylcarbamoyl- (C)₁-C₂) Alkyl and piperidinyl-, pyrrolidinyl-or morpholinyl (C)_2-3) An alkyl group.

Similarly, if a compound of the invention contains an alcohol functional group, a prodrug may be formed by substituting the hydrogen atom of the alcohol group with a group such as: (C)₁-C₆) Alkanoyloxymethyl, 1- ((C)₁-C₆) Alkanoyloxy) ethyl, 1-methyl-1- ((C) ₁-C₆) Alkanoyloxy) ethyl group, (C)₁-C₆) Alkoxycarbonyloxymethyl, N- (C)₁-C₆) Alkoxycarbonylaminomethyl, succinyl, (C)₁-C₆) Alkanoyl, alpha-amino (C)₁-C₄) Alkanoyl, aroyl and α -aminoacyl or α -aminoacyl- α -aminoacyl, wherein each α -aminoacyl is independently selected from: naturally occurring L-amino acids, -P (O) (OH)₂、-P(O)(O(C₁-C₆) Alkyl radical)₂Or a glycosyl (a group obtained by removing one hydroxyl group from a hemiacetal form of a carbohydrate).

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of said compounds as well as mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if the compound contains a double bond, then cis and trans forms (denoted as S and E, respectively) and mixtures are contemplated.

Mixtures of stereoisomers (such as mixtures of diastereomers) can be separated into their individual stereochemical components by known methods such as chromatography and/or fractional crystallization, depending on their physicochemical differences. Enantiomers can also be isolated as follows: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., an alcohol), the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Some compounds may also be atropisomers (e.g., substituted biaryls).

The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrates), ethanol, and the like. The present invention encompasses and encompasses both solvated and unsolvated forms.

The compounds of the invention may also exist in different tautomeric forms. The present invention encompasses all tautomers of the compounds of the invention. For example, the present invention includes all tautomers of the imidazole moiety. For example, the invention also includes all keto-enol or imine-enamine forms of the compounds.

One skilled in the art will recognize that the compound names and structures contained herein may be based on specific tautomers of the compounds. Although only the name or structure of a particular tautomer may be used, unless otherwise indicated, the present invention is intended to encompass all tautomers.

The invention is also intended to encompass compounds synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists, or synthesized using in vivo techniques, such as by metabolism, fermentation, digestion, and the like. It is also desirable that the compounds of the invention can be synthesized using a combination of in vitro and in vivo techniques.

The invention also includes isotopically-labeled compounds identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually known per se. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、 ¹⁵N、¹⁶O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶Cl。

compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. incorporating moieties such as³H and¹⁴those compounds of the radioisotope of C are suitable for use in drug and/or substrate tissue distribution assays. For ease of preparation and detection, tritium (i.e., tritium)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred. In addition, with heavier isotopes such as deuterium (i.e., deuterium)²H) Substitution of (a) may provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances. Isotopically-labelled compounds of the present invention can generally be prepared by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent.

The compounds of the present invention may exist in a variety of solid states, including crystalline and amorphous states. Different crystalline (also referred to as polymorphic) and amorphous states of the compounds of the invention are encompassed as part of the invention.

In synthesizing the compounds of the present invention, it may be desirable to use certain leaving groups. The term "leaving group" ("LG") generally refers to a group that can be displaced by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halogen (i.e., I, Br, F, Cl), sulfonates (e.g., mesylate, p-toluenesulfonate), thioethers (e.g., SCH)₃) N-hydroxysuccinimide, N-hydroxybenzotriazole and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxy, amine groups, carbanions), and the like.

The compounds of the invention are useful in the treatment of PI3K and/or mTOR mediated diseases and disorders, including melanoma, malignant epithelial tumors, and other cancers. In one embodiment of the invention there is provided a method of modulating the PI3K and/or mTOR enzyme in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a PI3K and/or mTOR mediated disease, such as cancer. In another embodiment, more than one compound of the invention may be administered to a patient. For example, a PI3K inhibitor and an mTOR inhibitor, or any combination thereof, may be administered, including compounds that inhibit PI3K and mTOR.

The term "patient in need thereof" means a patient having or at risk of having a PI3K and/or mTOR mediated disease or condition.

The term "cancer" means a physiological condition characterized by dysregulation of cell growth in mammals. Typical cancer types include malignant epithelial tumors, lymphomas, sarcomas, and cytomas.

The compounds of the invention may be used to treat cancer. A method of treating cancer comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Cancers that may be treated with the compounds of the present invention include, without limitation, malignant epithelial tumors such as bladder, breast, colon, rectal, kidney, liver, lung (small cell lung and non-small cell lung), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocytic leukemia, chronic non-lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, villous cell lymphoma, and Burkett's lymphoma); hematopoietic tumors of the myeloid system (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcomas and rhabdomyosarcomas, as well as other sarcomas such as soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytomas, neuroblastomas, gliomas, and schwannomas); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, pigmented xeroderma, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma). Other cancers that may be treated with the compounds of the present invention include endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and hematopoietic tumors.

The compounds of the invention may also be used to treat hyperproliferative disorders such as thyroid hyperplasia, particularly Grave's disease, and cysts such as ovarian interstitial vascular hyperplasia, classic polycystic ovarian syndrome (Stein-Leventhal syndrome).

The compounds of the present invention may also be used to treat the following diseases or conditions: asthma, Chronic Obstructive Pulmonary Disease (COPD), emphysema, psoriasis, contact dermatitis, conjunctivitis, allergic rhinitis, Systemic Lupus Erythematosus (SLE), ulcerative colitis, Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, atherosclerosis and Huntington's disease.

The compound of formula I or a pharmaceutically acceptable salt thereof may also be administered in combination with one or more other pharmaceutically active compounds/agents. In a particular embodiment, the additional pharmaceutically active agent is an agent used to treat cancer. For example, the additional pharmaceutically active agent may be selected from anticancer agents, anti-angiogenic drugs, chemotherapeutic agents and peptide cancer therapeutics. In another embodiment, the anti-cancer agent is selected from the group consisting of antibiotic-type drugs, alkylating agents, anti-metabolite-type drugs, hormonal drugs, immunological-type drugs, interferon-type drugs, kinase inhibitors, miscellaneous agents, and combinations thereof. It should be noted that the other pharmaceutically active compounds/agents may be conventional small organic chemical molecules or may be macromolecules such as proteins, antibodies, peptide antibodies, DNA, RNA or fragments of these macromolecules.

Examples of specific pharmaceutically active agents that may be used to treat cancer and which may be used in combination with one or more compounds of the present invention include methotrexate, tamoxifen (tamoxifen), fluorouracil, 5-fluorouracil, hydroxyurea, mercaptopurine, cisplatin, carboplatin, daunorubicin (daunorubicin), doxorubicin (doxorubicin), etoposide, vinblastine (vinblastine), vincristine, paclitaxel, thioguanine, noroxydomycin, dactinomycin (dactinomycin), imatinib (imatinib), gemcitabine (gemcitabine), altretamine, asparaginase, bleomycin (bleomycin), capecitabine (capecitabine), carmustine (carmustine), cladribine (claribine), cyclazacitidine, dacarbazine (dacarbazine), docetaxel (docetaxel), idarubicin (idarubicin), norflurazole (irinotecan), and norflurazone (irinotecan), and the like, Mitomycin (mitomycin), mitotane (mitoxanne), mitoxantrone (mitoxantrone), topotecan (topotecan), vinorelbine (vinorelbine), doxorubicin, mithram (mithram), imiquimod (imiquimod), alemtuzmab (alemtuzmab), exemestane (exemestane), bevacizumab (bevacizumab), cetuximab (cetuximab), azacitidine (azacitidine), clofarabine (clofarabine), decitabine (decitabine), dasatinib (desatinib), dexrazoxane (dexrazoxane), docetaxel (docetaxel), epirubicin (epirubicin), oxaliplatin (oxepirubicin), erlotinib (erlotinib), raloxifenesin (raloxifene), valsartan (troglitinib), flutolazanib (trovatamine (fluazululazululazole), felbinamide (felbinab), fluazululabine (felbinab), felbinazine (felbinab), fluazulmidine (letinib (letrozole), fluazululabine (felbinab), fluazulmidine (felbinab), fluazulmib (felbinab), fluazulmidine), fluazulmib (felone (felbinab), fluazulmib), fluazulmintic (e (felbinab), fluazulmide (fluazulmib), fluazulmintic (e (fluazulmib), fluazulmide), fluazulmintic, Nelarabine (nelarabine), sorafenib (sorafenib), nilotinib (nilotinib), pemetrexed (pemetrexed), rituximab (rituximab), dasatinib (dasatinib), thalidomide (thalidomide), pellucine (bexarotene), sirolimus (temsirolimus), bortezomib (bortezomib), vorinostat (vorinostat), capecitabine (capecitabine), zoledronic acid, anastrozole (anastrozole), sunitinib (sunitinib), aprepitant (aprepitant), and nelarabine (nelarabine), or a pharmaceutically acceptable salt thereof.

Other pharmaceutically active agents that may be used to treat cancer and that may be used in combination with one or more compounds of the present invention include: afoetin (epoetin alfa), afoetin (darbeptin alfa), panitumumab (panitumumab), pegylated filgrastim (pegfilgrastim), recombinant keratinocyte growth factor, filgrastim (filgrastim), denosumab (denosumab), ansamifost (ancetim), AMG 102, AMG 386, AMG 479, AMG 655, AMG 745, AMG 951, and AMG 706, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may also be used in combination with pharmaceutically active agents for the treatment of nausea. Examples of agents that may be used to treat nausea include: dronabinol (dronabinol), granisetron (granisetron), metoclopramide, ondansetron (ondansetron) and prochlorperazine (prochlorperazine), or a pharmaceutically acceptable salt thereof.

Furthermore, the compounds of the present invention may be used in combination with other agents that may be used to treat cancer, such as acemannan (acemannan), aclarubicin (aclarubicin), aldesleukin (aldesleukin), alitretinoin (aldiretinoin), amifostine (amifostine), amrubicin (amrubicin), amfenadine (amsacrine), anagrelide (anagrelide), argalaban (arglabin), arsenic trioxide, BAM 002(Novelos), bicalutamide (bicalutamide), bromouridine, simoleukin (morleukin), cetrorelix (cetrorelix), cladribine (cladribine), clotrimazole (clotrimazole), DA 3030(Dong-a), dallizumab (daclizumab), decitabine (zelizine), cladribine (diclavine), cladribine (cladribine), clinocrelix (clavine), diclofenac (crocetin), crocetin (diclofenac, doxorubine (diclofenac), diclofenac (brevicepirubicin), diclofenac (diclofenac), doxine (diclofenac), doxine (diclofenac), doxine (e), doxine (c) and (e, Edelfosine (edelfosine), edrecolomab (edrecolomab), eflornithine (eflornithine), ethirimofluor (emiteflur), epirubicin (epirubicin), betaepoetin (epoetin beta), etoposide phosphate, isosulline (exisulind), fadrozole (fadrozole), finasteride (finasteride), fludarabine phosphate (fludarabine phosphate), formestane (formestane), fotemustine (fotemustine), gallium nitrate, gemtuzumab ozolomicin (gemtuzumab zomicin), gimeracil (gimeracil)/oteracil (oteracil)/tegafur (tegafur), glycuropine, sertraline (goserelin), platinum, human fetal membrane hormone, epitomedin, fetoprotein, interferon alpha-2, interferon alpha- α -2, interferon alpha-2, alpha-interferon, alpha-2, alpha-4, alpha-interferon, alpha-2, alpha-4, alpha-interferon, alpha-, Interferon-1 complex, interferon alpha, interferon beta-1 a, interferon beta-1 b, natural interferon gamma, interferon gamma-1 a, interferon gamma-1 b, interleukin-1 beta, iobenguanide, isosorafedine (irsogladine), lanreotide (lanreotide), LC 9018(Yakult), leflunomide (leflunomide), legrastim (lentiogltim), lentinan sulfate, letrozole (letrozole), leukocyte alpha interferon, leuprolide (leuprorelin), levamisole + fluorouracil, liazole (liarozole), lobaplatin, lonidamine (lonamide), lovastatin (lostavatin), masoprocol (mamoprocol), melarsol (laresol), metoclopramide (metoprolone), temmifeprinomide (temipramine), timipramine (timidol), neotamipramine (mitomycin), diguanil (mismatching RNA, guargoline (mitomycin), diguanil (mitomycin), furametprogenin (mitomycin), and so-1, Mitoxantrone, moraxelin (molgramostim), nafarelin (nafarelin), naloxone (naloxone) + pentazocine (pentazocine), nartostim (nartographtim), nedaplatin, nilutamide (nilutamide), noscapine (noscapine), novel erythropoiesis stimulating protein, NSC 631570 octreotide (octreotide), olprin interleukin, oxaterone (osaterone), paclitaxel, pamidronic acid (pamidronic acid), peginterferon alpha-2 b, xylopolythiol, pentostatin (pentastatin), streptolysin, pirarubicin (pirarubicin), rabbit anti-thymocyte polyclonal antibody, peginterferon alpha-2 a, porphine sodium (porficosidium), raltitrexed (brazzein), raltitrirase (rhenium), texaphydroxide (Sm), sartansinoid (153), sambuconazole (sambuconazole), sargramoxone (saratin), sartorine (sartori (186), sartorine (sartorine), sartorine (sargrastim), sarcin (r), sartorine (sarcin), sartorine (sartorine), sartori), sartorine (sarcin), sartori (e), soranamine (sonermemin), strontium chloride-89, suramin (suramin), tasonemin (tasonemin), tazarotene (tazarotene), tegafur, temoporfin (temoporfin), teniposide, tetrachlorodecaoxide, thymalfasin, thyrotropin alpha, toremifene (toremifene), tositumomab-iodine 131, troosulfan (treosulfan), tretinoin, trolsartan (trilostane), trimetrexate (trimetrexate), triptorelin, natural tumor necrosis factor alpha, ubenimex (ubenimex), bladder cancer vaccine, Eluyamama vaccine (Marumavaccine), melanoma lysis vaccine, valrubicin, verteporfin (verterfin), vitamin E such as lixin, stastine, abarelix (antisense), aspartix (azlactone), gentamitriptan (941), genistein-2, arginine (arginine), arginine acetate), arginine (antisense 8015), arginine (arginine), arginine (antisense), arginine (arginine), arginine (arginine), arginine, EM 800(Endorecherche), eniluracil, etanidazole (etanidazole), tretinoamide, filgrastim SD01(Amgen), galocitabine (galocitabine), gastrin 17 vaccinogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony stimulating factor, histamine dihydrochloride, temozolomab, ilomastat (ilomastat), IM 862(Cytran), interleukin-2, iproxifene (iproxifene), LDI 200(Milkhaus), lerisitine (leriditim), lintuzumab (lintuzumab), CA 125 monoclonal antibody (MAb) (Biomira), cancer MAb (Japan Pharmaceutical medetop), HER-2 and Fc MAb (arex), idiotypic 105AD7MAb (idiotypic), CEA (LYM-1-mer), Myostatin (LYM-1-iodine polymorphism (yttrium-5), and arginine polymorphism (Technical) Mitumomab (mitumomab), motaxane gadolinium (motexafin), MX 6(Galderma), nolatrexed (nolatrexed), P30 protein, pegvisomant (pegvisomant), podofycin, prinostat (prinomastat), RL 0903(Shire), rubitecan (rubitecan), satraplatin, sodium phenylacetate, fosmenadioc acid, SRL 172(SR Pharma), SU 5416(Pfizer), TA 077(Tanabe), ammonium tetrathiomolybdate, thalidomide, thrombopoietin, stannyl-primeverin, tirapazamine (tirapazamine), cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (slow lung cancer Institute), melanoma lytic agent (New York virus), melanoma cell lysate (hovale virus), or rotavapreovirus (rocast). It should be noted that the agents cited above may also be administered as pharmaceutically acceptable salts where appropriate.

The compounds of the present invention may also be used in combination with radiation therapy, hormonal therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.

All patents and other publications cited herein are incorporated by reference.

Examples

The examples presented below illustrate specific embodiments of the invention. These examples are intended to be representative and are not intended to limit the scope of the claims in any way. Unless otherwise specified, the starting materials for the specific examples below are generally commercially available. Where assistance is needed, commercial sources may be specified explicitly.

The analysis method comprises the following steps:

unless otherwise specified, the HPLC analysis and liquid chromatography-mass spectrometry (LC-MS) procedures were performed on an Agilent model 1100 system using one of two columns and methods:

(A) an Agilent Technologies Zorbax SB-C8(5 μ) reverse phase column (4.6X 150mm) was used at 30 ℃ with a flow rate of about 1.50 mL/min. The mobile phase uses solvent A (H)₂O/0.1% TFA) and solvent B (ACN/0.1% TFA), and a gradient from 5% to 100% ACN over 11 min. The gradient was followed by a 2min return to 5% ACN and a rebalancing (flushing) of about 2.5 min.

(B) A Synergy MAX-RP, 5 μ, 50X 2.0mm column with the same solvent system was used, with a flow rate of 0.8ml/min and a gradient of 10% to 100% B for the first two minutes, then 100% B for 1.8 minutes, and then a return of 10% B over 0.2 minutes.

LC-MS method:

at 30 ℃ in the presence of Agilent Technologies XDB-C₈Samples (3.5 μ) were run on an Agilent model-1100 LC-MSD system on an inverse column (4.6X 75 mm). Flow rateConstant and in the range of about 0.75mL/min to about 1.0 mL/min.

Solvent A (H) for mobile phase₂O/0.1% HOAc) and solvent B (ACN/0.1% HOAc), gradient 10% to 90% solvent B over a 9min period. The gradient was followed by a 0.5min period back to 10% solvent B and 2.5min 10% solvent B re-equilibration (wash) of the column.

Preparative HPLC method:

in the indicated cases, the compounds of interest were purified via reverse phase HPLC using a Gilson (Gilson, Middleton, WI) workstation using one of the following three columns and methods:

(A) A50X 100mm column (Waters, Exterra, C18, 5. mu.s, Waters, Milford, MA) was used, 50 mL/min. The mobile phase uses solvent A (H at pH about 10)₂O/10mM ammonium carbonate from concentrated NH₄OH) and solvent B (85: 15 ACN/water, 10mM ammonium carbonate pH about 10, from concentrated NH ₄OH) to adjust). Each purification run utilized a 10min gradient of 40% to 100% solvent B followed by a 5min flow of 100% solvent B. The gradient was followed by 2min back to 40% solvent B.

(B) 20mL/min 20X 50mm column was used. Solvent A (H) for mobile phase₂O/0.1% TFA) and solvent B (ACN/0.1% TFA), and a gradient of 5% to 100% solvent B over 10 min. The gradient was followed 2min back to 5% ACN.

(C) A100X 50mm column (Gemini, 10. mu.l, C18, Phenomenex, Torrance, CA) was used, 100 ml/min. The same mobile phase and solvent system as in method B was used. The time gradient was 10% to 100% solvent B for 28 minutes followed by 2min back to 10% solvent B.

Proton NMR spectrum:

unless otherwise specified, all¹The H NMR spectra were both run on a Varian series Mercury 300MHz instrument (Varian, Palo Alto, Calif.) or a Bruker series 400MHz instrument (Bruker, Bilerica, Mass.). In turn, proceed the tableAt characterization, all observed protons are described as: parts per million (ppm) shift from Tetramethylsilane (TMS) or other internal standard in the indicated appropriate solvent.

Mass Spectrum (MS):

unless otherwise specified, all mass spectral data for the starting materials, intermediates, and/or exemplary compounds are described as: belt (M + H) ⁺) Or (M-H)^-) Mass/charge (m/z) of molecular ions. The recorded molecular ions were obtained by electrospray detection method. As will be appreciated by those skilled in the art, compounds having isotopic atoms (e.g., bromine and the like) are described in terms of the type of isotope being detected.

The following abbreviations may be used herein:

unless otherwise specified, percentages specified for solid agents are weight percentages with respect to total weight, and solvent percentages are stated as volume percentages with respect to total volume.

Synthetic schemes

Example 1: 6-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

A suspension of 6-chloro-9H-purine (25.36g, 164mmol) (Alfa Aesar, Ward Hill, MA) and 4-methylbenzenesulfonic acid (0.565g, 3.28mmol) in EtOAc (250mL) was treated with 3, 4-dihydro-2H-pyran (44.9mL, 492 mmol). At 90 ℃, the mixture was heated and the solid was slowly dissolved for 1 h. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated in vacuo.

The light yellow residue was dissolved in DCM and purified by flash chromatography (50% EtOAc/hexanes) (1L silica/4L solvent) to give 6-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (38.90g, 99% yield) as a colorless oil which slowly crystallized. ¹H NMR(400MHz，d6-DMSO)δ8.91(s，1H)，8.82(s，1H)，5.80(d，1H)，4.04(m，1H)，3.75(m，1H)，2.35(m，1H)，2.01(m，2H)，1.76(m，1H)，1.62(m，2H)。

Example 2: 6- (2-Fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine

Water (7.2mL), 2-fluoropyridin-3-yl boronic acid (Asymchem Laboratories, inc., Morrisville, NC.) (5.31g, 37.7mmol), sodium carbonate monohydrate were used in that order(9.35g, 75.4mmol) and PdCl₂(dppf) (Strem Chemicals, Inc., Newburyport, MA) (0.616g, 0.754mmol) to treat 6-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (1) (6.00g, 25.1mmol) of bisAlkane (54mL) solution. The stirred mixture was degassed (alternating vacuum/nitrogen) and heated at 100 ℃ under nitrogen for 10 h. The mixture was cooled and extracted from water (400mL) into EtOAc (500 mL). The aqueous layer was extracted with EtOAc (200mL) and the combined organic extracts were dried (MgSO)₄) Through Celite(celite) filtration and concentration. The crude product was dissolved in a small volume of DCM and purified by flash chromatography (50% to 75% to 100% EtOAc/hexanes) to give 6- (2-fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine as an off-white solid (3.96g, 53% yield).¹H NMR(400MHz，d6-DMSO)δ9.11(s，1H)，8.91(s，1H)，8.58(m，1H)，8.49(s，1H)，7.62(m，1H)，5.85(d，1H)，4.05(m，1H)，3.75(m，1H)，2.38(m，1H)，2.05(m，2H)，1.79(m，1H)，1.61(m，2H)。

Example 3: 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

Step 1: 6-chloro-2-methylpyrimidine-4, 5-diamine

2-methyl-4, 6-dichloro-5-aminopyrimidine (Aldrich, 1.05g) and ammonium hydroxide (3.0mL, J.T.Baker, Phillipsburg, NJ, 28.0% -30.0%) were placed in a microwave vial. The vial was sealed and heated at 120 ℃ and 40 watts for 25 minutes in a CEM microwave reactor (CEM Corporation, Matthews, NC). The reaction was cooled to room temperature. This procedure was repeated a total of 9 times under the same reaction conditions using the following amounts of 2-methyl-4, 6-dichloro-5-aminopyrimidine:

Operation 2: 1.027g, 2.5mL ammonium hydroxide.

Operation 3: 1.034g, 2.5mL ammonium hydroxide.

And operation 4: 1.118g, 2.6mL ammonium hydroxide.

Operation 5: 1.117g, 2.5mL ammonium hydroxide.

Operation 6: 1.149g, 2.7mL of ammonium hydroxide.

Operation 7: 1.264g, 2.6mL ammonium hydroxide.

Operation 8: 1.106g, 2.6mL ammonium hydroxide.

Operation 9: 1.075g, 2.7mL ammonium hydroxide.

All the manipulations were combined, concentrated and used in step 2. MS (ESI cation) m/z: 159. c₅H₇ClN₄The accurate mass calculation value of (2): 158.

step 2: 6-chloro-2-methyl-9H-purine

In a flask equipped with a reflux condenser, 6-chloro-2-methylpyrimidine-4, 5-diamine (8.89g, 56.1mmol, material from step 1) was suspended in ethyl orthoformate (100mL, 601mmol) and the flask was placed in a preheated oil bath (100 ℃ C.) and stirred for 75 minutes. Subsequently, the reaction was cooled to room temperature, concentrated, treated with hexane and filtered. The solid was washed with hexane, collected and used in step 3. MS (ESI cation) m/z: 169. c₆H₅ClN₄The accurate mass calculation value of (2): 168.

and step 3: 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9H-purine (9.45g, 56mmol, material from step 2) was suspended in DCM (100mL) and p-toluenesulfonic acid (Acros Organics, Geel, Belgium, 12% in acetic acid, 0.90mL, 5.6mmol) and 2, 3-dihydropyran was added (6.6mL, 73 mmol). The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (50 ℃) and stirred under nitrogen for 30 minutes. Subsequently, the reaction was cooled to room temperature and stirred overnight. After stirring overnight, the reaction was diluted with DCM and treated with saturated sodium bicarbonate (75 mL). The layers were separated and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried at 45 ℃ (in a water bath) and then at room temperature, then at 60 ℃, and finally again at room temperature under high vacuum to give 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (13.73g, 97% over 3 steps). MS (ESI cation) m/z: 253. c₁₁H₁₃ClN₄Accurate mass calculation of O: 252.¹H NMR(CDCl₃，400MHz)δ8.26(s，1H)，5.78(d，J＝10.56Hz，1H)，4.19(d，J＝11.93Hz，1H)，3.84-3.76(m，1H)，2.80(s，3H)，2.20-1.96(m，3H)，1.89-1.64(m，3H)。

example 4: 6- (2-Fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

In N₂A mixture of 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (3) (531.6mg, 2104. mu. mol), 2-fluoropyridin-3-yl boronic acid (Asymchem Laboratories, Inc., Morrisville, NC) (596mg, 4230. mu. mol), potassium acetate (629mg, 6409. mu. mol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO) (37.2mg, 52.6. mu. mol) was suspended in EtOH (5.0mL) and H under an atmosphere ₂O (1.0mL) and degassed, and heated at gentle reflux for 2 h. LCMS indicated reaction completion. The mixture was poured into NaHCO₃Saturated aqueous solution and extracted into EtOAc. The EtOAc extract was dried (MgSO)₄) Concentrated and purified by flash chromatography (EtOAc) to give 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine as a pale yellow oil (519mg, 78.7% yield), which was purified with Et₂Crystallization after O trituration gave a white solid.¹H NMR (400MHz, d 6-DMSO). delta.8.79 (s, 1H); 8.46-8.53(m, 1H); 8.43-8.46(m, 1H); 7.55-7.62(m, 1H); 5.78-5.85(m, 1H); 4.00-4.08(m, 1H); 3.70-3.80(m, 1H); 2.78(s, 3H); 2.26-2.40(m, 1H); 1.95-2.06(m, 2H); 1.72-1.87(m, 1H); 1.56-1.67(m, 2H). M/z (ESI, cation) 314.0(M + H)⁺。

Example 5: 4-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d ] pyrimidine

LDA was prepared by dropwise addition of a 2.5M solution of N-butyllithium in hexane (Aldrich, St. Louis, MO) (14.7mL, 36.8mmol) to N, N-diisopropylamine (5.42mL, 38.4mmol) in THF (40mL) cooled in an ice bath. The LDA solution was cooled to-78 deg.C and a solution of 4, 6-dichloro-2-methylpyrimidine (Aldrich, St. Louis, Mo) (5.448g, 33.4mmol) in THF (50mL) was added dropwise over 1 h. A dark solution is obtained. To the solution was added dropwise a solution of N-methyl-N- (2-pyridyl) formamide (TCI Tokyo Kasei Kogyo co., Ltd.) (4.80mL, 40.1mmol) in THF (20mL) at-78 ℃ over 20 min. The resulting solution was stirred for 30min and then quenched by the dropwise addition of a solution of acetic acid (2.10mL, 36.8mmol) in THF (20mL) at-78 deg.C over 10 min. The solution was stirred for 30min at-78 ℃.

The resulting solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde was treated dropwise with a solution of anhydrous hydrazine (1101. mu.L, 35071. mu. mol) at-78 ℃. The mixture was stirred for 15min and then the cooling bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between water (110mL) and EtOAc (110 mL). The organic layer was washed with NaHCO₃Washed with saturated aqueous solution (100mL), separated and dried (MgSO)₄) Treated with charcoal and filtered through a silica gel packed column, washed with EtOAc. The filtrate was concentrated and purified by flash chromatography on silica, eluting with 5% acetone/DCM to 25% EtOAc/hexaneTo purify it. The residue was suspended in DCM (3mL), cooled in a refrigerator and filtered to give 4-chloro-6-methyl-1H-pyrazolo [3, 4-d as a tan solid]Pyrimidine (330mg, 5.86% yield).¹H NMR(400MHz，d6-DMSO)δ14.25(bs，1H)；8.35(s，1H)；2.68(s，3H)。

4-chloro-6-methyl-1H-pyrazolo [3, 4-d ] was treated with 3, 4-dihydro-2H-pyran (528. mu.L, 5783. mu. mol) and MP-TsOH resin (Biotage) (72mg, 4.3mmol/g, 0.15 equiv.)]A suspension of pyrimidine (325mg, 1928 μmol) in EtOAc (3mL) and the resulting suspension was heated at 90 ℃ for 3h, after which LCMS indicated that the conversion was substantially complete. The solution was filtered, washed with EtOAc and concentrated to give a light yellow oil. Purification by flash chromatography (EtOAc/hexanes; 5% to 20%) afforded 4-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d as a colorless oil ]Pyrimidine (482mg, 98.9% yield).¹H NMR(400MHz，d6-DMSO)δ8.44(s，1H)；5.91-6.02(m，1H)；3.91-3.99(m，1H)；3.67-3.77(m，1H)；2.72(s，3H)；2.36-2.48(m，1H)；1.96-2.08(m，1H)；1.87-1.95(m，1H)；1.32-1.84(m，3H)。

Example 6: 4- (2-fluoropyridin-3-yl) -6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d ] pyrimidine

A mixture of 4-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d ] pyrimidine (5) (107.8mg, 427. mu. mol), 2-fluoropyridin-3-ylboronic acid (120mg, 853. mu. mol) (Asymchem Laboratories, Inc., Morrisville, NC) and potassium acetate (105mg, 1066. mu. mol) dissolved in EtOH (1.25mL) and water (0.25mL) was placed under vacuum for 5min, followed by flushing with nitrogen for 5min, and treatment with bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (8.0mg, 11. mu. mol) (Aldrich, St.Louis, Mo.). The solution was then heated to 80 ℃. After 60min, reaction completion was indicated by LCMS analysis.

The reaction mixture was poured into EtOAc/NaHCO₃Saturated aqueous solution and extracted. The organic extract was dried (MgSO)₄) Filtered and concentrated. The residue was purified by flash chromatography (25% to 50% EtOAc/hexanes) to give 4- (2-fluoropyridin-3-yl) -6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d as a pale yellow oil]Pyrimidine (105mg, yield 79%), which slowly crystallizes upon standing.¹H NMR(400MHz，d6-DMSO)δ8.46-8.57(m，2H)；8.41(d，J＝3.51Hz，1H)；7.64(s，1H)；6.04(d，J＝8.03Hz，1H)；3.92-4.02(m，1H)；3.68-3.79(m，1H)；2.82(s，3H)；2.41-2.48(m，1H)；2.00-2.10(m，1H)；1.88-1.99(m，1H)；1.72-1.87(m，1H)；1.59(d，J＝3.51Hz，2H)。

Example 7: 2, 4-dichloro-6-methyl-1, 3, 5-triazine

3M Methylmagnesium bromide in diethyl ether (Aldrich, St. Louis, MO) (10.0mL, 30mmol) was slowly added to a white suspension of 2, 4, 6-trichloro-1, 3, 5-triazine (Aldrich, St. Louis, MO) (3.68g, 20mmol) in DCM (25.0mL, 389mmol) at 0 deg.C, and the resulting yellow suspension was warmed to room temperature and stirring continued until the starting material disappeared (TLC, KMnO)₄Staining, 3 h). At 0 ℃ with NH₄The reaction was carefully quenched with Cl (aq) and then diluted with water and DCM (25.0 mL). The separated organic layer was dried, filtered and concentrated to give 2, 4-dichloro-6-methyl-1, 3, 5-triazine (2.94g, 90%) as a yellow solid, which was used for further reaction without purification.¹H-NMR(CDCl₃，400MHz)δ2.74(s，3H)。

Example 8: 2-chloro-4-methyl-6- (methylthio) -1, 3, 5-triazine

Sodium methyl mercaptide (0.49g, 7.0mmol) was added portionwise to a stirred turbid solution of 2, 4-dichloro-6-methyl-1, 3, 5-triazine (7) (1.04g, 6.3mmol) in toluene (10mL, 94mmol) at 0 ℃ over 15 min. After the addition, the pale yellow mixture was stirred at the same temperature for another 1h, and water (10mL) was added. The separated aqueous layer was extracted with EtOAc (2X 20mL) and the combined organic layers were washed with brine, Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (hexane to 70% DCM dissolved in hexane) to give 2-chloro-4-methyl-6- (methylthio) -1, 3, 5-triazine (0.87g, 78% yield) as a white solid. MS (API-ES) M/z 176(M + H) ⁺；¹H NMR(d6-DMSO，400MHz)δ2.55(s，3H)2.51(br.s.，3H)。

Example 9: 4-chloro-6-methyl-1, 3, 5-triazin-2-amine

At room temperature (slightly exothermic), a solution of ammonia in 2.0M methanol (Aldrich, St. Louis, MO)36.0mL, 72mmol) was added dropwise over 1.5h to a stirred yellow suspension of 2, 4-dichloro-6-methyl-1, 3, 5-triazine (from example 7) (2.94g, 18mmol) in toluene (20.0mL, 188 mmol). The resulting mixture was stirred for an additional 2.5h, concentrated and purified (ISCO, DCM to 10% MeOH in DCM) to give the desired product 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (1.88g, 73%) as a yellow solid. MS (API-ES) M/z145(M + H)⁺；¹H NMR(CD₃OD，300MHz)δ2.32(s，3H)。

Example 10: 6-chloro-2-methylpyrimidin-4-amine

2.0M aqueous ammonia in methanol (6.0mL, 12mmol) was added to 4, 6-dichloro-2-methylpyrimidine (Aldrich) (0.487g, 3mmol) of 1, 4-bis-pyridine at room temperatureThe yellow suspension was stirred with an alkane (10.0 mL). The resulting mixture was sealed and stirred at 70 ℃ overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and reacted with SiO₂And (4) mixing. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 10% MeOH in DCM) to give 6-chloro-2-methylpyrimidin-4-amine (0.25g, 58%) as a white solid. MS (API-ES) M/z 144(M + H) ⁺。

Example 11: 6-chloro-5-fluoro-2-methylpyrimidin-4-amine

A mixture of 4, 6-dichloro-5-fluoro-2-methylpyrimidine (1.55g, 8.6mmol) in aqueous ammonium hydroxide (10.00mL, 90mmol) and MeOH (1.00mL, 25mmol) was heated at 70 ℃ for 2h (sealed tube). After cooling, 10mL of water was added and stirred for 30 min. The solid was isolated, washed with water and dried to give the desired product 6-chloro-5-fluoro-2-methylpyrimidin-4-amine (0.9244g, 67%) as a white solid. MS (API-ES) M/z 163(M + H)⁺。

Example 12: 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine

Step 1: 4-chloro-2-methyl-6- (tributylstannyl) pyrimidine

Dissolving in hexane (0.18 deg.C)4mL, 2.200mmol, Aldrich, St.Louis, Mo.) of a 1.6M solution of n-butyllithium was added to a solution of diisopropylamine (0.314mL, 2.200mmol) in THF (5 mL). The reaction mixture was stirred at 0 ℃ for 15 min. Tributyltin hydride (0.527mL, 2.000mmol, Aldrich, St. Louis, Mo.) was added dropwise. The solution was stirred at 0 ℃ for 15 min. The mixture was cooled down to-78 ℃, followed by the addition of 4, 6-dichloro-2-methylpyrimidine (326mg, 2.000mmol, Aldrich, st. louis, MO) in THF (2mL) and the mixture was stirred at-78 ℃ for 8 h. The mixture was quenched with aqueous saturated KF (4mL) and extracted with EtOAc (30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give 4-chloro-2-methyl-6- (tributylstannyl) pyrimidine as a pale yellow oil. The crude material was used directly in the next step without purification.

Step 2: 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine

Sodium thiomethoxide (140mg, 2mmol) was added to 4-chloro-2-methyl-6- (tributylstannyl) pyrimidine (835mg, 2mmol) dissolved in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/hexanes to give 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine (256mg, 30% yield).¹H NMR(300MHz，CDCl₃)δ7.07(s，1H)；2.62(s，3H)；2.51(s，3H)；1.44-1.70(m，6H)；1.21-1.42(m，6H)；0.98-1.21(m，6H)；0.91(t，9H)。

Example 13: 4-Nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (13A) and 4-nitro-2- (tetrahydro-2H-pyran-2-yl) -2H-indazole (13b)

A suspension of 4-nitro-1H-indazole (Bionet Research, Cornwall, UK) (4.07g, 24.9mmol) in EtOAc (50mL) was treated with 3, 4-dihydro-2H-pyran (6.83mL, 74.8mmol) and MP-TsOH resin (Biotage, Uppsala, Sweden) (380mg, 4.3mmol/g, 0.06 equiv) and heated at mild reflux for 2H. The mixture was filtered, concentrated and purified by flash silica gel chromatography (5% EtOAc/hexanes to 10% EtOAc/10% DCM/hexanes) to give 4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3.040g, 49.3% yield) as a light yellow crystalline solid (recrystallized from EtOAc/hexanes) followed by 4-nitro-2- (tetrahydro-2H-pyran-2-yl) -2H-indazole (2.336g, 37.9% yield) as a light yellow oil. The structural arrangement was confirmed by NOESY (N-CH-O of aromatic protons).

4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (13 a):¹h NMR (400MHz, d 6-DMSO). delta.8.57 (s, 1H); 8.32(d, J ═ 8.53Hz, 1H); 8.21(d, J ═ 7.53Hz, 1H); 7.69(t, J ═ 8.03Hz, 1H); 6.04(dd, J ═ 9.54, 2.01Hz, 1H); 3.84-3.93(m, 1H); 3.74-3.83(m, 1H); 2.36-2.46(m, 1H); 1.98-2.12(m, 2H); 1.70-1.84(m, 1H); 1.56-1.67(m, 2H). Found M/z (ESI, cation) 270.0(M + Na)⁺。

4-nitro-2- (tetrahydro-2H-pyran-2-yl) -2H-indazole (13 b):¹h NMR (400MHz, d 6-DMSO). delta.8.92 (s, 1H); 8.22-8.26(m, 2H); 7.54(t, J ═ 8.03Hz, 1H); 5.93(dd, J ═ 9.54, 2.51Hz, 1H); 4.01(m., 1H); 3.71-3.83(m, 1H); 2.18-2.30(m, 1H); 2.15-1.34(m, 5H). Found M/z (ESI, cation) 270.0(M + Na)⁺。

Example 14: 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine

Treatment of 4-Nitro-1- (Tetrakis) with Pd/C (60mg)hydro-2H-pyran-2-yl) -1H-indazole (1.05g, 4247. mu. mol) in EtOAc (100mL) in H₂Stirring under an atmosphere. The reaction was monitored by LCMS and found to be complete after 22 h. The reaction was filtered and concentrated (note: tendency to foam/bumping). With Et₂The residue was triturated to give 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (892mg, 96.7% yield) as an off-white solid. ¹H NMR (400MHz, d 6-DMSO). delta.8.11 (s, 1H); 7.03(t, J ═ 7.82Hz, 1H); 6.74(d, J ═ 8.22Hz, 1H); 6.18(d, J ═ 7.43Hz, 1H); 5.78(s, 2H); 5.59-5.67(m, 1H); 3.82-3.92(m, 1H); 3.63-3.74(m, 1H); 2.30-2.45(m, 1H); 1.96-2.08(m, 1H); 1.84-1.94(m, 1H); 1.65-1.80(m, 1H); 1.55(br.s., 2H). M/z (ESI, cation) found 218(M + H)⁺。

Example 15: 2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine

A solution of 4-nitro-2- (tetrahydro-2H-pyran-2-yl) -2H-indazole (2.336g, 9448. mu. mol) was dissolved in EtOAc (100mL) and treated with 10% Pd/C (100 mg). The resulting suspension was stirred under an atmosphere of H2 for 16H, after which time the reduction was complete. The reaction mixture was filtered, concentrated and purified by flash silica gel chromatography (50% EtOAc/hexanes) to give 2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine (584mg, 28.5% yield) as a dry orange foam.¹H NMR (400MHz, d 6-DMSO). delta.8.47 (s, 1H); 6.92(t, J ═ 7.82Hz, 1H); 6.72(d, J ═ 8.61Hz, 1H); 5.99(d, J ═ 7.04Hz, 1H); 5.54-5.69(m, 3H); 3.98(d, J ═ 11.74Hz, 1H); 3.63-3.78(m, 1H); 2.02-2.13(m, 2H); 1.87-2.00(m, 1H); 1.65-1.80(m, 1H); 1.59(br.s., 2H). M/z (ESI, cation) found 218.1(M + H) ⁺。

Example 16: n- (5- (3- (9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide

Pyridin-2-yl) acetamides

A mixture of 6- (2-fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine (300mg, 1002. mu. mol) and 2-acetamido-5-aminopyridine (Aldrich, St. Louis, MO) (152mg, 1002. mu. mol) was suspended in THF (2mL) and treated with LiHMDS (1.0M in THF, Aldrich, St. Louis, MO) (4009. mu. l, 4009. mu. mol). The mixture was stirred for 16h and then poured into NaHCO₃Saturated aqueous solution, extracted with EtOAc. Some dark orange insoluble material was observed. The EtOAc extract was dried (MgSO)₄) Filtered and concentrated to give N- (5- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide as an orange solid (324mg, 75% yield).¹H NMR(CDCl₃，300MHz)δ12.35(s，1H)，9.73(dd，1H)，9.04(s，1H)，8.69(bs，1H)，8.37(s，1H)，8.35(dd，1H)，8.21(bs，2H)，8.00(bs，1H)，6.96(dd，1H)，5.89(dd，1H)，4.23(m，1H)，3.84(m，1H)，2.21(s，3H)，2.3-17(m，8H)；m/z(API-ES)431，(M+H)⁺。

Step 2: n- (5- (3- (9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide

A suspension of N- (5- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide (19.6mg, 46. mu. mol) in MeOH (about 0.2mL) was treated with 2M aqueous HCl (about 6 drops, excess) and heated gently. An almost clear solution was initially obtained and a red solid crystallized from the solution. The solution was allowed to stand overnight and the solid was collected by filtration and washed with a small amount of MeOH. N- (5- (3- (9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide hydrochloride (12mg, 69% yield) was obtained as a dark solid. ¹H NMR(d6-DMSO，400MHz)δ12.61(bs，1H)，10.81(bs，1H)，9.76(d，1H)，9.14(s，1H)，8.86(s，1H)，8.73(s，1H)，8.36(dd，1H)，8.31(dd，1H)，7.97(d，1H)，7.10(dd，1H)，5.76(s，1H) 4.3(bs, water + alternative); m/z (API-ES)347, (M + H)⁺。

Example 17: n3- (3- (9H-purin-6-yl) pyridin-2-yl) pyridine-3, 6-diamine

After heating N- (5- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) pyridin-2-yl) acetamide (18.8mg, 44. mu. mol) in 5N aqueous HCl (1mL) for 1H at 95 deg.C, LCMS indicated conversion to the desired product. The solution was made weakly basic with 5N aqueous NaOH (about pH 8) and the resulting precipitate was collected by filtration, washed with water and dried to give N3- (3- (9H-purin-6-yl) pyridin-2-yl) pyridine-3, 6-diamine as a dark solid (6.0mg, 45% yield).¹H NMR(d6-DMSO，400MHz)δ12.17(bs，1H)，9.74(d，1H)，8.98(s，1H)，8.55(s，1H)，8.21(m，2H)，7.77(dd，1H)，6.89(dd，1H)，6.49(d，1H)，5.65(bs，3H)；m/z(API-ES)305，(M+H)⁺。

Example 18: n- (3- (9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amin-2-yl) -N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purine

-6-yl) pyridin-2-yl) -2H-indazol-4-amine

A solution of 2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine (37.4mg, 172 μmol) and 6- (2-fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine (51.5mg, 172 μmol) in THF (1.0mL) was cooled in an ice bath and treated dropwise with LHMDS (0.55mL of a 1.0M solution in THF, 3 equivalents). A dark red solution was obtained. The mixture was stirred for 60min and then quenched with water (0.050 mL). From NaHCO with EtOAc ₃The mixture was extracted with saturated aqueous solution and dried (MgSO)₄) And is concentratedCondensed to give a dark residue. Flash silica gel chromatography (50% EtOAc/hexanes) (yellow band on column) afforded 2- (tetrahydro-2H-pyran-2-yl) -N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -2H-indazol-4-amine (36.6mg, 42.8% yield) as a yellow oil, which crystallized upon standing.¹H NMR(400MHz，CDCl₃)δ12.75(br.s.，1H)；9.77(d，J＝7.82Hz，1H)；9.12(s，1H)；8.44(d，J＝3.52Hz，1H)；8.38(s，2H)；8.06(d，J＝7.04Hz，1H)；7.41(d，1H)；7.35(d，J＝7.63Hz，1H)；6.92-7.03(m，1H)；5.88(d，1H)；5.73(d，1H)；4.13-4.30(m，2H)；3.84(br.s.，2H)；2.17-2.35(m，3H)；2.00-2.16(m，3H)；1.79(br.s.，6H)。m/z(API-ES)497.1(M+H)⁺。

Step 2: n- (3- (9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine

A solution of 2- (tetrahydro-2H-pyran-2-yl) -N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -2H-indazol-4-amine (34.8mg, 70. mu. mol) in DCM/MeOH (4 mL; 1: 1) was treated with (+/-) -10-camphorsulfonic acid (8mg, 0.5 eq.) and the mixture was stirred for 16H. About 50% of single deprotection was observed in a clean reaction. An additional 20mg CSA (1.7 equivalents total) was added. After 1h, almost complete single deprotection and about 10% double deprotection were observed. After 3h, about 27% conversion to the fully deprotected compound was observed in a complete reaction by LCMS. An additional 8mg of CSA (2.2 equivalents total) was added and the temperature of the reaction mixture was raised to 40 ℃. After an additional 3h, deprotection was indicated to be substantially complete by LCMS. In N ₂The volume of the reaction mixture was reduced to about 50% under a stream of air to remove DCM and Et₂O trituration of the solution, causing the formation of a precipitate, collecting said precipitate by filtration, Et₂O was washed and dried in vacuo to give N- (3- (9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine (+/-) -10-camphorsulfonic acid salt as a brown solid (33.7mg, 86% yield).¹H NMR(400MHz，DMSO-d6)δ13.17(br.s.，1H)；9.89(d，1H)；9.33(s，1H)；8.76(s，1H)；8.41-8.46(m，1H)；8.31(s，1H)；8.24(d，1H)；7.35(t，1H) (ii) a 7.21(d, 1H); 7.14(t, 1H); 2.88(d, 1H); 2.63-2.73(m, 1H); 2.34-2.42(d, 1H); 2.18-2.29(m, 1H); 1.90-1.97(m, 1H); 1.74-1.90(m, 2H); 1.27(m, 2H); 1.05(s, 3H); 0.75(s, 3H). M/z (ESI, cation) 329.0(M + H)⁺。

Example 19: n- (3- (9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine

6- (2-Fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine (115.0mg, 0.3842mmol) and 1H-indol-4-amine (Aldrich, St. Louis, MO, 70.7mg, 0.535mmol) were suspended in EtOH (1.8mL) and aqueous hydrochloric acid (5.0M, 0.090mL, 0.45mmol) was added. The flask was fitted with a reflux condenser and placed in a pre-heated oil bath (100 ℃) and the reaction was stirred for 3 hours. Subsequently, the reaction was cooled to room temperature and diluted with DCM, 2N aqueous ammonia in MeOH, EtOH and MeOH, and concentrated. The residue was treated with MeOH and filtered. Neither the filtrate nor the solid contained pure material, therefore, they were combined, concentrated, treated with DMF and filtered. The filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). Fractions with product were collected, concentrated and filtered through a silica gel packed column (ca. 1 inch, 50: 1 DCM/2N aqueous ammonia in MeOH to 20: 1 DCM/2N aqueous ammonia in MeOH to 5: 1 DCM/2N aqueous ammonia in MeOH) to give N- (3- (9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine (6.9mg, 5% yield). MS (ESI cation) m/z: 328, (M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ12.90(s，1H)，11.16(s，1H)，9.87(d，J＝7.82Hz，1H)，9.24(s，1H)，8.73(s，1H)，8.43(dd，J＝4.69Hz，1.96Hz，1H)，8.28(dd，J＝4.6Hz，3.81Hz，1H)，7.38-7.35(m，1H)，7.09(s，1H)，7.08-7.06(m，1H)，7.04(dd，J＝7.82Hz，4.69Hz，1H)，6.79-6.76(m，1H)。

Example 20: n- (6-methoxypyridin-3-yl) -3- (9H-purin-6-yl) pyridin-2-amine

Step 1: 6-methoxy-N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine

A solution of 6- (2-fluoropyridin-3-yl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purine (196.6mg, 657. mu. mol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, MO) (101.9mg, 821. mu. mol) in THF (2.0mL) was cooled in an ice bath and treated with LiHMDS (3.0mL, 3.0 mmol). A blood red solution was obtained. The mixture was stirred for 1h and then quenched with water (0.1 mL). The mixture is separated from NaHCO₃The saturated aqueous solution was extracted into EtOAc, concentrated and purified by flash silica gel chromatography (50% EtOAc/hexanes; yellow band of the column) to give 6-methoxy-N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine (190mg, 71.7% yield) as a yellow crystalline solid.¹HNMR(400MHz，CDCl₃) δ 12.06(s, 1H); 9.68(dd, J ═ 7.82, 1.76Hz, 1H); 8.99(s, 1H); 8.44(d, J ═ 2.54Hz, 1H); 8.28(dd, J ═ 4.69, 1.76Hz, 1H)8.34(s, 1H); 8.05(dd, J ═ 8.90, 2.64Hz, 1H); 6.88(dd, J ═ 7.82, 4.69Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 5.86(dd, J ═ 10.37, 2.35Hz, 1H); 4.16-4.25(m, 1H); 3.95(s, 3H); 3.82(s, 1H); 1.98-2.24(m, 3H); 1.61-1.89(m, 3H). M/z (ESI, cation) 404.0(M + H) ⁺。

Step 2: n- (6-methoxypyridin-3-yl) -3- (9H-purin-6-yl) pyridin-2-amine

6-methoxy-N- (3- (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine (190mg, 471 μmol) in 2N aqueous HCl (2.0mL, 4mmol) was heated briefly in an oil bath at 100 deg.C, and then the heater was turned off and the mixture was allowed to cool slowly and stand overnight. Essentially complete conversion was observed. With ammonia waterThe solution was neutralized and the precipitated product was collected by filtration, washed with a small volume of water and dried in vacuo. N- (6-methoxypyridin-3-yl) -3- (9H-purin-6-yl) pyridin-2-amine was obtained as an orange solid (120.4mg, 80.1% yield).¹H NMR (400MHz, DMSO-d6) delta 13.80(br.s., 1H); 12.33(br.s., 1H); 9.73(br.s., 1H); 9.10(s, 1H); 8.70(s, 1H); 8.50-8.58(m, 1H); 8.25-8.34(m, 1H); 8.08-8.20(m, 1H); 6.95-7.07(m, 1H); 6.79-6.90(m, 1H); 3.85(s, 3H). M/z (ESI, cation) 320.0(M + H)⁺。

Example 21: n- (3- (6-amino-2- (trifluoromethyl) pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

Step 1: 6- (2-Fluoropyridin-3-Yl) -2- (trifluoromethyl) pyrimidin-4-Amines

The title compound was prepared in a similar manner to that described in example 4 above using 2-fluoropyridin-3-yl boronic acid and 6-chloro-2- (trifluoromethyl) pyrimidin-4-amine (SynChem inc., Elk Grove Village, IL) and the desired product 6- (2-fluoropyridin-3-yl) -2- (trifluoromethyl) pyrimidin-4-amine was isolated as a white solid (34%). LCMS (API-ES) M/z 259(M + H) ⁺；¹HNMR(400MHz，d6-DMSO)δ8.57(t，J＝8.80Hz，1H)8.38(d，J＝3.91Hz，1H)7.83(br.s.，2H)7.46-7.63(m，1H)7.15(s，1H)。

Step 2: n- (3- (6-amino-2- (trifluoromethyl) pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

1, 4-Di-6- (2-Fluoropyridin-3-yl) -2- (trifluoromethyl) pyrimidin-4-amine and 1H-indol-4-amine (1.2 equiv.) are reacted at 100 deg.C in a similar manner as described in example 22, step 2The mixture of alkanes and 2N HCl (aq) (10: 1) was heated overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and reacted with SiO₂And (4) mixing. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) to give N- (3- (6-amino-2- (trifluoromethyl) pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine (13%) as a yellow solid. LCMS (API-ES) M/z372(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δppm 13.06(br.s.，1H)10.82(s，1H)8.36(d，J＝4.52Hz，1H)8.11(d，J＝7.53Hz，1H)7.99(s，1H)7.89(d，J＝7.53Hz，1H)7.81(b r.s.，2H)7.29(t，J＝7.53Hz，1H)7.14(d，J＝8.03Hz，1H)7.07(s，1H)6.95-7.05(m，1H)。

Example 22: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indol-4-amine

Step 1: 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

1, 4-twoAn alkane (6.00mL, 2927. mu. mol) was added to a mixture of 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (423.1mg, 2927. mu. mol), 2-fluoropyridin-3-ylboronic acid (619mg, 4390. mu. mol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (91.0mg, 146. mu. mol) and potassium acetate (862mg, 8780. mu. mol) and the mixture was heated at 100 ℃ overnight. After cooling, the mixture was passed through Celite (diatomaceous earth) short packed columns. The filter cake was washed with EtOAc (3X 15 mL). The combined organic phases were concentrated to give a crude residue. Flash column chromatography purification (short column, SiO)₂Pure DCM to 3% MeOH in DCM) to afford the title compound, which was washed with MeOH to afford a light brown powder4- (2-Fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (454mg, 76%). LCMS (API-ES) M/z 206(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ8.48(ddd，J＝9.91，7.65，2.01Hz，1H)8.39(d，J＝5.02Hz，1H)7.65(br.s.，2H)7.51(ddd，J＝7.15，5.14，1.76Hz，1H)2.37(s，3H)。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indol-4-amine

2N HCl (aq) (0.42mL, 833 μmol) was added to 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (171mg, 833 μmol) and 1H-indol-4-amine (132mg, 1000 μmol) 1, 4-bisThe mixture was stirred with an alkane (4.00mL, 46762. mu. mol) and the brown mixture was heated at 100 ℃ overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and reacted with SiO₂And (4) mixing. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by washing of the eluted concentrate with EtOAc to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indol-4-amine (58mg, 22%) as a yellow solid. LCMS (API-ES) M/z 318(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δppm12.00(s，1H)11.15(br.s.，1H)8.77(dd，J＝7.78，1.76Hz，1H)8.38(dd，J＝4.52，1.51Hz，1H)8.09(d，J＝6.02Hz，1H)7.53-7.81(m，2H)7.35(t，J＝2.76Hz，1H)6.99-7.19(m，2H)6.90(dd，J＝7.78，4.77Hz，1H)6.66(br.s.，1H)2.55(s，3H)。

Example 23: 3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) phenol

In a similar manner to that described in example 22, 4- (2-fluoropyridine) was used-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 3-aminophenol to prepare the title compound and isolate it as a yellow solid (34%). LCMS (API-ES) M/z 295(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ11.97(s，1H)9.27(s，1H)8.76(dd，J＝7.78，1.76Hz，1H)8.35(dd，J＝4.77，1.76Hz，1H)7.64-7.92(m，2H)7.51(s，1H)6.99-7.28(m，2H)6.89(dd，J＝7.53，4.52Hz，1H)6.40(d，J＝7.03Hz，1H)2.45(s，3H)。

Example 24: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indazol-4-amine

The title compound was prepared in a similar manner to that described in example 22 using 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 1H-indazol-4-amine and was isolated as a yellow solid (13%). LCMS (API-ES) M/z 319(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.10(s，1H)12.26(s，1H)8.80(d，J＝7.82Hz，1H)8.42(d，J＝4.50Hz，1H)8.19(s，1H)8.13(d，J＝7.43Hz，1H)7.75(br.s.，2H)7.31(t，J＝8.02Hz，1H)7.16(d，J＝8.41Hz，1H)6.89-7.07(m，1H)2.56(s，3H)。

Example 25: 4- (2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner to that described in example 22 using 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 5-amino-2-methoxypyridine (Aldrich) and isolated as a yellow solid (80%). LCMS (API-ES) M/z 310(M + H)⁺； ¹H NMR(400MHz，d6-DMSO)δ11.74(br.s.，1H)8.77(dd，J＝5.02，2.51Hz，1H)8.53(br.s.，1H)8.29(br.s.，1H)8.08-8.23(m，1H)7.84(br.s.，1H)7.71(br.s.，1H)6.88(ddd，J＝7.78，4.27，4.02Hz，1H)6.82(dd，J＝8.78，4.27Hz，1H)3.84(d，J＝5.02Hz，3H)2.42(d，J＝4.02Hz，3H)。

Example 26: 3- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) phenol

The title compound was prepared in a similar manner as described in example 22 using 6-chloro-2-methylpyrimidin-4-amine and 3-aminophenol and was isolated as a yellow solid (3%). LCMS (API-ES) M/z 294(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ12.23(s，1H)9.25(d，J＝2.35Hz，1H)8.18-8.35(m，1H)8.02(d，J＝7.63Hz， 1H)7.36(br.s.，1H)6.95-7.16(m，4H)6.84-6.93(m，1H)6.74(d，J＝1.76Hz，1H)6.35(dd，J＝6.65，1.96Hz，1H)2.51-2.62(s，3H)。

Example 27: n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

The title compound was prepared in a similar manner to that described in example 22 using 6-chloro-2-methylpyrimidin-4-amine and 1H-indazol-4-amine and was isolated as a yellow solid (17%). LCMS (API-ES) M/z 318(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.09(br.s.，1H)12.29(s，1H)8.35(d，J＝4.52Hz，1H)7.89-8.22(m，3H)7.29(t，J＝7.78Hz，1H)6.86-7.20(m，4H)6.79(s，1H)2.62(s，3H)。

Example 28: 5-fluoro-6- (2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine

DME (6.00mL, 57722. mu. mol) and water (0.6mL, 3152. mu. mol) were added to 2-fluoropyridin-3-ylboronic acid (666mg, 4728. mu. mol), 6-chloro-5-fluoro-2-methylpyrimidin-4-amine (0.5093g, 3152. mu. mol) and Pd (Ph) under nitrogen₃P)₄(364mg, 315. mu. mol). The mixture was sealed and heated under microwave irradiation at 100 ℃ for 60 min. After cooling, the mixture was diluted with water and the precipitate was collected, washed with DCM and isolated as an off white powder of 5-fluoro-6- (2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine (418mg, 60%). LCMS (API-ES) M/z 223(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ8.39(d，J＝4.02Hz，1H)8.18(t，J＝8.03Hz，1H)7.53(t，J＝5.27Hz，1H)7.38(br.s.，2H)2.37(s，3H)。

Example 29: n- (3- (6-amino-5-fluoro-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

2N aqueous HCl (0.45mL, 900. mu. mol) was added to 5-fluoro-4- (2-fluoropyridin-3-yl) -6-methylpyrimidin-2-amine (400mg, 1800. mu. mol) and 1H-indazol-4-amine (360mg, 2700. mu. mol) in 1, 4-bis The mixture was stirred with an alkane (3.00mL, 1800. mu. mol) and the mixture was sealed and heated under microwave irradiation at 150 ℃ for 40 min. After cooling, the mixture was concentrated. Flash column chromatography purification (short column, SiO)₂Pure DCM to 10% MeOH in DCM) provided the title compound, which was washed with MeOH to give N- (3- (6-amino-5-fluoro-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine (134mg, 22% yield) as a yellow powder.LCMS(API-ES)m/z 336(M+H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.07(br.s.，1H)10.87(s，1H)8.34(d，J＝3.72Hz，1H)7.82-8.18(m，3H)7.47(br.s.，2H)7.19-7.36(m，1H)7.11(d，J＝8.22Hz，1H)6.75-7.05(m，1H)2.56(s，3H)。

Example 30: 3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol

A mixture of 5, 6-dichloro-3-pyridinemethanol (2.9967g, 16.8mmol) in DCM (3.00mL, 46.6mmol) was treated with Dess-Martin periodinane (7.14g, 16.8mmol) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was washed with NaHCO₃(aq) and water (5mL each) and diluted with DCM (5 mL). The separated aqueous layer was extracted with DCM (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a pale yellow solid which was used directly in the next step.

Step 2: 1- ((5, 6-dichloropyridin-3-yl) methyl) -4- (methylsulfonyl) piperazine

1-Methanesulfonylpiperazine (1.1g, 6.8mmol) followed by a catalytic amount of AcOH (0.020mL, 0.34mmol) was added to a stirred solution of 5, 6-dichloronicotinaldehyde (1.20g, 6.8mmol) in EtOH (100mL, 1713mmol), the mixture was stirred at room temperature for 1h (white precipitate formed) and the resulting suspension was treated portionwise with sodium cyanoborohydride (0.43g, 6.8mmol) (slightly exothermic) and stirred for a further 2 h. The mixture was concentrated and quenched with 1N HCl (aq), water (10 mL each), and EtOAc (50 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 50mL), and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, pure DCM to DCM3% 2M NH in (C)₃MeOH) to give 1- ((5, 6-dichloropyridin-3-yl) methyl) -4- (methylsulfonyl) piperazine as a white solid (1.16g, 52%). LCMS (API-ES) M/z 325(M + H)⁺；¹H NMR(400MHz，CDCl3)δ8.23(s，1H)7.78(s，1H)3.54(s，2H)3.26(br.s.，4H)2.80(s，3H)2.57(br.s.，4H)。

And step 3: 3- (3-chloro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol

The title compound was prepared in a similar manner as described in example 22, step 2, above, using 1- ((5, 6-dichloropyridin-3-yl) methyl) -4- (methylsulfonyl) piperazine and 3-aminophenol under microwave irradiation conditions (150 ℃, 30min) and was isolated as a pale yellow solid (70%). LCMS (API-ES) M/z 398(M + H) ⁺。

And 4, step 4: 3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol

1, 4-twoAlkane (4.00mL, 46762 μmol) was added to a mixture of 3- (3-chloro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol (390mg, 983 μmol), bis-valerylboron (299mg, 1179 μmol), X-Phos (46.8mg, 98.3 μmol), tris (dibenzylideneacetone) dipalladium (0) (45.0mg, 49.1 μmol) and potassium acetate (0.154mL, 2457 μmol), and the mixture was stirred at 100 ℃ for 3 h. After cooling to room temperature, 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (213mg, 1474 μmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, st. louis, MO) (61.1mg, 98.3 μmol) were added and the mixture was resealed and heating continued at 100 ℃ overnight. The mixture was cooled to room temperature and passed through CeliteThe short column was filtered and the filter cake was washed with EtOAc (2X 20 mL). The combined organic phases were concentrated with SiO2 and passed through a flash columnChromatography (ISCO CombiFlash)System, Teledyne ISCO, Lincoln, NE, pure DCM to 10% 2M NH dissolved in DCM₃MeOH) to give 3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenol as a yellow solid (7mg, 1.5%). LCMS (API-ES) M/z471(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ11.98(br.s.，1H)9.27(d，J＝4.89Hz，1H)8.59-8.78(m，1H)8.26(d，J＝2.93Hz，1H)7.61-7.92(m，1H)7.50(d，J＝1.76Hz，1H)6.81-7.26(m，2H)6.24-6.50(m，1H)3.49(br.s.，2H)3.11(br.s.，4H)2.87(d，J＝5.87Hz，3H)2.37-2.48(m，7H)。

Example 31: 4- (2- (6-methoxypyridin-3-ylamino) -5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N-butyllithium (2.5M solution in hexane, 9.6mL, 24mmol) was added to a mixture of diisopropylamine (3.4mL, 24mmol) in THF (5.00mL, 61mmol) at 0 deg.C, and the resulting pale yellow solution was stirred for 30min at the same temperature and then cooled to-78 deg.C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo) (2.22g, 20mmol) in THF (5.00mL, not completely dissolved) was added slowly. The resulting bright yellow solution was stirred at-78 ℃ for 1h, treated with triisopropyl borate (6.9mL, 30mmol) in THF (10.00mL) and then allowed to warm to room temperature. The yellow suspension was quenched with 1N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6N aqueous HCl until slightly acidic and then extracted with EtOAc (× 3). The combined organic layers were dried (Na)₂SO₄) Filtered and concentrated. The resulting white solid was washed with diethyl ether to obtain 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196g, product yield) as a white solidThe rate 94%). LCMS (API-ES) M/z 156(M + H)⁺。

Step 2: 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

1, 4-twoAn alkane (3.00mL, 8.5mmol) was added to a mixture of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO) (0.27g, 0.43mmol), 2-fluoro-5-methylpyridin-3-ylboronic acid (1.6g, 10mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (1.24g, 8.5mmol) and potassium acetate (2.5g, 26mmol) and the mixture was sealed and heated under microwave irradiation at 120 ℃ for 30 min. After cooling, the mixture was passed through Celite(diatomaceous earth) short packed columns. The filter cake was washed with DCM (3X 20 mL). The combined organic phases were concentrated. Flash column chromatography purification (short column, SiO)₂Neat DCM to 5% MeOH in DCM) provided 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.76, 41%) as a white solid, which was used for the next step. LCMS (API-ES) M/z 220(M + H)⁺。

And step 3: 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-yl-dicarbamic acid di-tert-butyl ester

NaH (0.41g, 10mmol) was added to a solution of 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.9046g, 4.1mmol) in DMF (3.00mL, 39mmol) and the mixture was stirred at room temperature overnight. The resulting red-yellow solution was quenched with ice and the resulting yellow solid was washed with water to give the desired product as a yellow solid. LCMS (API-ES) M/z 420(M + H) ⁺。

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Dissolve in THF (0.80mL, 801. mu. mol) at room temperature) To a stirred mixture of di-tert-butyl 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-yl-dicarbamate (112mg, 267. mu. mol) and 3-amino-6-methoxypyridine (Aldrich, St.Louis, MO) (50mg, 401. mu. mol) in THF (3.00mL, 36613. mu. mol) was added LiHMDS at 1.0M and the mixture was stirred at room temperature for 1 h. Reacting the mixture with NH₄Cl (aq) and water (10mL each) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL), and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue, which was taken up in DCM (2.00mL) and TFA (2.00mL) was added. The mixture was stirred for 1 h. The reaction mixture was concentrated and reused with DCM, NaHCO₃(aqueous solution) and water (10mL each). The separated aqueous layer was extracted with DCM (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by another column chromatography (hexane to 80% ethyl acetate in hexane) to give the desired product 4- (2- (6-methoxypyridin-3-ylamino) -5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (11mg, 13% yield). LCMS (API-ES) M/z 324(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ11.53(br.s.，1H)8.66(br.s.，1H)8.35(br.s.，1H)8.16(br.s.，1H)8.09(d，J＝10.37Hz，1H)6.79(d，J＝9.19Hz，1H)5.38(br.s.，2H)3.95(s，3H)2.56(s，3H)2.29(s，3H)。

Example 32: methyl-6- (5-methyl-2- (pyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

In a similar manner to that described in step 4 of example 31, di-tert-butyl 4- (2-fluoro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-yl-dicarbamate andpyridin-3-amine (Aldrich, St. Louis, Mo.) the title compound was prepared and isolated as a yellow solid (19%). LCMS (API-ES) M/z 294(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ12.29(s，1H)9.36(br.s.，1H)8.69(d，J＝2.15Hz，1H)8.65(d，J＝8.41Hz，1H)8.36(d，J＝4.69Hz，1H)8.30(d，J＝1.76Hz，1H)7.95(br.s.，1H)7.84(br.s.，1H)7.71(dd，J＝7.34，6.16Hz，1H)2.46(s，3H)2.32(s，3H)。

Example 33: 4- (5-methoxy-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 3-bromo-2-chloro-5-methoxypyridine

Will K₂CO₃(0.50g, 3.6mmol) followed by methyl iodide (0.20mL, 2.9mmol) was added to a stirred mixture of 5-bromo-6-chloropyridin-3-ol (Asymchem Laboratories, Inc., Morrisville, N.C.) (0.50g, 2.4mmol) in DMF (3.00mL) and the mixture was sealed and heated at 45 ℃ for 4h and then allowed to stand at room temperature overnight. The resulting mixture was diluted with water and the precipitate was collected and dried to give the product as a tan solid. LCMS (API-ES) M/z 223(M + H)⁺；¹H NMR(400MHz，CDCl₃)δ8.04(s，1H)7.49(d，J＝1.37Hz，1H)3.86(s，3H)。

Step 2: 2-chloro-5-methoxypyridin-3-ylboronic acid

2.5M n-BuLi in hexane (3.7mL, 9.3mmol) was added slowly to a premixed solution of 3-bromo-2-chloro-5-methoxypyridine (1.73g, 7.8mmol) and triisopropyl borate (2.1mL, 9.3mmol) in THF (10.0mL, 122mmol) at-78 deg.C and the resulting dark mixture was stirred at the same temperature for 1h and then allowed to warm to room temperature over 1 h. The reaction was quenched with 1N NaOH (aq) and then with some EtOAc. The separated aqueous layer was washed with 5N HCl Acidified until pH about 5 and then extracted with EtOAc (x2), and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give 2-chloro-5-methoxypyridin-3-ylboronic acid (1.0276g, 71%) as a brown solid. LCMS (API-ES) M/z 188(M + H)⁺。

And step 3: 4- (2-chloro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

1, 4-twoAlkyl (10.00mL) and water (2.5mL) were added 2-chloro-5-methoxypyridin-3-ylboronic acid (1.03g, 5.48mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (0.72g, 4.98mmol), Na₂CO₃(1.32g, 12.5mmol) and Pd (PPh)₃)₄(0.576g, 0.1 eq.) was stirred in the mixture and the mixture was sealed and heated at 90 ℃ overnight. After cooling, the mixture was concentrated. Flash column chromatography purification (short column, SiO)₂Neat DCM to 5% MeOH in DCM) afforded 4- (2-chloro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.644g, 51%) as a white solid. LCMS (API-ES) M/z252(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ8.24(d，J＝1.17Hz，1H)7.68(br.s.，2H)7.65(d，J＝1.17Hz，1H)3.87(s，3H)2.36(s，3H)。

And 4, step 4: 4- (5-methoxy-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

1, 4-twoAn alkane (0.1mL, 1.169mmol) and 2N HCl (0.219mL, 0.437mmol) were added to a mixture of 4- (2-chloro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (110mg, 0.437mmol) and 5-amino-2-methoxypyridine (Aldrich, St. Louis, MO) (81mg, 0.656mmol) in a microwave reaction vessel and the mixture was sealed and heated in a Personal Chemistry microwave apparatus for 60min under microwave irradiation at 140 ℃. After the cooling down, the mixture is cooled down, The resulting dark mixture was concentrated. Flash column chromatography purification (short column, SiO2, pure DCM to 5% MeOH in DCM) afforded the title compound mixed with the starting material. This compound was washed several times with methanol and the solid was finally recrystallized from MeOH to give 4- (5-methoxy-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (21mg, 0.062mmol, 14.16% yield) as a yellow-green powder. LCMS (API-ES) M/z 340(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ11.47(s，1H)8.52(d，J＝2.74Hz，1H)8.39(d，J＝3.33Hz，1H)8.13-8.18(m，1H)8.12(d，J＝3.13Hz，1H)7.86(br.s.，1H)7.73(br.s.，1H)6.79(d，J＝8.80Hz，1H)3.83(s，3H)3.82(s，3H)2.44(s，3H)。

Example 34: n- (6-methoxypyridin-3-yl) -3- (4-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine

Step 1: 5- (bromomethyl) -2-fluoropyridines

Benzoyl peroxide (1.570g, 6.48mmol) and NBS (23.19g, 130mmol) were added to CCl of 2-fluoro-5-methylpyridine (SynQuest Labs, Inc., Alachua, FL, 14.4045g, 130mmol)₄The solution was stirred (125mL) and the suspension was heated at reflux for 2 h. After cooling, the solution was filtered to remove solids and concentrated, and the residue was purified by flash column chromatography (ISCO Combiflash system, Teledyne, Lincoln, NE, hexane to 10% ethyl acetate in hexane) to give 5- (bromomethyl) -2-fluoropyridine (15.11g, 80mmol, 61.3% yield) as a yellow solid. LCMS (API-ES) M/z191(M + H) ⁺。

Step 2: 4- ((6-Fluoropyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

Piperazine-1-carboxylic acid tert-butyl ester (Aldrich, St. Louis, MO, 17.77g, 9) was reacted at 0 deg.C5mmol) was added to a stirred solution of 5- (bromomethyl) -2-fluoropyridine (15.11g, 80mmol) in N, N-dimethylformamide (120mL) and the suspension was stirred at room temperature overnight. The resulting thick reaction mixture was quenched with cold water (50mL), the resulting suspension was stirred for 30min and the resulting solid was collected and washed with additional cold water (50 mL). The off-white precipitate was dried in vacuo to give the title compound tert-butyl 4- ((6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (19.7494g, 66.9mmol, 84% yield) as a white solid. LCMS (API-ES) M/z 296(M + H)⁺；¹H NMR(400MHz，d6-DMSO)8.13(s，1H)7.90(td，J＝8.02，1.37Hz，1H)7.15(dd，J＝8.31，2.05Hz，1H)3.51(s，2H)3.30(br.s.，4H)2.10-2.40(m，4H)1.39(s，9H)。

And step 3: 5- ((4- (tert-Butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid

N-butyllithium (2.5M in hexane, 36.1mL, 90mmol) was added to a stirred solution of diisopropylamine (12.8mL, 90mmol) in tetrahydrofuran (150mL, 75mmol) at-40 ℃ and the yellowish solution was stirred at the same temperature for 1h and then cooled to-78 ℃. A solution of tert-butyl 4- ((6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (22.22g, 75mmol) in THF (100mL) was slowly added to the LDA solution over 30min with a catheter. The brown mixture was stirred at the same temperature for 1.5h and then a solution of triisopropyl borate (25.9mL, 113mmol) in THF (50mL) was added slowly. The resulting mixture was stirred at the same temperature for 30min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the yellow heterogeneous mixture was quenched with 1.0M NaOH (aq) (50mL) and stirred for an additional 30 min. The separated aqueous layer was carefully acidified with 5N aqueous HCl until acidic (pH 4 to about 5) and the resulting cloudy mixture was diluted with EtOAc (150 mL). The separated aqueous layer was extracted with EtOAc (2X 150mL) and the combined organic phases were dried (Na) ₂SO₄) Filtered and concentrated to give 5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (21.93g, 64.7mmol, 86% yield) as a pale yellow solid. LCMS (API-ES) M/z 340(M + H)⁺。

And 4, step 4: 4- ((6-fluoro-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

1, 4-twoAlkane (15mL) and H₂O (3.00mL) was added 2-chloro-4-methyl-6- (methylthio) -1, 3, 5-triazine (0.560g, 3.19mmol), 5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (1.03g, 3.04mmol), Na₂CO₃(0.805g, 7.59mmol) and Pd (Ph)₃P)₄(0.175g, 0.152mmol) and the stirred suspension was heated at 80 ℃ overnight. After cooling, the mixture was passed over Na₂SO₄The column was short packed, washed with EtOAc (× 2) and concentrated. The residue was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, pre-packed silica gel column (hexane to 30% ethyl acetate in hexane) for chromatography to give tert-butyl 4- ((6-fluoro-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate as a white solid (0.9676g, 74%). LCMS (API-ES) M/z 435(M + H) ⁺；¹H NMR(400MHz，CDCl₃)δ8.57(d，J＝9.00Hz，1H)8.30(s，1H)3.58(s，2H)3.44(b r.s.，4H)2.66(s，3H)2.64(s，3H)2.43(d，J＝4.50Hz，4H)1.46(s，9H)。

And 5: 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine

TFA (4.00mL, 51.9mmol) was added slowly to a stirred solution of tert-butyl 4- ((6-fluoro-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.853g, 1.963mmol) in DCM (5.00mL, 78mmol) cooled in an ice bath and then the mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the viscous residue was dissolved in DCM (10mL) and cooled in an ice bathAnd triethylamine (1.368mL, 9.82mmol) was added. Methanesulfonyl chloride (0.459mL, 5.89mmol) was slowly added to the mixture, then the mixture was stirred at the same temperature for 1h, concentrated, and the residue was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, pre-packed silica gel column (pure DCM to 10% MeOH in DCM) to chromatographe to give a solid, which was washed with IPA to give 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (0.64g, 79%) as a white solid. LCMS (API-ES) M/z 413(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ8.58(dd，J＝9.29，2.25Hz，1H)8.37(s，1H)3.67(s，2H)3.01-3.19(m，4H)2.87(s，3H)2.61(s，3H)2.60(s，3H)2.47-2.49(m，4H)。

Step 6: 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-1, 3, 5-triazine

An aqueous suspension of raney nickel (76mg, 1.297mmol) was added to a mixture of 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (107mg, 0.259mmol) in EtOH (5.00mL, 86mmol) and the mixture was heated at 70 ℃ under nitrogen for 1.5 h. Passing the resulting mixture through Celite(diatomaceous earth) short packed columns. The filter cake was washed with MeOH (3X 10 mL). The combined organic phases were concentrated to give the crude product, which was used directly in the next step without purification.

And 7: n- (6-methoxypyridin-3-yl) -3- (4-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine

LiHMDS (1.0M in THF, 557. mu.L, 0.557mmol) was added to 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridine at 0 deg.C-3-yl) -4-methyl-1, 3, 5-triazine (68.0mg, 0.186mmol) and 3-amino-6-methoxypyridine (Aldrich) (34.6mg, 0.278mmol) in THF (928. mu.L, 0.186mmol) were stirred in solution and the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (10mL) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL) and the combined organic layers were washed with brine, over Na ₂SO₄Dried and concentrated. The crude product was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, pre-packed silica gel column (DCM to 5% MeOH in DCM) for chromatographic separation followed by washing with iPrOH to give N- (6-methoxypyridin-3-yl) -3- (4-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine as a yellow solid (15mg, 17%). LCMS (API-ES) M/z 471(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ11.44(s，1H)9.29(s，1H)8.81(s，1H)8.51(br.s.，1H)8.29(br.s.，1H)8.11(d，J＝9.19Hz，1H)6.85(d，J＝9.19Hz，1H)3.85(s，3H)3.53(s，2H)3.11(br.s.，4H)2.87(s，3H)2.75(s，3H)2.34-2.49(m，4H)。

Example 35: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine

1.0M LiHMDS in THF (0.754mL, 0.754mmol) was added dropwise to 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (0.311g, 0.754mmol) at-10 deg.C (example)Example 34, step 5) and 3-amino-6-methoxypyridine (0.094g, 0.754mmol) in tetrahydrofuran (10mL, 0.754mmol) were stirred and the mixture was stirred at the same temperature for 1 h. Reacting the mixture with NH ₄Cl (aq) and water (10 mL each) and diluted with ethyl acetate (20 mL). The separated aqueous layer was extracted with ethyl acetate (2X 20mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne, Lincoln, NE, DCM to 5% MeOH in DCM) to give N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine (237mg, 0.459mmol, 60.8% yield) as a yellow solid.

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

2M NH dissolved in 2-propanol (2.00mL, 92mmol)₃To N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine (221mg, 0.428mmol) was added and the mixture was sealed and heated at 90 ℃ overnight. After cooling, the reaction mixture was concentrated, adsorbed onto a silica gel packed column and passed through RediSepTeledyne ISCO, Lincoln, NE, silica gel column pre-packed (DCM to 10% MeOH in DCM) followed by washing the isolated solid with MeOH to give 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (117mg, 0.241mmol, 56.3% yield). LCMS (API-ES) M/z486(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ11.76(br.s.，1H)8.71(br.s.，1H)8.55(br.s.，1H)8.03-8.28(m，2H)7.87(br.s.，1H)7.73(br.s.，1H)6.82(d，J＝7.63Hz，1H)3.84(br.s.，3H)3.48(br.s.，2H)3.11(br.s.，4H)2.87(br.s.，3H)2.52-2.58(m，3H)2.44(br.s.，4H)。

Example 36: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-indazol-4-amine

Step 1: n- (3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine

The title compound was prepared in a similar manner as described above for example 35, step 1, using 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine and isolated as a yellow solid (69%).

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-indazol-4-amine

2M NH dissolved in 2-propanol (2.00mL, 92mmol)₃To N- (3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (97mg, 0.159mmol) was added and the mixture was sealed and heated at 90 ℃ overnight. After cooling, the precipitate was collected and dried to give a yellow solid, which was dissolved in DCM (3.00mL, 46.6mmol) and then TFA (1.50mL, 19.47mmol) was added slowly. The mixture was stirred at room temperature for 1h and then concentrated, adsorbed onto a silica gel packed column and passed through a RediSep Teledyne ISCO, Lincoln, NE, Pre-packed silica gel column (DCM to 10% MeOH in DCM) for chromatography to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-indazol-4-amine (18 m) as a yellow solidg, 0.036mmol, 22.88% yield). LCMS (API-ES) M/z 495(M + H)⁺； ¹H NMR(400MHz，d6-DMSO)δ13.10(br.s.，1H)12.27(s，1H)8.75(s，1H)8.32(br.s.，1H)8.19(s，1H)8.13(d，J＝7.04Hz，1H)7.78(br.s.，2H)7.31(t，J＝8.31Hz，1H)7.15(d，J＝8.22Hz，1H)3.53(s，2H)3.12(br.s.，4H)2.87(s，3H)2.57(s，3H)2.37-2.49(m，4H)。

Example 37: 4-methyl-6- (5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (6- (trifluoromethyl) pyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner as described in example 35 above using 6- (trifluoromethyl) pyridin-3-amine in step 1 and isolated as a yellow solid (27%, two steps). LCMS (API-ES) M/z 524(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ12.49(s，1H)9.12(d，J＝2.54Hz，1H)8.79(d，J＝2.15Hz，1H)8.74(dd，J＝8.70，2.05Hz，1H)8.36(d，J＝2.15Hz，1H)7.97(br.s.，1H)7.84(d，J＝8.61Hz，2H)3.55(s，2H)3.12(br.s.，4H)2.87(s，3H)2.48-2.50(m，4H)2.47(s，3H)。

Example 38: 4-methyl-6- (5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyrimidin-5-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner as described above for example 35 using pyrimidin-5-amine in step 1 and isolated as a yellow solid (37%, two steps). LCMS (API-ES) M/z 457(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ12.12(s，1H)9.35(s，2H)8.81(s，1H)8.77(d，J＝2.35Hz，1H)8.33(d，J＝2.15Hz，1H)7.97(br.s.，1H)7.81(br.s.，1H)3.54(s，2H)3.11(br.s.，4H)2.87(s，3H)2.50(m，4H)2.46(s，3H)。

Example 39: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] Oxazol-6-amine.

Benzo [ d ] in step 1 was used in a similar manner as described in example 35, supra] Oxazol-6-amine (Bionet Research Intermediates, UK) to prepare the title compound and isolate it as a yellow solid (35%, two steps). LCMS (API-ES) M/z 496(M + H)⁺； ¹H NMR(400MHz，d6-DMSO)δ12.30(s，1H)8.75(d，J＝2.35Hz，1H)8.65(s，1H)8.61(s，1H)8.33(d，J＝2.15Hz，1H)7.89(br.s.，1H)7.78(br.s.，1H)7.67-7.75(m，1H)7.59-7.67(m，1H)3.52(s，2H)3.30(s，3H)3.12(br.s.，4H)2.87(s，3H)2.47(s，4H)。

Example 40: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

A1L 3-necked round-bottomed flask containing p-bis-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 51) (20g, 52.0mmol), 5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (example 34, step 3) (21.15g, 62.4mmol), potassium acetate (8.12mL, 130mmol) and Amphos (bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO) (1.913g, 2.70mmol) at 100 deg.CA mixture of alkane (300mL, 3528mmol) and water (60mL, 52.0mmol) was stirred overnight. The solution was partitioned between water and EtOAc, and the organic layer was separated, washed with water, and Na ₂SO₄Dried, filtered and concentrated in vacuo to give the crude product, which is adsorbed onto silica gel and passed through Redi-SepSilica gel column (Teledyne ISCO, Lincoln, NE) (330g) was pre-packed and chromatographed with a gradient of 10% to 50% EtOAc in hexanes to give tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (25.2g, 39.1mmol, 75% yield). M/z (ESI, cation) M/z644(M + H)⁺。

Step 2: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

Stirring the oven-dried mix N at a temperature between-5 ℃ and-10 ℃₂A solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (25g, 38.8mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem LLC, Monmouth NJ) (8.28g, 58.3mmol) in tetrahydrofuran (400mL, 38.8mmol) in an imported 1L 3-neck round bottom flask and with lithium bis (trimethylsilyl) amideTetrahydrofuran (117mL, 117mmol) in 1.0M was treated drop by drop. The dark pink solution was stirred between-5 ℃ and-10 ℃ for 1 h. The reaction was washed with water (100mL) and NH ₄Cl (100mL) was quenched and diluted with EtOAc (350 mL). The separated aqueous layer was extracted with EtOAc (2X 300mL) and the combined organic extracts were extracted over Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude product, which is adsorbed onto silica gel and passed through Redi-SepSilica gel column (Teledyne ISCO, Lincoln, NE) (330g) was pre-packed and chromatographed with a gradient of 10% to 50% EtOAc in hexanes to give tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate (26.8g, 35.0mmol, 90% yield). M/z (ESI, cation) M/z 766(M + H)⁺。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate (25g, 32.6mmol) in dichloromethane (150mL, 32.6mmol) and trifluoroacetic acid (150mL, 2019mmol) was stirred at room temperature for 1 h. The solution was concentrated and the residue was dissolved in DCM and carefully washed with NaHCO ₃And (4) neutralizing with saturated aqueous solution. The aqueous layer was extracted with DCM and the organic extracts were taken over Na₂SO₄Dried, filtered and concentrated in vacuo to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (20g, 30.0mmol, 92% yield). The crude product was used in the next step without purification.

And 4, step 4: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (25.1g, 37.7mmol) in methylene chloride (500mL, 37.7mmol) was charged to a 1L 3-neck round bottom flask equipped with a thermometer. The suspension was stirred at-15 ℃ and treated dropwise with triethylamine (52.4mL, 377 mmol). The resulting solution was treated with methanesulfonyl chloride (8.92mL, 113mmol) and stirred at 0 deg.C for 1 h. The resulting mixture was sonicated and the solid was filtered, washed with water and dried in vacuo to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (26.5g, 35.6mmol, 94% yield). M/z (ESI, cation) M/z744(M + H) ⁺。

And 5: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (26.9g, 36.2mmol) and TFA (175mL) were charged to a 3-neck 500mL flask equipped with an overhead stirrer, thermocouple and nitrogen inlet. The dissolution of the solid is exothermic. After complete dissolution, the solution was warmed to 45 ℃ and trifluoromethanesulfonic acid (16.06mL, 181mmol) was added dropwise. The reaction mixture was stirred for 1h and then cooled to 20 ℃.

500mL of 10 wt% trisodium citrate (aq) was charged to a separate 2L flask equipped with an overhead stirrer and thermocouple and cooled to 0 ℃. The reaction mixture was added dropwise to the cooled aqueous solution. The product precipitated from solution, DCM was added and the slurry was stirred at 20 ℃ for 16 h. The solid was collected by filtration and washed with water, then ethanol, and dried under reduced pressure to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piper-ine) as a yellow solidOxazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (15.06g, 83%). M/z (ESI, cation) M/z 504(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.96(s，1H)；8.73(d，J＝2.15Hz，1H)；8.42(d，J＝2.15Hz，1H)；8.37(dd，J＝12.72，2.15Hz，1H)；8.26(d，J＝2.15Hz，1H)；7.93(br.s.，1H)；7.78(br.s.，1H)；3.93(s，3H)；3.50(s，2H)；3.11(br.s.，4H)；2.87(s，3H)；2.45-2.49(m，4H)；2.44(s，3H)。

Example 41: 4- (2- (6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

Step 1: 4- ((6- (6-methoxypyridin-3-ylamino) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

LiHMDS (1.519mL, 1.0M in THF, 1.519mmol) was added to a stirred solution of tert-butyl 4- ((6-fluoro-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.220g, 0.506mmol) and 5-amino-2-methoxypyridine (0.094g, 0.759mmol) in THF (3.00mL, 36.6mmol) at 0 deg.C and the mixture was stirred at the same temperature for 1 h. Reacting the mixture with NH₄Cl (aq) and water (10mL each) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne, Lincoln, NE, hexane to 50% ethyl acetate dissolved in hexane) to give tert-butyl 4- ((6- (6-methoxypyridin-3-ylamino) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.133g, 49%) as a yellow solid. LCMS (API-ES) M/z 538(M + H) ⁺；¹H NMR(400MHz，CDCl₃)δ11.42(s，1H)8.81(br.s.，1H)8.36(d，J＝2.74Hz，1H)8.27(br.s.，1H)8.10(dd，J＝8.71，2.64Hz，1H)6.79(d，J＝8.80Hz，1H)3.95(s，3H)3.50(s，2H)3.43(br.s.，4H)2.67(s，3H)2.66(br.s.，3H)2.42(br.s.，4H)1.45(s，9H)。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a stirred mixture of tert-butyl 4- ((6- (6-methoxypyridin-3-ylamino) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (66mg, 0.123mmol) in DCM (2.mL, 31.1mmol) was added TFA (2mL, 26.0mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and reused with DCM, NaHCO₃(aqueous solution) and water (10 mL each). The separated aqueous layer was extracted with DCM (3X 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The crude product was treated with aqueous ammonia (2.0M solution in 2-propanol, 2.00mL, 92mmol) and the mixture was sealed and heated at 90 ℃ overnight. After cooling, the reaction mixture was concentrated, adsorbed onto a silica gel packed column and passed through RediSepTeledyne ISCO, Lincoln, NE, pre-packed silica gel column (DCM to 10% MeOH in DCM) followed by washing the isolated solid with ether and ethyl acetate to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (2.5mg, 6.14 μmol, 13.45% yield) as a yellow solid. LCMS (API-ES) M/z408(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ11.74(br.s.，1H)8.69(br.s.，1H)8.55(br.s.，1H)8.19(br.s.，1H)8.16(br.s.，1H)7.87(br.s.，1H)7.72(br.s.，1H)6.82(d，J＝8.41Hz，1H)3.94-4.21(m，2H)3.84(br.s.，3H)3.42(d，J＝13.50Hz，4H)2.84(br.s.，4H)2.40-2.45(m，3H)2.32(br.s.，1H)。

Example 42: 5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid

Step 1: 5- (1, 3-Dioxolan-2-yl) -2-fluoropyridines

6-Fluoronicotinaldehyde (Asymchem Laboratories, Inc., Morrisville, NC, 3.035g, 24.26mmol) was suspended in toluene (80mL) and ethylene glycol (1.40mL, 25.1mmol) and p-toluenesulfonic acid (Acros Organics, Geel, Belgium, 12% in acetic acid, 0.15mL) was added. The flask was fitted with a reflux condenser and placed in a pre-heated oil bath (120 ℃) and stirred under nitrogen for 20 minutes. At this point, the reflux condenser was replaced with a Dean Stark trap (Dean Stark trap) and stirring was continued at 120 ℃ for 25 minutes. Subsequently, the reaction was cooled and diluted with saturated sodium bicarbonate solution (20mL) (before it was cooled to room temperature). The reaction was then diluted with water (20mL) and EtOAc (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (about 3 inches, 40: 1 DCM/MeOH to 30: 1 DCM/MeOH) to give 5- (1, 3-dioxolan-2-yl) -2-fluoropyridine (3.858g) which was used in the next step. MS (ESI cation) M/z 170(M + H)⁺。

Step 2: 5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid

Diisopropylamine (4.60mL, 32.5mmol) was dissolved in THF (80mL) and cooled in an ice-water bath. Subsequently, an n-butyllithium solution (1.6M in hexane, 21.0mL, 33.6mmol) was added via syringe. After 30 minutes, the reaction was cooled to-78 ℃ and a solution of 5- (1, 3-dioxolan-2-yl) -2-fluoropyridine (3.73g, 22.1mmol) in THF (12mL) was added dropwise over 5 minutes via syringe, followed by a rinse with THF (4 mL). The reaction was stirred at-78 ℃ under nitrogen for 1 hour, and then triisopropyl borate (Fluka 98 +%, 8.0mL, 34.9mmol) was added via syringe and the reaction was allowed to warm to room temperature. After 4.5 hours, the mixture is cooledThe reaction was quenched with 1N NaOH (75 mL). The layers were separated and the aqueous phase was treated with 5N HCl to reduce the pH to between 6 and 7. The aqueous phase was extracted with 10: 1 DCM/MeOH. 5N HCl was added to the aqueous phase to reduce the pH to about 5 and extraction was continued with 10: 1 DCM/MeOH. The organic extracts were combined, concentrated and dried under high vacuum to give 5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid (3.165g, 91% purity, 61% yield over 2 steps). MS (ESI cation) M/z 214(M + H)⁺。

Example 43: 4- (2- (6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

1, 4-twoAlkyl (16mL) and water (3.3mL) were added 5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid (0.715g, 3.53mmol), 2-chloro-4-methyl-6- (methylthio) -1, 3, 5-triazine (0.682g, 3.88mmol), Pd (PPh)₃)₄(0.408g, 0.353mmol) and Na₂CO₃(0.935g, 8.82mmol) and the suspension is heated at 90 ℃ for 2 h. After cooling, the mixture was filtered, washed with EtOAc (2 × 20mL), and the combined organic phases were concentrated. The crude product was adsorbed onto a silica gel packed column and chromatographed via a Redi-Sep pre-packed silica gel column (hexane to 30% ethyl acetate in hexane) to give 2- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (0.5259g, 1.706mmol, 48.3% yield) as a white solid. LCMS (API-ES) M/z 309(M + H)⁺。

Example 44: 4- (2- (6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5- (1, 3-Dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-2-amine

LiHMDS (1.0M in THF, 4.14mL, 4.14mmol) was added to a stirred solution of 2- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (0.425g, 1.379mmol) and 5-amino-2-methoxypyridine (0.257g, 2.068mmol) in THF (3.00mL, 36.6mmol) at 0 deg.C and the mixture was stirred at the same temperature for 1 h. Reacting the mixture with NH ₄Cl (aq) and water (10mL each) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Drying, concentrating and passing the residue through flash column chromatography (ISCO Combiflash)Teledyne, Lincoln, NE, hexane to 50% ethyl acetate in hexane) to give 5- (1, 3-dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-2-amine (35mg, 0.085mmol, 6.15% yield) as a yellow solid. LCMS (API-ES) M/z 413(M + H)⁺。

Step 2: 6- (6-methoxypyridin-3-ylamino) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) nicotinaldehyde

2M aqueous HCl (1.50mL, 3.00mmol) was added to a stirred solution of 5- (1, 3-dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyridin-2-amine (35mg, 0.085mmol) in THF (3.00mL, 36.6mmol) and the mixture stirred at 25 ℃ for 2 h. A yellow precipitate gradually formed. Minimizing volatile solvents and collecting and drying the precipitate to give 6- (6-methoxypyridin-3-ylamino) -5- (4-methyl) amino as a yellow solid Yl-6- (methylthio) -1, 3, 5-triazin-2-yl) nicotinaldehyde (27mg, 0.073mmol, 86% yield). LCMS (API-ES) M/z 369(M + H)⁺。

And step 3: n- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-amine

Morpholine (0.018mL, 0.204mmol) and a few drops of AcOH (3.88. mu.L, 0.068mmol) were added to a stirred suspension of 6- (6-methoxypyridin-3-ylamino) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) nicotinaldehyde (25mg, 0.068mmol) in EtOH (3.00mL, 51.4mmol), and the mixture was stirred at room temperature for 1h, then treated with sodium cyanoborohydride (4.26mg, 0.068mmol) and stirred at room temperature overnight. The mixture was diluted with water and EtOAc (10 mL each). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude product which is passed through flash column chromatography (ISCO Combiflash)Teledyne, Lincoln, NE, DCM to 10% DCM in MeOH) to give N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-amine (19mg, 0.043mmol, 63.7% yield) as a yellow solid. LCMS (API-ES) M/z 440(M + H) ⁺。

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-amine (19mg, 0.043mmol) in 2.0M NH₃the/iPrOH (3.0mL) stirred mixture was sealed and heated at 90 ℃ for 24 h. The reaction mixture was concentrated and the crude product was adsorbed onto a silica gel packed column and passed through RediSepTeledyne ISCO，Lincoln, NE, Pre-packed with silica gel column (DCM to 5% MeOH in DCM) for chromatography to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (6.00mg, 0.015mmol, 34.0% yield) as a yellow solid. LCMS (API-ES) M/z 409(M + H)⁺；¹H NMR(400MHz，CDCl₃A drop of d6-DMSO) δ 11.69(br.s., 1H)8.76(br.s, 1H)8.39(br.s, 1H)8.23(br.s, 1H)8.12(br.s, 1H)6.77(d, J ═ 9.00Hz, 1H)5.92(br.s, 2H)3.93(br.s, 3H)3.49(br.s, 2H)2.55(br.s, 3H)2.50(br.s, 4H)2.23(br.s, 4H) is used.

Example 45: 4- (2-chloro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-6-methyl-1, 3, 5-triazin-2-amine (0.350g, 2mmol), 2-chloro-5-methylpyridin-3-ylboronic acid (combi-blocks catalog No. BB-3511) (0.6g, 3mmol), sodium carbonate, monohydrate, crystals (J.T.Baker catalog No. 3600-01) (0.450g, 7mmol), tetrakis (triphenylphosphine) palladium (0) (Strem chemicals catalog No. 46-Z150) (0.3g, 0.2mmol) were charged into a glass microwave reaction vessel. Degassed 1, 2-dimethoxyethane (Aldrich Cat. No. 255527) (11mL, 109mmol) and water (1mL, 2mmol) were added to the mixture. At 90 ℃ in a Smith Synthesizer The reaction mixture was stirred and heated in a microwave reactor (Personal Chemistry, inc., Upssala, Sweden) for 30 min. Passing the mixture through Celite(celite) was filtered and washed with ethyl acetate. The crude product was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (40g) to 5% to 10% 2M NH in dichloromethane₃Chromatographed with a MeOH gradient to afford 4- (2-chloro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.210g, 36% yield).

Example 46: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methylpyridin-2-yl) -1H-indol-4-amine

The experimental procedure for this compound was the same as that of example 22, step 2, using 4- (2-chloro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 1H-indol-4-amine (Bionet Research, Cornwall, UK). LCMS (API-ES) M/z 332(M + H)⁺。¹H NMR (400MHz, d 6-DMSO). delta.11.84 (s, 1H); 11.34(s, 1H); 8.62(d, J ═ 1.17Hz, 1H); 8.24(d, J ═ 0.59Hz, 1H); 8.14(d, J ═ 0.59Hz, 1H); 7.84(d, J ═ 0.59Hz, 1H); 7.33(br.s., 1H); 7.05(s, 1H); 7.04(d, J ═ 3.33Hz, 1H); 6.65(d, J ═ 1.17Hz, 1H); 3.17(d, J ═ 2.74Hz, 3H); 3.16(br.s., 3H). Example 47: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methylpyridin-2-yl) -1H-indazol-4-amine

The experimental procedure for this compound was the same as that of example 22, step 2, using 4- (2-chloro-5-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 1H-indazol-4-amine. LCMS (API-ES) M/z 333(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.08(d，J＝2.35Hz，1H)；12.12(br.s.，1H)；8.64(br.s.，1H)；8.28(dd，J＝3.81，2.05Hz，1H)；8.14(d，J＝5.28Hz，2H)；7.74(br.s.，2H)；7.31(d，J＝7.63Hz，1H)；7.32(br.s.，1H)；7.13(d，J＝12.91Hz，1H)；3.32(d，J＝1.37Hz，6H)。

Example 48: 4- (5-bromo-2- (4-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

This compound was synthesized in 2 steps according to the procedures in example 45 and example 31, using 5-bromo-2-fluoropyridin-3-ylboronic acid (Combi-Blocks, Inc.) and 4-chloro-6-methyl-1, 3, 5-triazin-2-amine in the first step. LCMS (API-ES) M/z387/389(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.70(d，J＝1.17Hz，1H)；8.84(br.s.，1H)；8.49(d，J＝4.30Hz，1H)；8.37(br.s.，1H)；8.07(dd，J＝4.21，1.86Hz，1H)；7.81(br.s.，1H)；6.84(d，J＝2.35Hz，1H)；3.84(br.s.，3H)；2.50(d，J＝0.98Hz，3H)。

Example 49: 4- (2- (6-ethoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-Fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.100g, 0.49mmol), 5-amino-2-ethoxypyridine (Combi-Blocks, Inc., San Diego, Calif.), 1, 4-bis-bipyramidAn alkane (0.75mL, 8.8mmol) (Aldrich, St. Louis, Mo.) and 2N aqueous HCl (0.24mL, 0.49mmol) were added to a 50mL round bottom flask. The suspension was stirred at 100 ℃ overnight. The crude product was adsorbed onto a silica gel packed column and purified by chromatography via RediSepTeledyne ISCO, Lincoln, NE, pre-packed silica gel column (40g) and purified by elution with a gradient of 5% to 20% methanol in dichloromethane to give 4- (2- (6-ethoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine. LCMS (API-ES) M/z 324(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.80(br.s.，1H)；8.83(br.s.，1H)；8.27(d，J＝4.11Hz，1H)；8.26(d，J＝4.11Hz，1H)；8.11(br.s.，1H)；7.82(dd，J＝2.93，1.56Hz，1H)；8.81(d，J＝4.11Hz，1H)；6.92(br.s.，1H)；6.86(d，J＝9.39Hz，1H)；4.28-4.37(m，2H)；2.44(br.s.，3H)；1.33(t，J＝7.04Hz，3H)。

Example 50: n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine

The title compound was prepared according to the procedure for example 49 using 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and 2, 5-diaminopyridine (Aldrich). LCMS (API-ES) M/z 295(M + H)⁺。¹H NMR (400MHz, d 6-DMSO). delta.11.52 (s, 1H); 8.75(d, J ═ 7.83Hz, 1H); 8.74(dt, J ═ 7.83, 1.08Hz, 1H); 8.34(d, J ═ 2.74Hz, 1H); 8.27(d, J ═ 1.76Hz, 1H); 8.26(d, J ═ 2.15Hz, 1H); 7.87(d, J ═ 8.80Hz, 1H); 7.88(dt, J ═ 9.00, 1.08Hz, 1H); 7.68(br.s., 1H); 6.83(dd, J ═ 7.82, 4.70Hz, 1H); 6.62(d, J ═ 8.80Hz, 1H); 2.42(s, 3H). Example 51: 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Cesium carbonate (0.860mL, 10.74mmol) was added at room temperature4-chloro-6-methyl-1, 3, 5-triazin-2-amine (1.10g, 7.61mmol) and 1- (chloromethyl) -4-methoxybenzene (1.10mL, 8.11mmol) in a mixture of DMF (8.0 mL). After 40min, more 1- (chloromethyl) -4-methoxybenzene (1.10mL, 8.11mmol) was added. After another 1h, more cesium carbonate (0.860mL, 10.74mmol) was added. After another 30min, the mixture was diluted with EtOAc (30mL) and passed through Celite (diatomaceous earth) pad filtration. The filtrate was transferred to a separatory funnel, diluted with more EtOAc and washed with water (3 × 20 mL). Subjecting the organic layer to Na₂SO₄Dried and concentrated. The resulting slurry was filtered and washed with 1: 1 hexane-EtOAc. The filtrate was purified by silica gel chromatography using 5 to 100% DCM dissolved in hexane to give the product as a soft white solid (1.8 g). LCMS (ES, cation): c₂₀H₂₁ClN₄O₂Calculated values: 384.1; measured value: 385.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ7.16(t，J＝8.12Hz，4H)；6.81-6.95(m，4H)；4.74(s，2H)；4.69(s，2H)；3.81(s，6H)；2.45(s，3H)。

Example 51: alternative procedure

Step 1: 2, 4-dichloro-6-methyl-1, 3, 5-triazine

To a 5-L reactor was added 2, 4, 6-trichloro-1, 3, 5-triazine (180g, 976mmol) and DCM (180 mL). Methyl magnesium bromide (390mL, 1171mmol) was added to the solution cooled in the dry ice bath at 0 ℃ over 30min while maintaining the temperature of the reaction below room temperature. After the addition, the reaction mixture was placed in an ice-water bath to keep the internal temperature stable at 20 ℃. After the mixture was stirred at room temperature overnight, it was cooled to-20 ℃ and slowly quenched with ice water (500mL) (internal temperature controlled below 0 ℃). The mixture was warmed to room temperature and transferred to a separatory funnel. The organic layer was washed with water (500mL) and concentrated to give 2, 4-dichloro-6-methyl-1, 3, 5-triazine (127g, 774mmol, 79% yield) as a solid, which was used in the next step.

Step 2: 4-chloro-N- (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 2, 4-dichloro-6-methyl-1, 3, 5-triazine (190g, 1159mmol) in DMF (1500mL) was slowly added to (4-methoxyphenyl) methylamine over 15min while controlling the temperature below 20 ℃. This was followed by the slow addition of N-ethyl-N-isopropylpropan-2-amine (222mL, 1274mmol) over 15 min. After completion of the reaction, EtOAc (2000mL) was added and the mixture was taken up with dilute brine (200mL saturated NaCl plus 500mL water), water (500mL), saturated NH₄Cl (250mL) and finally water (250 mL). The organic layer was concentrated to give 4-chloro-N- (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (290.5g, 1097mmol, 95% yield) as a solid. M/z 265.2(M + H).

And step 3: 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a solution of 4-chloro-N- (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (160g, 604mmol) in DMF (800mL) at 0 deg.C over 5min was slowly added sodium hydride (18.86g, 786 mmol). 1- (chloromethyl) -4-methoxybenzene (91mL, 665mmol) was added slowly over 15 min. The reaction mixture was stirred at 0-5 ℃ for 30min and allowed to warm to room temperature 25 ℃. After 1h, cold water (2.5L) was added and the mixture was stirred overnight. The resulting slurry was filtered, washed with water (150mL, x2) and dried to give 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (215.3g, 559mmol, 93% yield) as a solid. LCMS (ES, cation): c ₂₀H₂₁ClN₄O₂Calculated values: 384.1; measured value: 385.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ7.16(t，J＝8.12Hz，4H)；6.81-6.95(m，4H)；4.74(s，2H)；4.69(s，2H)；3.81(s，6H)；2.45(s，3H)。

Example 52: 4- (2-Fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of potassium acetate (0.38g, 3.87mmol), 2-fluoro-3-pyridineboronic acid (0.28g, 1.987mmol) and 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.60g, 1.559mmol) in DCM (8.0mL) was evaporated to dryness under nitrogen. THF (5.0mL) was added followed by bis [4- (di-tert-butylphosphino) -N, N-dimethyl]Palladium dichloride (Am-phos) (0.060g, 0.085 mmol). The mixture was heated in an oil bath at 80 ℃. After 1h, EtOH (5mL) was added and heating continued overnight. The mixture was cooled to room temperature. Water (10mL) and DCM (10mL) were added. The organic layer was separated. The aqueous layer is replaced by CH₂CL₂Extracting, and passing the organic layer over MgSO₄And (5) drying. The solution was filtered and concentrated in vacuo. The orange oil was adsorbed onto a silica gel packed column and purified by chromatography eluting with 2: 1 hexane-acetone to provide 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (80mg, 0.180mmol, 11.52% yield) as a white foam. LCMS (ES, cation): c₂₅H₂₄FN₅O₂The calculated value of (a): 445.2, respectively; measured value: 446.2(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ8.49-8.62(m，1H)；7.86-7.99(m，1H)；7.27-7.36(m，1H)；7.23(dd，J＝8.31，4.99Hz，4H)；6.87(t，J＝8.51Hz，4H)；3.81(s，3H)4.81(s，4H)；3.80(s，3H)；2.55(s，3H)。

Example 53: 4- (2- (6-Chloropyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

1.0M LHMDS in THF (600. mu.L, 0.600mmol) was added to a solution of 5-amino-2-chloropyridine (49mg, 0.381mmol) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (80mg, 0.180mmol) in THF (4mL) at room temperature under nitrogen. A dark orange mixture formed. After 1.5h, the mixture was heated to about 50 ℃. After overnight, more 5-amino-2-chloropyridine (49mg, 0.381mmol) and LHMDS (600 μ L, 0.600mmol) were added. The reaction mixture was heated for an additional 2h and cooled to room temperature. The mixture was neutralized with HCl (5N, 0.3mL) and diluted with EtOAc (10mL) and water (10 mL). The aqueous layer was extracted twice with DCM and the combined organics were taken over Na₂SO₄Dried and concentrated. The residue was purified on silica (10-80% EtOAc in hexane) to give a yellow oil (70 mg). LCMS (ES, cation): c₃₀H₂₈FN₇O₂The calculated value of (a): 553.2, respectively; measured value: 554.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ12.19(s，1H)；8.84(dd，J＝7.83，1.76Hz，1H)；8.47(d，J＝2.74Hz，1H)；8.33(dd，J＝4.70，1.76Hz，1H)；8.26(dd，J＝8.71，2.84Hz，1H)；7.16-7.24(m，5H)；6.80-6.91(m，5H)；4.84(s，4H)；3.80(d，J＝5.87Hz，6H)；2.59(s，3H)。

Example 54: 4- (2- (6-Chloropyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (6-chloropyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (70mg, 0.126mmol) in TFA (10mL) was heated to 80 ℃. After 24h, the mixture was concentrated to a slurry. Water (5mL) was added followed by addition of Na in portions ₂CO₃Until the pH is basic. The mixture was filtered and the solid was washed with water followed by MeOH to give the product as a brown solid (39 mg). LCMS (ES, cation): c₁₄H₁₂ClN₇The calculated value of (a): 313.1; measured value: 314.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.16(s，1H)；8.87(d，J＝2.74Hz，1H)；8.82(dd，J＝7.83，1.76Hz，1H)；8.48(dd，J＝8.80，2.74Hz，1H)；8.39(dd，J＝4.50，1.76Hz，1H)；7.92(br.s.，1H)；7.78(br.s.，1H)；7.46(d，J＝8.61Hz，1H)；7.01(dd，J＝7.83，4.70Hz，1H)；2.44(s，3H)。

Example 55: n- (3- (6-methyl-1H-pyrazolo [3, 4-d ] pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

Step 1: n- (3- (6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d ] pyrimidin-4-yl) pyridin-2-yl) -2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine

2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine (80.2mg, 369. mu. mol) and 4- (2-fluoropyridin-3-yl) -6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d) were stirred in an ice bath]Pyrimidine (112.0mg, 357. mu. mol) in THF (1.0mL) and treated dropwise with LHMDS (1.0M in THF, 1.1mL, 3 equivalents). The mixture was stirred for 45min and then quenched with water (0.1 mL). The mixture is separated from NaHCO₃The saturated aqueous solution was extracted into EtOAc and dried (MgSO)₄) And concentrated to give a dark residue. The residue was purified by flash silica gel chromatography (25-30% EtOAc/hexanes) to give N- (3- (6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d) as a yellow oil]Pyrimidin-4-yl) pyridin-2-yl) -2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine (56.9mg, 31.2% yield). ¹H NMR(400MHz，CDCl₃)δ11.97(br.s，1H)；8.43-8.53(m，1H)；8.30-8.42(m，3H)；7.96(br.s.，1H)；7.38-7.48(m，1H)；7.34(d，J＝7.43Hz，1H)；6.94-7.03(m，1H)；6.16(d，J＝10.17Hz，1H)；5.71(d，J＝9.00Hz，1H)；4.14(d，J＝9.98Hz，2H)；3.73-3.95(m，2H)；3.04(s, 3H); 2.58-2.76(m, 1H); 2.26-2.39(m, 1H); 1.94-2.25(m, 4H); 1.59-1.93(m, 6H). M/z (ESI, cation) 511.1(M + H)⁺。

Step 2: n- (3- (6-methyl-1H-pyrazolo [3, 4-d ] pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine

Mixing N- (3- (6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d)]A solution of pyrimidin-4-yl) pyridin-2-yl) -2- (tetrahydro-2H-pyran-2-yl) -2H-indazol-4-amine (56.9mg, 111. mu. mol) in DCM (1mL) and MeOH (2mL) was treated with (+/-) -10-camphorsulfonic acid (57mg, 2.2 equivalents) and stirred for 16H. LCMS indicated complete single deprotection with only a small amount of fully deprotected compound. Additional (+/-) -10-camphorsulfonic acid (57mg, 2.2 equivalents) was added and the solution was stirred at 60 ℃ for 1h, after which time the reaction was complete. The mixture was concentrated and purified by SCX ion exchange chromatography, washed with MeOH and washed with 2N NH₃MeOH to give N- (3- (6-methyl-1H-pyrazolo [3, 4-d) as a brown solid]Pyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine (35mg, 87% yield). Of the free base thus obtained¹H NMR gave a broad peak signal, so it was converted to the HCl salt in small amounts by dissolving in MeOH containing 2 drops of 2M aqueous HCl followed by concentration to dryness for better performance ¹H NMR analysis. HCl salt:¹h NMR (400MHz, d 6-DMSO). delta.14.18 (br.s., 1H); 11.38(s, 1H); 10.43(s, 1H); 9.76(s, 1H); 9.42(d, 1H); 9.04(s, 1H); 8.64(d, 1H); 8.46(s, 1H); 7.85-7.98(m, 2H); 7.69(d, J ═ 9.54Hz, 1H); 2.14(s, 3H). M/z (ESI, cation) 343.0(M + H)⁺。

Example 56: n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine

6- (2-Fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (270mg, 0.862mmol) and4-Aminoindole (159.3mg, 1.205mmol) was suspended in EtOH (5.0mL) and then aqueous hydrochloric acid (5N, 0.21mL, 1.1mmol) was added. The reaction flask was fitted with a reflux condenser, placed in a preheated oil bath (100 ℃) and stirred for 3 hours. Subsequently, the reaction was cooled to room temperature, diluted with 2N aqueous ammonia dissolved in MeOH (4.0mL) and allowed to stand overnight. Subsequently, the material was concentrated, treated with DMF and filtered. The solid was washed with DCM and the filtrate was concentrated and purified by preparative HPLC (10% to 100% MeCN in water with 0.1% TFA, total flow rate 100mL/min over 30 min). Fractions with product were collected, concentrated and filtered through a silica gel packed column (about 1 inch) with 10: 1 DCM/2N aqueous ammonia in MeOH to give N- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine (13.7mg, 5%). MS (ESI cation) M/z 342(M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ13.60(s，1H)，12.44(s，1H)，11.16(s，1H)，9.77(d，J＝7.04Hz，1H)，8.61(s，1H)，8.37(dd，J＝4.69Hz，1.76Hz，1H)，8.05(dd，J＝6.85Hz，1.56Hz，1H)，7.37(t，J＝ 2.64Hz，1H)，7.11-7.04(m，2H)，7.01(dd，J＝7.82Hz，4.69Hz，1H)，6.72(s，1H)，2.92(s，3H)。

Example 57: n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine

6- (2-Fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (24.9mg, 0.079mmol) and 1H-indazol-4-amine (Bionet Research, Cornwall, UK, 13.8mg, 0.104mmol) were suspended in EtOH (0.9mL) and aqueous hydrochloric acid (5M, 0.020mL, 0.10mmol) was added. The reaction flask was fitted with a reflux condenser and placed in a pre-heated oil bath (100 ℃) and the reaction stirred for 90 minutes. Subsequently, the reaction was cooled to room temperature and treated with 2N aqueous ammonia dissolved in MeOH. In a separate flask, 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (295mg, 0.943mmol) and 1H-indazol-4-amine (Bionet Research, Comwall, UK, 173.3mg, 1.302mmol) were suspended in EtOH (9.5mL) and aqueous hydrochloric acid (5N, 0.23mL, 1.2mmol) was added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (100 ℃) and stirred for 75 minutes. Subsequently, the reaction was cooled to room temperature and treated with 2N aqueous ammonia dissolved in MeOH (4.8 mL).

The two reactions were combined, concentrated, diluted with DMF and DCM, and filtered. The filtrate was concentrated and purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). Fractions with product were collected, concentrated, and filtered through a silica gel filter (about 1 inch, 10: 1 DCM/2N aqueous ammonia in MeOH) to give N- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine (33.9mg, 10% yield). MS (ESI cation) M/z343(M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ13.12(s，1H)，12.72(s，1H)，9.78(s，1H)，8.62(s，1H)，8.41(dd，J＝4.50Hz，1.76Hz，1H)，8.27(s，1H)，8.10(d，J＝7.43Hz，1H)，7.33(t，J＝8.02Hz，1H)，7.17(d，J＝8.22Hz，1H)，7.09(dd，J＝7.83Hz，4.69Hz，1H)，2.94(s，3H)。

Example 58: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

Step 1: 6-methoxy-N- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine

A solution of 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (190mg, 606. mu. mol) and 6-methoxypyridin-3-amine (94.1mg, 758. mu. mol) (Aldrich, St.Louis, Mo.) in THF (2.0mL) was cooled in an ice bath and treated with LiHMDS (3.0mL, 3.0mmol) (1.0M in THF). A blood red solution was obtained. The mixture was stirred for 1h and then quenched with water (0.1 mL).The mixture is separated from NaHCO₃The saturated aqueous solution was extracted into EtOAc, concentrated and purified by flash silica gel chromatography (25 to 50% EtOAc/hexanes; yellow band of the column) to give 6-methoxy-N- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine (96.3mg, 38.0% yield) as a yellow crystalline solid.¹H NMR (400MHz, d 6-DMSO). delta.12.50 (s, 1H); 9.72(dd, J ═ 7.82, 1.71Hz, 1H); 8.87(s, 1H); 8.53(d, J ═ 2.69Hz, 1H); 8.32(dd, J ═ 4.65, 1.96Hz, 1H); 8.18(dd, J ═ 8.93, 2.81Hz, 1H); 7.01(dd, J ═ 7.82, 4.65Hz, 1H); 6.85(d, J ═ 9.05Hz, 1H); 5.80-5.89(m, 1H); 3.97-4.12(m, 1H); 3.85(s, 3H); 3.67-3.82(m, 1H); 2.89(s, 3H); 2.27-2.38(m, 1H); 1.93-2.12(m, 2H); 1.72-1.88(m, 1H); 1.55-1.70(m, 2H). M/z (ESI, cation) 418.1(M + H) ⁺。

Step 2: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

An aqueous solution of 6-methoxy-N- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridin-3-amine (95.3mg, 228 μmol) in 2N hcl (2.0mL, 4mmol) was briefly heated at 100 ℃ in an oil bath and then the heater was turned off and the mixture was allowed to cool slowly. The solution was concentrated and purified by SCX ion exchange chromatography, washed with MeOH and washed with 2N NH₃MeOH eluted to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine as an orange solid (72mg, 95% yield).¹H NMR (400MHz, d 6-DMSO). delta.13.60 (br.s., 1H); 12.68(s, 1H); 9.80(dd, J ═ 7.82, 1.96Hz, 1H); 8.60(s, 1H); 8.54(d, J ═ 2.69Hz, 1H); 8.31(dd, J ═ 4.65, 1.96Hz, 1H); 8.20(dd, J ═ 8.92, 2.81Hz, 1H); 7.00(dd, J ═ 7.95, 4.77Hz, 1H); 6.85(d, J ═ 8.80Hz, 1H); 3.85(s, 3H); 2.86(s, 3H). M/z (ESI, cation) 334.0(M + H)⁺。

Example 59: 6- (5-chloro-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.500g, 1.979mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388g, 7.91mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25mL) were charged to a 100mL round bottom flask. Potassium acetate (0.583g, 5.94mmol) was added to the mixture, followed by water (1 mL). The mixture was vented and then back-filled with nitrogen. Subsequently, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.050g) (Aldrich, st. louis, MO) was added to the mixture. The mixture was vented and then back-filled with nitrogen. The flask was fitted with a reflux condenser, then placed in a preheated (90 ℃) oil bath and allowed to stir under an inert atmosphere for 2 h. The reaction progress was monitored by LCMS, which mainly showed the production of the desired product. The reaction mixture was cooled to room temperature, diluted with water (10mL) and CH ₂Cl₂(3X 25 mL). The organic extract is extracted with Na₂CO₃Washed with saturated aqueous solution (1X 20mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude product was adsorbed onto a silica gel packed column and chromatographed via Redi-Sep RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (120g) to dissolve in CH₂Cl₂Purification was performed by gradient elution with 1% to 40% EtOAc in order to give 6- (5-chloro-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine as a yellow solid (0.502g, 1.443mmol, 73.0% yield).¹H NMR(400MHz，CDCl₃) δ 8.37-8.45(m, 1H); 8.27-8.33(m, 2H); 5.79-5.92(m, 1H); 4.14-4.26(m, 1H); 3.74-3.91(m, 1H); 2.89(s, 3H); 1.96-2.25(m, 3H); 1.63-1.91(m, 3H). M/z (ESI, cation) 348(M + H)⁺。

Example 60: n- (5-chloro-3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine

A solution of 6- (5-chloro-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (75.3mg, 217. mu. mol) and 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (49.4mg, 227. mu. mol) in THF (1.0mL) was cooled in an ice bath and treated dropwise with LHMDS (0.68mL of a 1.0M solution, 3 equivalents) in THF to give a dark red solution. The mixture was stirred for 45min and then quenched with water (0.1 mL). From NaHCO ₃The saturated aqueous solution was extracted into EtOAc and dried (MgSO)₄) And concentrated to give a dark yellow oil. Purification by flash silica gel chromatography eluting with 40% EtOAc/hexanes afforded N- (5-chloro-3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (96.8mg, 82.0% yield) as a bright yellow solid (yellow band on column).¹H NMR(400MHz，CDCl₃) δ 12.70(br.s., 1H); 9.82(d, J ═ 2.74Hz, 1H); 8.21-8.40(m, 3H); 8.06(dd, J ═ 7.53, 1.66Hz, 1H); 7.42(t, J ═ 8.02Hz, 1H); 7.20-7.30(m, 1H); 5.87(dd, J ═ 10.47, 2.25Hz, 1H); 5.72(dd, J ═ 9.59, 2.54Hz, 1H); 4.15-4.28(m, 1H); 4.02-4.12(m, 1H); 3.70-3.88(m, 2H); 3.00(s, 3H); 2.52-2.71(m, 1H); 1.98-2.27(m, 5H); 1.58-1.92(m, 6H). M/z (ESI, cation) 545.1(M + H)⁺。

Example 61: n- (5-chloro-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine

Treatment of N- (5-chloro-3- (2-methyl-9- (tetrahydro-2H-py-ro-ridine) with (+/-) -10-camphorsulfonic acid (91mg, 391. mu. mol)Pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (96.8mg, 178 μmol) in DCM/MeOH (4.0mL, 1: 1) and the stirred mixture was placed in an oil bath at 40 ℃. The heater was turned off and the mixture was stirred for 16 h. LCMS showed significant single deprotection, so an additional 90mg CSA was added (4.4 equivalents total). At 40 ℃, the mixture was heated until LCMS indicated complete deprotection. The mixture was cooled and purified by ion exchange chromatography (washing with MeOH, eluting with 2N NH 3/MeOH). The product was concentrated, taken up in MeOH (3mL), sonicated and allowed to stand. N- (5-chloro-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine (55mg, 82% yield) was crystallized out and collected by filtration as an orange solid. Of the free base thus obtained ¹H NMR gave a broad peak signal, so it was converted to the HCl salt in small amounts by dissolving in MeOH containing 2 drops of 2M aqueous HCl followed by concentration to dryness for better performance¹H NMR analysis. HCl salt:¹h NMR (400MHz, d 6-DMSO). delta.11.29 (br.s., 1H); 10.17(br.s., 1H); 10.04(s, 1H); 9.27(d, J ═ 2.69Hz, 1H); 8.93(s, 1H); 8.40(s, 1H); 8.30(d, J ═ 2.69Hz, 1H); 7.89(d, J ═ 9.54Hz, 1H); 7.52(d, J ═ 9.54Hz, 1H); 2.15(s, 3H). M/z (ESI, cation) 377.0(M + H)⁺。

Example 62: 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine

A solution of 6-methoxypyridin-3-amine (0.357g, 2.88mmol) (Source: Aldrich) in THF (10mL) was treated with lithium bis (trimethylsilyl) amide (5.03mL, 5.03mmol) (Source: Aldrich) and the mixture was stirred under an inert atmosphere for 20 minutes. Subsequently, 6- (5-chloro-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.500g, 1.438mmol) was added to the mixture and the mixture was stirred throughAnd (4) at night. The reaction mixture was diluted with DCM and brine solution. The organic layer was collected by extracting the aqueous layer with DCM (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by ISCO silica gel chromatography, Teledyne ISCO, Lincoln, NE, (120 gram column) over 37 minutes using a gradient of 10-60% EtOAc/DCM. Fractions with desired material were combined and concentrated to give 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine as a yellow solid (0.590g, 1.306mmol, 91% yield). M/z (ESI, cation) 452(M + H) ⁺。 ¹H NMR(400MHz，CDCl₃)δ9.76(s，1H)；8.40(s，1H)；8.23(s，1H)；8.16(s，2H)；7.19(s，1H)；6.75(d，J＝8.80Hz，1H)；5.80(d，1H)；4.14(d，1H)；3.91(s，4H)；3.76(t，1H)；2.83(s，3H)；1.46-2.25(m，5H)。

Example 63: 6- (5-bromo-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.525g, 2mmol), 5-bromo-2-fluoropyridine-3-boronic acid (0.5g, 2mmol) (Alfa Aesar, Ward Hill, MA), potassium carbonate (0.5g, 9mmol) (Aldrich, St. Louis, MO), dichloro [1, 1' -bis (diphenylphosphino) ferrocene]The dichloropalladium (II) dichloromethane adduct (0.2g, 0.2mmol) (Strem Chemicals, inc., Newburyport, MA) was charged to a glass microwave reaction vessel. A deoxygenated mixture of 1, 2-dimethoxyethane (10mL, 96mmol) (Aldrich, St. Louis, Mo.) and water (1mL) was added. The vial was deoxygenated for 5 minutes, capped and the reaction mixture stirred at 100 ℃ for 2 h. The crude product was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (120g) toChromatographed with a gradient of 20% to 80% ethyl acetate in hexane to provide 6- (5-bromo-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2-H-pyran-2-yl-9H-purine. M/z (ESI, cation) 392/394(M + H)⁺。

Example 64: n- (5-bromo-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine

A solution of 6- (5-bromo-2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.250g, 0.637mmol) and 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (0.138g, 0.637mmol) in THF (10mL) was stirred at 0 deg.C and treated dropwise with lithium bis (trimethylsilyl) amide, a 1.0M solution in THF (1.912mL, 1.912mmol) (Aldrich Cat. 225770) and stirred at 0 deg.C for 30 minutes. The mixture was quenched with water (10mL), diluted with water (50mL) and extracted with dichloromethane. The crude material was adsorbed onto a silica gel packed column and purified by chromatography via RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (40g) to 5% to 10% 2M NH in dichloromethane₃Purification was performed with a MeOH gradient elution to provide N- (5-bromo-3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine as yellow crystals. This material was treated with dichloromethane (5mL) and trifluoroacetic acid (5mL) (Aldrich, st. louis, MO) to give N- (5-bromo-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine. M/z (ESI, cation) 421/423(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.75(br.s.，1H)；13.25(br.s.，1H)；12.85(br.s.，1H)；8.69(br.s.，1H)；8.48(br.s.，1H)；7.99(br.s.，1H)；7.32(br.s.，1H)；7.23(br.s.，1H)；2.93(s，3H)。

Example 65: n- (3- (2-methyl-9H-purin-6-yl) -5- (trifluoromethyl) pyridin-2-yl) -1H-indazol-4-amine

This compound was synthesized according to procedures analogous to those described in example 63 and example 64, substituting 2-fluoro-5- (trifluoromethyl) pyridin-3-ylboronic acid (Anichem, llc., North Brunswick, NJ) for 5-bromo-2-fluoropyridine-3-boronic acid in the first step. M/z (ESI, cation) 411(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.24(br.s.，1H)；10.26(br.s.，1H)；8.72(br.s.，1H)；8.28(br.s.，1H)；7.96-8.05(m，1H)；7.37(br.s.，1H)；7.30(d，J＝2.35Hz，1H)；7.31(br.s.，1H)；2.93(br.s.，3H)。

Example 66: 2-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) pyrimidin-5-amine

The title compound was prepared according to the procedure described in example 58 using the alternative 5-amino-2-methoxypyrimidine (Ryan Scientific, inc., mt. pleasant, SC) in a first step. M/z (ESI, cation) 335(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.62(br.s.，1H)；12.63(br.s.，1H)；9.00(s，2H)；8.60(s，1H)；8.32(dd，J＝4.50，1.76Hz，1H)；7.04(dd，J＝7.82，4.69Hz，1H)；3.92(s，3H)；2.85(s，3H)。

Example 67: 3-bromo-5- (bromomethyl) -2-fluoropyridines

N-Bromosuccinimide (4.732g, 26.59mmol) and benzoyl peroxide (0.1356g, 0.5598mmol) were added to CCl of 3-bromo-2-fluoro-5-methylpyridine (Matrix Innovation Inc., Montreal, Quebec, Canada, 5.318g, 27.99mmol)₄(50mL) in solution and under gentle reflux under N₂The mixture was heated under atmosphere for 16 h. The mixture was filtered and washed with CCl₄Washing, and the residue was concentrated and purified by flash silica gel chromatography (1% to 1.5% EtOAc/hexanes) to give 3-bromo-5- (bromomethyl) -2-fluoropyridine as a white solid (1.593g, 21.17% yield). ¹H NMR(400MHz，CDCl₃)δ8.15(s，1H)；8.03(dd，J＝8.02，2.15Hz，1H)；4.43(s，2H)；¹⁹F NMR(376MHz，CDCl₃) Delta-65.17 (br.s., 1F). The sample was not sufficiently ionized in ESI + mode.

Example 68: 3-bromo-2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridine

3-bromo-5- (bromomethyl) -2-fluoropyridine (5.63g, 20.9mmol) was dissolved in MeCN (135mL) and 4-methoxybenzyl alcohol (5.20mL, 41.9mmol), silver (I) oxide (7.169g, 30.9mmol) and tetrabutylammonium iodide (2.208g, 5.98mmol) were added. The reaction flask was covered with aluminum foil and the reaction was stirred at room temperature under nitrogen overnight. The reaction was passed through CeliteThe pad was filtered and washed with DCM, MeOH and MeCN. The filtrate was concentrated and purified on silica gel column (3: 1 to 2: 1 to 3: 2 hexane/DCM to 3: 2 DCM/hexane to 2: 1 DCM/hexane to 3: 1 DCM/hexane to DCM) to give 3-bromo-2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridine (1.62g, 24%). MS (ESI cation) M/z326/328(M + H)⁺。

Example 69: 2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-ylboronic acid

3-bromo-2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridine (1.615g, 4.952mmol) was dissolved in PhMe (25.0mL) and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Subsequently, an n-butyllithium solution (Fluka, Buchs, Switzerland, 1.6M in hexane, 3.7mL, 5.9mmol) was added via syringe to turn the solution yellow. The reaction was stirred at-78 ℃ for 45 minutes and then triisopropyl borate (Alfa Aesar, Ward Hill, MA 98 +%, 1.7mL, 7.2mmol) was added via syringe. The reaction was allowed to slowly warm to room temperature and after 90 minutes the dry ice/acetone bath was removed. After a further 25 minutes, the reaction was quenched with water and diluted with 10: 1 DCM/MeOH. The biphasic solution was treated with 5N HCl to reduce the pH of the aqueous phase from 9 to about 4 and the aqueous phase was extracted with 10: 1 DCM/MeOH. The organic extracts were concentrated and dried under high vacuum in a water bath (about 45-60 ℃) and then Et ₂The solid was washed and dried again under high vacuum at room temperature over the weekend to give 2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-ylboronic acid (1.389g, purity 68%, yield 66%). MS (ESI cation) M/z 292(M + H)⁺。

Example 70: 6- (2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (38.7mg, 0.153mmol), 2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-ylboronic acid (51.2mg, 0.176mmol), potassium carbonate (87.8mg, 0.635mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride) The complex with dichloromethane (21.0mg, 0.0257mmol) was suspended in DME (1.0mL) and water (0.30 mL). The flask was fitted with a reflux condenser and placed in a preheated oil bath (100 ℃), stirred under nitrogen for 2 hours and cooled to room temperature. In a separate flask, 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (933mg, 3.69mmol), 2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-ylboronic acid (1.338g, 4.597mmol), potassium carbonate (2.096g, 1.517. mu. mol), and [1, 1' -bis (diphenylphosphino) ferrocene]-Palladium (II) dichloride complex with dichloromethane (360.9mg, 0.4419mmol) suspended in DME (15mL) and water (4.0 mL). Nitrogen was bubbled through the suspension for about 30 seconds, and then the flask was fitted with a reflux condenser and placed into a preheated oil bath (100 ℃) and stirred under nitrogen. After 1 hour and 45 minutes, the reaction was allowed to cool to room temperature. At this point, the two reactants were combined and the aqueous phase was removed via pipette. Subsequently, the combined reactants were passed through Celite The pad was filtered and washed with DCM and MeOH. The filtrate was concentrated and taken up in Et₂And (4) O treatment. No precipitate was observed, so it was concentrated and the residue was purified on a silica gel filter (about 3 inches, 50: 1 DCM/2N aqueous ammonia in MeOH to 25: 1 DCM/2N aqueous ammonia in MeOH to 10: 1 DCM/2N aqueous ammonia in MeOH). Note that: the product was eluted with 50: 1 DCM/2N aqueous ammonia. Fractions with product were collected, concentrated, and dried under high vacuum overnight to give 6- (2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (1.688g, 69% purity, 68% yield). MS (ESI cation) M/z 464(M + H)⁺。

Example 71: n- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine

6- (2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (171.2mg, 0.3694mmol) and 4-aminoindole (Aldrich, St. Louis, MO, 69.2mg, 0.524mmol) were suspended in EtOH (2.0mL) and hydrochloric acid (J.T.Baker, Phillipsburg, NJ, 5N, 0.090mL, 0.45mmol) was added. The flask was fitted with a reflux condenser and placed in a pre-heated oil bath (100 ℃) and stirred for about 105 minutes. Subsequently, the reaction was cooled to room temperature and diluted with MeOH and 2N aqueous ammonia dissolved in MeOH. The reaction was concentrated, treated with DMF and DCM and filtered. The filtrate was filtered again and the solid was washed again with DCM. This filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). Fractions with product were collected, concentrated, and filtered through a silica gel filter (approximately 1 inch, 10: 1 DCM/2N aqueous ammonia in MeOH) to give N- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine (13.1mg, 7% yield). MS (ESI cation) M/z492(M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ12.49(s，1H)，11.17(s，1H)，9.84(s，1H)，8.64(s，1H)，8.33(s，1H)，8.04(d，J＝6.85Hz，1H)，7.38-7.32(m，3H)，7.12-7.04(m，2H)，6.93(d，J＝8.80Hz，2H)，6.72(s，1H)，4.53(s，2H)，4.51(s，2H)，3.75(s，3H)，2.92(s，3H)。

Example 72: (6- (1H-indazol-4-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol

Step 1: n- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine

Coupling 6- (2-fluoro-5- ((4-methoxybenzyloxy) methyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (1.223g, 2.634mmol)And 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (0.596g, 2.74mmol) were dissolved in THF (23.5mL) and the flask was cooled under nitrogen in an ice-water bath. Subsequently, LiHMDS (1.0M in THF, 7.8mL, 7.8mmol) was added via syringe and the reaction was stirred at 0 ℃ under nitrogen for 35 minutes. Subsequently, the reaction was quenched with water (40mL) and diluted with water (40mL), and then extracted with DCM and 10: 1 DCM/MeOH. Brine was added to break the emulsion. The organic extracts were combined, concentrated, and purified on a silica gel filter (about 3 inches, 50: 1 DCM/2N aqueous ammonia in MeOH to 40: 1 DCM/2N aqueous ammonia in MeOH) to give N- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (1.343g, 54% purity, 43% yield). MS (ESI cation) M/z661(M + H) ⁺。

Step 2: (6- (1H-indazol-4-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol

N- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (19.8mg, 0.0300mmol) was dissolved in DCM (1.0mL) and TFA (0.10mL) was added and the reaction was stirred at room temperature. After 2 hours, more TFA (0.15mL) was added and stirring was continued. After another hour, the reaction was quenched with saturated sodium bicarbonate (3.8mL) and stirred for about 10 minutes. In a separate flask, N- (5- ((4-methoxybenzyloxy) methyl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (178.5mg, 0.2701mmol) was dissolved in DCM (5.0mL) and TFA (0.50mL) was added. The reaction was stirred at room temperature for 3.5 hours, and then more TFA (0.75mL) was added and stirring was continued. After another hour, more TFA (0.80mL) was added and stirring was continued. After 45 min, the reaction was diluted with DCM (5mL) and quenched with saturated sodium bicarbonate (30 mL). At this point, the two reactants were combined and allowed to stand overnight. The layers were separated and brine was added to help break the emulsion. The aqueous phase was extracted with 10: 1 DCM/MeOH. However, it is not limited to Both the organic extract and the aqueous phase were found to contain product by LCMS. Thus, they were combined, concentrated and treated with 10: 1 DCM/MeOH, and filtered. The solid was washed with DCM and MeOH. The filtrate was concentrated and treated with DCM and MeOH, and filtered again. The filtrate was concentrated again and dried briefly under high vacuum, then redissolved in DCM and MeOH, and concentrated and dried over the weekend under high vacuum. Dissolve the material in MeOH and DMSO, concentrate and use Et₂O are repeatedly washed and these washings are discarded. Subsequently, the material was dissolved in EtOAc and MeOH, concentrated, treated with water and filtered. The solid was washed with water, collected and set aside. The filtrate was filtered again (solids had precipitated out) and this solid was washed with water. The filtrate from this second filtration was discarded and both sets of solids were collected, treated with MeOH and filtered. LCMS showed the solid was not pure, so the filtrate and solid were combined, concentrated, and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). The fractions with product were collected, concentrated and dried under high vacuum in a water bath (about 50 ℃). Subsequently, the solid was washed with DCM and repurified with HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 minutes) to give (6- (1H-indazol-4-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol (16.8mg, 17% yield). MS (ESI cation) M/z373(M + H) ⁺。¹H NMR(d6-DMSO)δ12.71(s，1H)，9.80(s，1H)，8.66(s，1H)，8.34(d，J＝1.96Hz，1H)，8.26(s，1H)，8.07(d，J＝7.82Hz，1H)，7.33(t，J＝8.4Hz，1H)，7.18(d，J＝8.41Hz，1H)，4.56(s，2H)，2.94(s，3H)。

Example 73: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5-vinylpyridin-2-amine

Step 1: 2-fluoro-5-vinylpyridines

5-bromo-2-fluoropyridine (Aldrich 99%, 5.14g, 29.2mmol) and potassium vinyltrifluoroborate (Aldrich, St. Louis, MO, 4.23g, 31.6mmol) were suspended in THF (80mL) and water (9.0mL) and dichlorobis (triphenylphosphine) palladium (II) (0.627g, 0.893mmol) and cesium carbonate (28.5g, 87.6mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (85 ℃) and stirred overnight under nitrogen. Subsequently, the reaction was cooled to room temperature and diluted with water (125 mL). The layers were separated and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated (using an unheated water bath and rotary evaporator pressure of 43-70 torr). The crude material was purified on a silica gel filter (about 3 inches) with DCM and fractions with product were collected, concentrated and dried briefly under high vacuum. Using Et to the material₂O triturated and filtered, and the solid was taken up in Et₂And O washing. The filtrate was concentrated and dried twice each for about 10 seconds under high vacuum to give 2-fluoro-5-vinylpyridine, which was used in the next step.

Step 2: 2-fluoro-5-vinylpyridin-3-ylboronic acid

2-fluoro-5-vinylpyridine (64.8mg, 0.526mmol) was dissolved in THF (2.0mL) and the reaction flask was cooled in a dry ice/acetone bath. Subsequently, n-butyllithium (1.6M solution in hexane, 0.40mL, 0.64mmol) was added dropwise via syringe to turn the solution red. The reaction was stirred at-78 ℃ for 45 minutes and then triisopropyl borate (Aldrich, st. louis, MO 98 +%, 0.190mL, 0.826mmol) was added and the reaction was allowed to warm slowly to room temperature (80 minutes after removal of the dry ice/acetone bath). The reaction was stirred at room temperature for 45 minutes and then quenched with water. The layers were separated and the organic phase was discarded. The aqueous phase was treated with 5N HCl to reduce the pH from 9 to 4. Subsequently, the aqueous phase was extracted with 10: 1 DCM/MeOH, and the organic extracts were combined and set aside. In a separate flask, 2-fluoro-5-vinylpyridine (4.15g, 33.7mmol) was decanted from the solid precipitate and washed with THF. 2-fluoro-5-vinylpyridine was dissolved in THF (120mL) and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Then, via syringeA solution of n-butyllithium (1.6M in hexane, 25.5mL, 40.8mmol) was added to turn the yellow solution to a deep red color. The reaction was stirred for 50 minutes at-78 ℃ and then triisopropyl borate (Aldrich, st. louis, MO 98 +%, 11.5mL, 50.0mmol) was added via syringe and the reaction was allowed to warm to room temperature (the dry ice/acetone bath was removed after 90 minutes). Approximately 5 hours after the addition of triisopropyl borate, the reaction was quenched with water (125ml) slowly at the beginning. The biphasic solution was stirred for 15 min and then the layers were separated. The organic phase was extracted once with saturated sodium bicarbonate. The sodium bicarbonate wash was discarded. The organic phase was extracted twice with 1N NaOH (60mL and then 50 mL). The aqueous extracts were combined, treated with concentrated HCl to reduce the pH to 4, and extracted with 10: 1 DCM/MeOH. These organic extracts contain no product and are therefore discarded with the aqueous secondary extract solutions. The original aqueous phase (from the initial phase separation after quenching the reaction with water) was treated with 5N HCl to reduce the pH to about 3-4. This aqueous phase was extracted with 10: 1 DCM/MeOH. These organic extracts were combined with the organic extract from the first reaction, concentrated and dried at room temperature under high vacuum to give 2-fluoro-5-vinylpyridin-3-ylboronic acid (882mg, 61% pure, 11% yield over 2 steps). MS (ESI cation) M/z 168(M + H) ⁺。

And step 3: 6- (2-fluoro-5-vinylpyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (984mg, 3.89mmol), 2-fluoro-5-vinylpyridin-3-ylboronic acid (882mg, 5.28mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphino) dichloropalladium (138mg, 0.195mmol) and potassium acetate (1.212g, 12.35mmol) were suspended in ethanol (12.0mL) and water (2.4mL) and the flask was fitted with a reflux condenser and nitrogen bubbled through the suspension for about 15 seconds. Subsequently, the flask was placed in a pre-heated oil bath (80 ℃) and stirred under nitrogen for 1 h. The reaction was cooled to room temperature, diluted with water (20mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel column (25: 1 to 20: 1 DCM/2N aqueous ammonia in MeOH) to give6- (2-fluoro-5-vinylpyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine, which was used in the next step. MS (ESI cation) M/z 340(M + H)⁺。

And 4, step 4: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-vinylpyridin-2-amine

6- (2-fluoro-5-vinylpyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (1.007g, 2.967mmol) and 5-amino-2-methoxypyridine (0.369g, 2.97mmol) were dissolved in THF (25mL) and the reaction flask cooled in an ice-water bath. Subsequently, LiHMDS (Aldrich, st. louis, MO, 1.0M in THF, 9.0mL, 9.0mmol) was added via syringe and the reaction stirred under nitrogen for 35 minutes. Subsequently, it was poured into water (50mL), and the layers were separated. The aqueous phase was extracted with DCM and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on silica gel column (40: 1 DCM/2N aqueous ammonia in MeOH to 30: 1 DCM/2N aqueous ammonia in MeOH) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-vinylpyridin-2-amine (410.3mg, 85% purity, 20% yield over 2 steps). MS (ESI cation) M/z 444(M + H) ⁺。

And 5: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5-vinylpyridin-2-amine

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-vinylpyridin-2-amine (76.3mg, 0.172mmol) was dissolved in DCM (2.9mL) and trifluoroacetic acid (Aldrich, st.louis, MO, hplc grade, 0.60mL, 7.8mmol) was added via syringe. The reaction was stirred at room temperature for 35 min, concentrated, treated with MeOH and filtered. Using the solid with Et₂O wash, but not pure enough (HPLC showed > 95%). Thus, the solid and filtrate were combined, concentrated, treated with 2N aqueous ammonia dissolved in MeOH, and concentrated again. Using Et to the material₂O treatment, but this does not precipitate the product. Thus, it was concentrated, treated with water and filtered. Washing the solid with waterBut still not 95% pure. Thus, the solid was collected and purified by HPLC (10% to 100% MeCN/water, total flow rate 100mL/min over 30 min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5-vinylpyridin-2-amine (68.6 mg). MS (ESI cation) M/z 360(M + H)⁺。¹H NMR(d6-DMSO)δ12.70(s，1H)，9.98(s，1H)，8.65(s，1H)，8.55(d，J＝2.54Hz，1H)，8.40(d，J＝2.35Hz，1H)，8.19(dd，J＝8.8Hz，2.74Hz，1H)，6.86(d，J＝8.8Hz，1H)，6.79(dd，J＝17.5Hz，10.9Hz，1H)，5.78(d，J＝16.4Hz，1H)，5.26(d，J＝11.0Hz，1H)，3.85(s，3H)，2.86(s，3H)。

Example 74: 5-Ethyl-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-vinylpyridin-2-amine (62.0mg, 0.140mmol) and palladium on charcoal (Aldrich, St. Louis, MO 10% Pd, 19.1mg) were added to MeOH (2.0mL) and TFA (0.30 mL). The reaction flask was evacuated and backfilled with hydrogen and the reaction was stirred at room temperature for 1 hour. Subsequently, the hydrogen balloon pressure was removed and stirring was continued at room temperature for 90 minutes without hydrogen balloon pressure. Subsequently, the reaction flask was fitted with a reflux condenser and placed in a pre-heated oil bath (45 ℃ -50 ℃) and stirring continued overnight under nitrogen. The reaction was cooled to room temperature and passed through CeliteThe pad was filtered and washed with DCM and MeOH and a few drops of TFA. The filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). The fractions with product were collected, concentrated and dried under high vacuum in a water bath (about 50 ℃). The material was then treated with Et₂O, MeOH and Et₂O wash, collect and dry under high vacuum overnight to give 5-ethyl-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine (17.8mg, 35% yield). MS (ESI cation) M/z 362(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.53(s，1H)，9.72(s，1H)，8.62(s，1H)，8.53(d，J＝2.54Hz，1H)，8.22-8.13(m，2H)，6.84(d，J＝8.8Hz，1H)，3.84(s，3H)，2.85(s，3H)，2.65(q，J＝7.37Hz，2H)，1.26(t，J＝7.53Hz，3H)。

Example 75: 2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) ethanol

Step 1: 2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol

Tetrahydrofuran (2.0mL) and cyclohexene (0.42mL, 4.15mmol) were cooled in an ice-water bath under nitrogen, and borane-dimethyl sulfide complex (0.19mL, 2.0mmol) was added via syringe. The reaction was allowed to warm to room temperature while stirring under nitrogen over 90 minutes to yield a suspension. In a separate flask, N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-vinylpyridin-2-amine (185.4mg, 0.418mmol) was dissolved in THF (6.0mL) and to the solution was added the resulting 1.6mL suspension in the first flask. The addition was made dropwise via syringe, with gas evolution taking place. The reaction was stirred at room temperature under nitrogen for 40 minutes, and then cooled in an ice/water bath and washed with MeOH (4.0mL), 2N aqueous NaOH (4.8mL), and 30% H₂O₂The aqueous solution (6.5mL) was quenched and all added via syringe. The reaction was stirred while it was allowed to warm to room temperature. After 75 minutes, more 2N aqueous NaOH (1.2mL) and aqueous hydrogen peroxide (3.5mL) were added and stirring was continued. Subsequently, at 3 hours thereafter, a 5N NaOH aqueous solution (1.60mL) and 30% hydrogen peroxide were added Aqueous solution (8.0mL) and stirring was continued for an additional 1 hour. Subsequently, the reaction was diluted with water (20mL), DCM (20mL) and MeOH (ca. 1mL) and allowed to stand at room temperature overnight. Subsequently, the layers were separated and the aqueous phase was extracted with 10: 1 DCM/MeOH. The organic extracts were combined, concentrated and used in step 2.

Step 2: 2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) ethanol

Crude 2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol (193mg, 0.418mmol) was dissolved in MeOH (5.0mL) and TFA (0.50mL, 6.49mmol) was added via syringe. The reaction was stirred at room temperature for 2.5 hours, and then more TFA (0.9mL) was added, and stirring was continued. Subsequently, the flask was fitted with a reflux condenser and placed in a preheated oil bath (60 ℃) and stirring was continued for 75 minutes. (this 75 minute period interruption was close to a 15 minute period during which the flask was not in the oil bath). The reaction was cooled to room temperature and passed through CeliteThe pad was filtered and washed with DCM and MeOH. The filtrate was concentrated and purified by preparative HPLC (10% to 100% MeCN in water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give 2- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) ethanol (56.0mg, 35% yield over 2 steps). MS (ESI cation) M/z 378(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.50(s，1H)，9.66(s，1H)，8.62(s，1H)，8.53(s，1H)，8.20-8.14(m，2H)，6.86(d，J＝8.8Hz，1H)，3.85(s，3H)，3.66(t，J＝6.86Hz，2H)，2.85(s，3H)，2.76(t，J＝6.86Hz，2H)。

Example 76: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol

Step 1: 6- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (3.200g, 12.66mmol), 5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl boronic acid (3.165g, 14.86mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphino) dichloropalladium (514.9mg, 0.7272mmol) and potassium acetate (4.180g, 42.59mmol) were suspended in EtOH (50mL) and water (10mL) and nitrogen bubbled through the suspension for about 15 seconds. Subsequently, the flask was fitted with a reflux condenser and placed in a preheated oil bath (80 ℃) and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, poured into water (125mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (600 mL sintered filter with about 3 inches of silica gel, 40: 1 DCM/2N aqueous ammonia in MeOH). The fractions with product were collected, concentrated and washed with hexane repeatedly and dried to give 6- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (4.557g) which was used in the next step. MS (ESI cation) M/z 386(M + H) ⁺。

Step 2: 5- (1, 3-Dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine

6- (5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (4.557g, 11.82mmol) and 5-amino-2-methoxypyridine (1.507g, 12.14mmol) were dissolved in tetrahydrofuran (80mL) and cooled in an ice-water bath. Subsequently, LiHMDS (Aldrich, 1.0M in solution THF, 36.0mL, 36.0mmol) was added via syringe over about 10 minutes. The reaction was stirred at 0 ℃ under nitrogen for 40 minutes and then treated with water (100mL) and warmed to room temperature. The layers were separated and the aqueous phase was extracted with DCM. The aqueous phase was diluted with brine and extracted further with DCM. To be combinedThe organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (600 mL sintered filter with about 3 inches of silica gel, 80: 1 DCM/2N aqueous ammonia in MeOH to 50: 1 DCM/2N aqueous ammonia in MeOH) to give 5- (1, 3-dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (4.500 g, 71% purity, 52% yield over 2 steps). MS MS (ESI cation) m/z 446. C ₂₃H₂₃N₇O₃The accurate mass calculation value of (2): 445(M + -C)₂H₄O)。¹H NMR(CDCl₃，400MHz)δ12.69(s，1H)，9.91(s，1H)，8.44(d，J＝2.74Hz，1H)，8.41(d，J＝2.15Hz，1H)，8.29(s，1H)，8.23(dd，J＝8.80Hz，2.74Hz，1H)，6.79(d，J＝8.80Hz，1H)，5.94(s，1H)，5.87(dd，J＝10.56Hz，2.15Hz，1H)，4.24-4.17(m，3H)，4.12-4.05(m，2H)，3.96(s，3H)，3.88-3.79(m，1H)，2.91(s，3H)，2.19-2.00(m，3H)，1.93-1.77(m，3H)。

And step 3: 6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde

5- (1, 3-Dioxolan-2-yl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (3.042g, 6.21mmol) was dissolved in tetrahydrofuran (50mL) and then 2.0M hydrochloric acid (15.5mL, 31.0mmol) was added via syringe followed by THF rinse (1.5 mL). The reaction was stirred at room temperature for 20 minutes, diluted with water (20mL) and filtered. The solid was washed with water, collected, and dried over the weekend under high vacuum to give 6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (1.7g, 61% yield). MS (ESI cation) M/z 446(M + H)⁺。¹H NMR(CDCl₃，400MHz)δ13.33(s，1H)，10.29(d，J＝2.15Hz，1H)，10.00(s，1H)，8.78(d，J＝1.96Hz，1H)，8.48(d，J＝2.74Hz，1H)，8.35(s，1H)，8.25(dd，J＝8.8Hz，2.74Hz，1H)，6.84(d，J＝8.8Hz，1H)，5.89(dd，J＝10.47Hz，2.05Hz，1H)，4.23(d，J＝11.74Hz，1H)，3.98(s，3H)，3.88-3.82(m，1H)，2.93(s，3H)，2.23-2.03(m，3H)，1.90-1.65(m，3H)。

And 4, step 4: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (157mg, 0.352mmol) was dissolved in methanol (5.0mL) and sodium borohydride (21.6mg, 0.571mmol) was added. The reaction was stirred at room temperature for 75 minutes and then more NaBH was added ₄(26mg, 0.69mmol) together with DCM (3 mL). After 40 more minutes, 5N aqueous HCl (0.50mL, 2.5mmo1) was added along with MeOH washes (about 1mL) and stirring continued at room temperature overnight. Subsequently, the reaction was diluted with water (20mL) and the suspension was filtered. Filtration was slow, the filtrate was discarded and the solid was collected and the unfiltered material was extracted with 10: 1 DCM/MeOH. These organic extracts were combined with the collected solids while the aqueous suspension was filtered again. The solid from this filtration was combined with the solid and the organic extract was collected earlier. The resulting solution was concentrated, treated with EtOAc, and filtered. The solid was washed with EtOAc and MeOH, but the solid was not 95% pure by HPLC, so the filtrate and solid were collected, concentrated, treated with DCM and filtered again. The solid was washed with DCM. HPLC showed the product to still not be 95% pure, so the filtrate and solid were collected again, concentrated, and this time purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol (91.1mg, 71% yield). MS (ESI cation) M/z 364(M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ12.62(s，1H)，9.79(s，1H)，8.62(s，1H)，8.54(s，1H)，8.24(s，1H)，8.17(d，J＝8.41Hz，1H)，6.86(d，J＝8.61Hz，1H)，4.52(s，2H)，3.85(s，3H)，2.86(s，3H)。

Example 77: 5- ((4-Methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (187.1mg, 0.4200mmol) was suspended in EtOH (3.8mL) and titanium tetraisopropoxide (Fluka, Buchs, Switzerland, 0.25mL, 0.84mmol) and 4-methoxyaniline (Aldrich, St. Louis, MO, 81.9mg, 0.665mmol) were added. After about 15 minutes, DCM (2mL) was added and the reaction stirred at room temperature under nitrogen overnight. Subsequently, sodium borohydride (36mg, 0.95mmol) was added along with DCM (3mL) and stirring was continued at room temperature, resulting in a precipitate. After stirring for 1 hour, the suspension was treated with MeOH (1.5mL) and 5N HCl (0.60 mL). Stirring was continued overnight at room temperature. Subsequently, the reaction was treated with water (20mL) and filtered, and the solid was washed with water. The solid and unfiltered material were combined together, concentrated and treated with MeOH, and filtered. Filtration was slow, so instead the suspension was concentrated, treated with TFA and DMSO, and filtered with DCM and MeOH. This filtration is also slow, so instead the suspension is passed through Celite (diatomaceous earth) pad filtration. The filtrate was concentrated, but was not filtered for HPLC purification despite treatment with DMSO, TFA, MeOH and DCM. Thus, this solution was concentrated and the microsuspension was passed through Celite(diatomaceous earth) pad filtration. This filtrate was purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give 5- ((4-methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine (149.4mg, 76% yield). MS (ESI cation) M/z469(M + H)⁺。¹H NMR(d6-DMSO，400MHz)δ12.60(s，1H)，9.72(s，1H)，8.62(s，1H)，8.53(d，J＝2.54Hz，1H)，8.27(s，1H)，8.14(dd，J＝9.10Hz，2.45Hz，1H)，7.22(s，1H)，7.09(s，1H)，6.97(s，2H)，6.90-6.80(m 3H)，4.38(s，2H)，3.85(s，3H)，3.67(s，3H)，2.85(s，3H)。

Example 78: 5- ((3-Methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (191.7mg, 0.4303mmol) was suspended in ethanol (4.0mL) and titanium tetraisopropoxide (0.26mL, 0.878mmol) and 3-methoxyaniline (0.080mL, 0.716mmol) were added. The reaction was stirred at room temperature under nitrogen overnight, and then more DCM (about 3mL) was added along with more Ti (OiPr)₄) (0.13mL, 0.44mmol) and 3-methoxyaniline (0.050mL, 0.45 mmol). Stirring was continued overnight and then sodium borohydride (32.3mg, 0.854mmol) was added along with MeOH (1 mL). The reaction was stirred at room temperature for 35 minutes and then quenched with 5N HCl (0.60mL) added dropwise. Stirring was continued over the weekend at room temperature. Subsequently, the suspension was diluted with DCM and MeOH and passed through Celite (diatomaceous earth) pad filtration. Mixing CeliteThe (Celite) pad was washed with DCM and MeOH, and the filtrate was concentrated, treated with water and passed through a sintered filter again (no Celite)(diatomaceous earth)) to filter. The solid was washed with water, collected and dried under high vacuum in a water bath at 50 ℃ andfollowed by drying at room temperature overnight to give 5- ((3-methoxyphenylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine (162.8mg, 81% yield). MS (ESI cation) M/z469(M + H)⁺.¹H NMR(d6-DMSO，400MHz)δ12.53(s，1H)，9.74(s，1H)，8.62(s，1H)，8.51(d，J＝2.54Hz，1H)，8.27(d，J＝2.15Hz，1H)，8.13(dd，J ＝8.80Hz，2.74Hz，1H)，7.00(t，J＝8.12Hz，1H)，6.87(d，J＝8.80Hz，1H)，6.38-6.17(m，3H)，4.29(s，2H)，3.85(s，3H)，3.66(s，3H)，2.84(s，3H)。

Example 79: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-3-ylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (153.3mg, 0.3441mmol) was suspended in ethanol (3.0mL) and dichloromethane (3.0mL), 3-aminopyridine (65.9mg, 0.700mmol) and titanium tetraisopropoxide (0.15mL, 0.51mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (50 ℃ -60 ℃) and stirred under nitrogen for 6 hours. Subsequently, the reaction was cooled to room temperature and allowed to stir overnight. After stirring overnight, sodium borohydride (26.7mg, 0.706mmol) was added and stirring continued at room temperature. After 35 minutes, the reaction was treated with 5N HCl (0.60mL) added dropwise and gas evolution occurred. The reaction was diluted with MeOH (about 1mL, before and after HCl addition) and stirred at room temperature for 5 hours. Subsequently, the reaction flask was fitted with a reflux condenser and placed in an oil bath heated to 50 ℃. Stirring was continued at this temperature for 1 hour and then the reaction was allowed to cool to room temperature. The suspension was diluted with DCM and MeOH and passed through Celite The pad was filtered and washed with DCM and MeOH. Will be provided withThe filtrate was concentrated and treated with water and filtered. The solid was collected and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-3-ylamino) methyl) pyridin-2-amine (27.3mg, 18%). MS (ESI cation) M/z 440(M + H)⁺。¹H NMR(d6-DMSO，400MHz)δ13.63(br s，1H)，12.59(s，1H)，9.79(s，1H)，8.57(s，1H)，8.54(d，J＝2.74Hz，1H)，8.35(d，J＝2.35Hz，1H)，8.19-8.10(m，2H)，8.04(d，J＝ 1.56Hz，1H)，7.75-7.68(m，2H)，7.57(br s，1H)，6.85(d，J＝8.80Hz，1H)，4.45(s，2H)，3.85(s，3H)，2.85(s，3H)。

Example 80: n- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) pyridazin-3-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (106.1mg, 0.2382mmol) was suspended in ethanol (1.5mL) and dichloromethane (1.5mL), and pyridazin-3-amine (39.2mg, 0.412mmol) and titanium tetraisopropoxide (0.11mL, 0.37mmol) were added. The reaction was stirred at room temperature overnight, and then more DCM (1mL), 3-aminopyridazine (40.4mg, 0.425mmol), and Ti (OiPr) were added₄(0.12mL, 0.41 mmol). The flask was fitted with a reflux condenser and placed in a preheated oil bath (50 ℃) and stirred for 5 hours. Subsequently, the temperature was raised to 70 ℃ and stirring was continued overnight. More DCM was added along with more 3-aminopyridazine (35.2mg, 0.370mmol) and Ti (OiPr) ₄(0.10mL, 0.34mmol) and stirring was continued at 65 ℃ for 6 h. Subsequently, the oil bath temperature was raised to 70 ℃ and stirring was continued. After 45 minutes more DCM was added and stirring was continued overnight at 70 ℃. Subsequently, the reaction was cooled to room temperature and MeOH (1mL) was added, followed by sodium borohydride (25.8mg, 0.682 mmol). At room temperature, the reactionThe contents were stirred for 75 minutes and then 5N HCl (0.50mL) was added dropwise via syringe, and the flask connected to the reflux condenser was placed in a preheated oil bath (50 deg.C) and the reaction was stirred for 4.5 hours. Subsequently, the reaction was cooled to room temperature, diluted with DCM and MeOH, and passed through Celite(diatomaceous earth) pad filtration. Mixing CeliteThe pad was washed with DCM, MeOH, and a 1: 1 mixture of DCM and MeOH. The filtrate was concentrated and filtered again (this time without Celite)(diatomaceous earth) pad). The filtrate was concentrated and passed through Celite again(celite) filtration. The filtrate was purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give N- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) pyridazin-3-amine (17.4mg, 17% yield). MS (ESI cation) M/z 441(M + H) ⁺。¹H NMR(d6-DMSO，400MHz)δ13.65(br s，1H)，12.63(br s，1H)，9.60(br s，1H)，9.16(br s，1H)，8.61(d，J＝3.33Hz，1H)，8.57(s，1H)，8.55(d，J＝2.74Hz，1H)，8.38(d，J＝2.35Hz，1H)，8.16(dd，J＝8.90Hz，2.84Hz，1H)，7.78(dd，J＝9.39Hz，4.30Hz，1H)，7.51(d，J＝9.19Hz，1H)，6.86(d，J＝9.0Hz，1H)，4.62(d，J＝5.09Hz，2H)，3.85(s，3H)，2.85(s，3H)。

Example 81: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-4-ylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (88.7mg, 0.199mmol) was suspended in dichloromethane (1.5mL) and EtOH (1.5mL) and 4-aminopyridine (47.9mg, 0.509mmol) and titanium tetraisopropoxide (0.12mL, 0.41mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (50 ℃) and stirred overnight under nitrogen. Subsequently, more 4-aminopyridine (45.9mg, 0.488mmol) and Ti (OiPr) were added₄(0.12mL, 0.41mmol) along with more DCM and stirring continued over the weekend at 70 ℃.

The reaction was cooled to room temperature, diluted with DCM (1mL) and MeOH (1mL) and sodium borohydride (25.3mg, 0.669mmol) was added. The reaction was stirred at room temperature for 45 min, diluted with DCM and MeOH, and treated with 5N HCl (0.55 mL). The reaction flask was placed in a preheated oil bath (50 ℃) and stirred for 1 hour, and then the reaction was cooled to room temperature. The suspension was diluted with DCM and MeOH and passed through CeliteThe pad was filtered and washed with DCM and MeOH, and a 1: 1 mixture of the two solvents. The filtrate was concentrated, diluted with DMF (about 0.5mL) and passed through another Celite The pad was filtered and washed with DCM and MeOH. The filtrate was concentrated, diluted with DMSO, and passed through Celite again(celite) filtration and the filtrate was purified by HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min). Fractions with product were combined, concentrated and purified a second time by preparative HPLC (10% to 100% MeCN in water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-4-ylamino) -lYl) methyl) pyridin-2-amine (33.3mg, 38% yield). MS (ESI cation) M/z 440(M + H)⁺。¹H NMR(d6-DMSO，400MHz)δ13.16(br s，1H)，12.64(br s，1H)，9.79(br s，1H)，9.06(t，J＝4.89Hz，1H)，8.60(s，1H)，8.55(d，J＝2.74Hz，1H)，8.36(d，J＝2.35Hz，1H)，8.27(t，J＝5.97Hz，1H)，8.16(dd，J＝9.00Hz，2.74Hz，1H)，8.12(t，J＝6.26Hz，1H)，7.04(d，J＝7.04Hz，1H)，6.95(d，J＝8.80Hz，1H)，6.86(d，J＝8.80Hz，1H)，4.59(d，J＝5.48Hz，2H)，3.85(s，3H)，2.86(s，3H)。

Example 82: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-2-ylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (121.8mg, 0.2734mmol) and 2-aminopyridine (72.0mg, 0.765mmol) were suspended in dichloromethane (1.5mL) and ethanol (1.5mL) and titanium tetraisopropoxide (0.16mL, 0.54mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (70 ℃) and stirred under nitrogen. After 5 hours, the reaction was diluted with DCM and stirring was continued overnight. Subsequently, more 2-aminopyridine (63.6mg, 0.676mmol) and Ti (OiPr) were added ₄(0.18mL, 0.61mmol) and DCM and stirring was continued at 70 ℃ for about 6 hours. Subsequently, the reaction was cooled to room temperature and sodium borohydride (38.9mg, 1.028mmol) was added. The reaction was stirred at room temperature for 25 minutes and then 5N aqueous HCl (0.55mL) was added. The flask was placed in a pre-heated oil bath (50 ℃) and stirring was continued overnight. Subsequently, the reaction was cooled to room temperature, diluted with DCM and MeOH, and passed through CeliteThe pad was filtered and washed with a 1: 1 mixture of DCM and MeOH. Concentrating the filtrate, and treating with waterAnd (5) processing and filtering. The solid was washed with water, collected, treated with DMSO (about 1mL), diluted with DCM and filtered. Subsequently, the solid was washed with DCM, collected and purified by preparative HPLC (10% to 100% MeCN in water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-2-ylamino) methyl) pyridin-2-amine (62.7mg, 52% yield). MS (ESI cation) M/z 440(M + H)⁺。¹H NMR(d6-DMSO，400MHz)δ13.60(br s，1H)，12.63(s，1H)，9.80(s，1H)，9.01(br s，1H)，8.56(s，1H)，8.55(d，J＝2.54Hz，1H)，8.36(d，J＝2.35Hz，1H)，8.15(dd，J＝8.80Hz，2.74Hz，1H)，7.98(d，J＝6.26Hz，1H)，7.92(t，J＝7.43Hz，1H)，7.11(d，J＝9.0Hz，1H)，6.90(t，J＝6.46Hz，1H)，6.86(d，J＝9.0Hz，1H)，4.61(s，2H)，3.85(s，3H)，2.85(s，3H)。

Example 83: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((phenylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (122mg, 0.274mmol) was suspended in dichloromethane (1.5mL) and ethanol (1.5mL), and aniline (0.080mL, 0.88mmol) and titanium tetraisopropoxide (0.25mL, 0.84mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (70 ℃ -74 ℃) and stirred under nitrogen for 45 minutes. Subsequently, the reaction was cooled to room temperature and treated with sodium borohydride (39.8mg, 1.05mmol) along with MeOH (about 1 mL). The reaction was stirred at room temperature for 45 minutes, and then MeOH (ca. 1mL) and 5N aqueous HCl (0.55mL) were added. The reaction flask was placed in a preheated oil bath (50 ℃ -61 ℃) and stirred for 3.5 hours, and then the reaction was cooled to room temperature. The resulting suspension was diluted with DCM and MeOH and passed through Celite The pad was filtered and washed with DCM, MeOH, and a 1: 1 mixture of the two solvents. The filtrate was concentrated, treated with water and filtered, and the solid was washed with water, collected and washed with DCM. The solid was then purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 30 min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((phenylamino) methyl) pyridin-2-amine (92.0mg, 77% yield). MS (ESI cation) M/z 439(M + H)⁺。¹H NMR(d6-DMSO，400MHz)δ12.56(br s，1H)，9.77(s，1H)，8.62(s，1H)，8.52(d，J＝2.54Hz，1H)，8.29(d，J＝1.56Hz，1H)，8.15(dd，J＝8.90Hz，2.64Hz，1H)，7.10(t，J＝7.82Hz，2H)，6.85(d，J＝9.00Hz，1H)，6.71(d，J＝7.63Hz，2H)，6.60(t，J＝6.85Hz，1H)，4.29(s，2H)，3.85(s，3H)，2.85(s，3H)。

Example 84: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine.

Step 1: 4- ((6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

5- ((4- (tert-Butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (655mg, 1.931mmol), 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (586mg, 2.317mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich) (25.6mg, 0.097mmol) and potassium acetate (285mg, 4.83mmol) in ethanol (6.00mL, 103mmol) and H at 80 deg.C ₂O (1.00mL, 55.5mmol) mixture was heated for 2 h. After cooling, the reaction mixture was concentrated and the crude product was adsorbed onto a silica gel packed column and passed through a RediSepTeledyne ISCO, Lincoln, NE, column pre-packed with silica gel (pure hexane to 50% ethyl acetate in hexane) for chromatographic separation to give tert-butyl 4- ((6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.877g, 89%) as a pale yellow foam. LCMS (API-ES) M/z 512(M + H)⁺。

Step 2: 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

LiHMDS (1.0M in THF, 3.75mL, 3.75mmol) was added slowly to a stirred mixture of tert-butyl 4- ((6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.6397g, 1.250mmol) and 3-amino-6-methoxypyridine (Aldrich, St.Louis, MO; 186mg, 1.50mmol) in tetrahydrofuran (10mL, 1.250mmol) at 0 deg.C, and the mixture was stirred for 1H at the same temperature before adding NH₄Cl (aq) (10mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc (3X 15mL) and the combined organic layers were washed with brine, Na ₂SO₄Dried, concentrated and purified by flash column chromatography (hexanes to 50% ethyl acetate/hexanes) to give tert-butyl 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.577g, 0.937mmol, 74.9% yield) as a yellow foam. LCMS (API-ES) M/z 616(M + H)⁺。

And step 3: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine.

TFA (2.00mL) was added to a stirred mixture of tert-butyl 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (112mg, 0.182mmol) in DCM (2.00mL) and the mixture was stirred at room temperature for 1H. The mixture was concentrated and taken up with DCM,NaHCO₃(aqueous solution) and water (10 mL each). The separated aqueous layer was extracted with DCM (4X 20mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried, concentrated and purified by flash column chromatography (DCM to 10% MeOH in DCM) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine (15mg, 0.035mmol, 19.11% yield) as a yellow solid. LCMS (API-ES) M/z 432(M + H) ⁺；¹H NMR(400MHz，d6-DMSO)δ12.63(br.s.，1H)9.69(br.s.，1H)8.60(br.s.，1H)8.54(br.s.，1 H)7.86-8.30(m，3H)6.85(d，J＝9.19Hz，1H)3.85(s，3H)3.52(br.s.，2H)2.90(br.s.，4H)2.85(br.s.，3H)2.37-2.49(m，4H)。

Example 85: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine

Step 1: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine

To a stirred mixture of tert-butyl 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (155mg, 0.252mmol) in DCM (3mL, 46.6mmol) was added TFA (3.00mL, 38.9mmol) and the mixture was stirred at room temperature for 1H. The reaction mixture was concentrated and then diluted with DCM, NaHCO₃(aqueous solution) and water (0 mL each). The separated aqueous layer was extracted with DCM (3X 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give crude N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine.

Step 2: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine

The crude residue from step 1 was taken up in DCM (3mL, 46.6mmol), cooled to 0 ℃, and DIEA (0.132mL, 0.755mmol) and methanesulfonyl chloride (0.029mL, 0.378mmol) were then added. The mixture was stirred at the same temperature for 1h and then with NH ₄Cl (aq) and water (10mL each) and diluted with DCM (10 mL). The separated aqueous layer was extracted with DCM (2X 15mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried, concentrated and chromatographed via a predi-Sep pre-packed silica gel column (DCM to 10% MeOH in DCM) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine as a yellow solid (21mg, 16%). LCMS (API-ES) M/z510(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.58(br.s.，1H)12.62(br.s.，1H)9.73(br.s.，1H)8.62(s，1H)8.54(d，J＝2.54Hz，1H)8.22(d，J＝1.56Hz，1H)8.18(dd，J＝8.90，2.45Hz，1H)6.85(d，J＝8.80Hz，1H)3.85(s，3H)3.56(s，2H)3.01-3.18(m，4H)2.86(s，3H)2.86(s，3H)2.53(br.s.，4H)。

Example 86: 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid methyl ester

Following a procedure analogous to that in example 85, step 2, using N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine and methyl chloroformate (Aldrich, st. louis, MO), the title compound was isolated as a yellow solid in 55% yield. LCMS (API-ES) M/z 490(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.60(br.s.，1H)12.62(s，1H)9.74(s，1H)8.62(s，1H)8.54(d，J＝2.54Hz，1H)8.21(br.s.，1H)8.19(dd，J＝9.19，2.35Hz，1H)6.85(d，J＝8.80Hz，1H)3.85(s，3H)3.58(s，3H)3.52(s，2H)3.34-3.45(m，4H)2.86(s，3H)2.40(br.s.，4H)。

Example 87: 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide

Following a procedure analogous to that in example 85, step 2, using N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine and dimethylcarbamoyl chloride (Aldrich, st. louis, MO), the title compound was isolated as a yellow solid in 86% yield. LCMS (API-ES) M/z 503(M + H) ⁺；¹H NMR(400MHz， d6-DMSO)δ13.62(br.s.，1H)12.65(br.s.，1H)9.75(br.s.，1H)8.63(s，1H)8.54(br.s.，1H)7.93-8.32(m，2H)6.86(s，1H)3.85(s，3H)3.52(br.s.，2H)3.11(br.s.，4H)2.86(s，3H)2.72(s，6H)2.42(br.s.，4H)。

Example 88: 4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-sulfonamide

Following a procedure analogous to that in example 85, step 2, using N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine and dimethylsulfamoyl chloride (Aldrich, st. louis, MO), the title compound was isolated as a yellow solid in 8% yield. LCMS (API-ES) M/z 539(M + H)⁺；¹H NMR(400MHz，d6-DMSO)13.62(br.s.，1H)12.64(br.s.，1H)9.74(br.s.，1H)8.63(br.s.，1H)8.54(br.s.，1H)8.22(br.s.，1H)8.19(d，J＝9.39Hz，1H)6.85(d，J＝8.41Hz，1H)3.85(br.s.，3H)3.54(br.s.，2H)3.17(br.s.，4H)2.86(br.s.，3H)2.75(br.s.，6H)2.37-2.48(m，4H)。

Example 89: 1- (4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethanone

Triethylamine (42.2mg, 0.417mmol) and Ac were added at room temperature₂O (0.013mL, 0.139mmol) was added to a stirred solution of N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (piperazin-1-ylmethyl) pyridin-2-amine (60mg, 0.139mmol) in DCM (3mL, 46.6mmol) and DMF (0.5mL, to improve solubility). The mixture was stirred for 1h and then with NH₄Cl (aq), water (10mL) and EtOAc (10mL each). The separated aqueous layer was extracted with EtOAc (3X 15mL) and the combined organic layers were washed with brine, Na₂SO₄Dried and concentrated. The residue was dissolved in CH with excess at 60 deg.C ₃Na in CN (5mL)₂CO₃(50mg) and water (1mL) were heated for 2 h. The resulting suspension was concentrated and washed with a minimal amount of cold MeOH to give 1- (4- ((6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethanone as a yellow solid (37mg, 56%). LCMS (API-ES) M/z474(M + H)⁺；¹H NMR(400MHz，d6-DMSO)δ13.63(br.s.，1H)12.64(br.s.，1H)9.73(br.s.，1H)8.60(s，1H)8.54(br.s.，1H)8.03-8.30(m，2H)6.85(d，J＝8.61Hz，1H)3.85(s，3H)3.53(br.s.，2H)3.39-3.49(m，4H)2.85(s，3H)2.25-2.46(m，4H)1.97(s，3H)。

Example 90: n5- (4-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

A mixture of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.115g, 0.254mmol) and 4-anisidine (0.117mL, 1.018mmol) (Aldrich, St. Louis, MO) in THF (10mL) was treated with sodium tert-butoxide (0.073g, 0.763mmol) (Aldrich, St. Louis, MO) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.025g) (Strem Chemicals, Inc., Newburyport, MA). Deoxidizing the mixture and adding into N₂Adding Pd₂(dba)₃(0.023g, 0.025mmol) (Strem Chemicals, Inc., Newburyport, MA). The flask was fitted with a reflux condenser, which was then placed in a pre-heated bath at 90 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water (10mL) and diluted with 4: 1 CH ₂Cl₂MeOH (5X 25mL) and extracted from brine. The combined organic extracts were extracted with NaHCO₃Washed with saturated aqueous solution (20mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. This crude material was adsorbed onto a silica gel packed column and chromatographed via RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (80g) to dissolve in CH₂Cl₂Gradient from 1% to 5% MeOH for 30 min to give N5- (4-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridine-2, 5-diamine as a tan oil. This material was diluted with methanol (3mL) and TFA (1.5mL) and placed in a pre-heated (60 ℃ C.) bath. The mixture was stirred under an inert atmosphere for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and then diluted with DCM. The mixture was made basic with 10N aqueous NaOH, diluted with water (15mL) and CH₂Cl₂(3X 15 mL). The organic extracts were washed with water (1X 10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. Adsorbing the substance onto silica gel packed columnAnd pre-filled with silica gel column (40g) by chromatography via Redi-Sep to dissolve in CH ₂Cl₂Gradient elution of 1% to 8% MeOH in 25 min to purify to afford N5- (4-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine as a tan solid (0.009g, 0.020mmol, 7.78% yield). MS (ESI cation) M/z 455(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ9.62(s，1H)；8.59(s，1H)；8.51(s，1H)；8.14(m，2H)；7.00(d，J＝8.80Hz，2H)；6.84(d，J＝8.80Hz，3H)；3.84(s，3H)；3.70(s，3H)；2.86(s，3H)。

Example 91: N5-benzyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

A solution of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.160g, 0.354mmol) and benzylamine (0.155mL, 1.416mmol) (source: Aldrich) in THF (10mL) was treated with sodium tert-butoxide (0.102g, 1.062mmol) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.030 g). Deoxidizing the mixture and adding into N₂Pd for lower use₂(dba)₃(0.032g, 0.035 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heated bath at 90 ℃ and stirred overnight. The reaction mixture was washed with NaHCO₃Saturated aqueous solution (10mL) diluted and CH₂Cl₂(2X 25 mL). The combined organic extracts were extracted with NaHCO₃(20mL) washed and passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. This material was adsorbed onto a silica gel packed column and pre-filled with silica gel column (40g) by chromatography via Redi-Sep to dissolve in CH ₂Cl₂Gradient elution of 1% to 5% MeOH in (B) for 25 min to afford N5-benzyl-N2- (6-methoxy) as a tan solidPyridylpyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridine-2, 5-diamine. This material was charged to a glass microwave reactor vial along with 1N aqueous HCl (1mL) and THF (3 mL). The mixture was stirred and heated at 100 ℃ for 10min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was concentrated in vacuo and diluted with DCM and 1N aqueous NaOH. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was diluted with ether and the precipitate was collected by filtration and washed with ether (5 × 25 mL). This gave N5-benzyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine as a tan solid (0.065g, 0.148mmol, 41.9% yield). MS (ESI cation) M/z 439(M + H)⁺。¹H NMR(400MHz，CD₃OD)δ8.56(s，1H)；8.21(s，1H)；8.11(s，1H)；7.80(d，1H)；7.59(s，1H)；7.35(d，2H)；7.22(t，2H)；7.12(m，1H)；6.64(d，1H)；4.31(s，2H)；3.76(s，3H)；2.69(s，3H)。

Example 92: n2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -N5-phenylpyridine-2, 5-diamine

A solution of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.200g, 0.443mmol) and aniline (0.161mL, 1.770mmol) (Fluka, Buchs, Switzerland) in THF (10mL) was treated with sodium tert-butoxide (0.128g, 1.328mmol) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.030 g). Deoxidizing the mixture and adding into N ₂Pd for lower use₂(dba)₃(0.041g, 0.044 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heat bath at 80 ℃ and stirred overnight. The reaction mixture was washed with NaHCO₃Saturated aqueous solution (15mL) diluted and CH₂Cl₂(2×25mL)And (4) extracting. The combined organic extracts were extracted with NaHCO₃Washed with saturated aqueous solution (20mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. The crude oil and aqueous HCl1N solution (1.5mL) in THF (2.5mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 8min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was diluted with methanol and then concentrated. The mixture was triturated with acetonitrile and allowed to stir for 5 minutes. The precipitate was collected by filtration and washed with diethyl ether (3X 25 mL). This gave N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -N5-phenylpyridine-2, 5-diamine as a tan solid (0.180g, 0.424mmol, 96% yield). MS (ESI cation) M/z425(M + H)⁺。¹H NMR(400MHz，CD₃OD)δ9.85(s，1H)；8.52(s，1H)；8.41(s，1H)；7.87(s，1H)；7.52(d，J＝7.43Hz，2H)；7.39(d，J＝7.43Hz，1H)；7.21-7.29(m，2H)；7.10(s，2H)；7.00(d，1H)；6.88(s，1H)；3.98(s，3H)；2.83(s，3H)。

Example 93: n5- (2-methoxyethyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

A solution of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.150g, 0.332mmol) and 2-methoxyethylamine (0.114mL, 1.328mmol) (Aldrich, St.Louis, Mo.) in THF (10mL) was treated with sodium tert-butoxide (0.096g, 0.996mmol) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.030 g). Deoxygenating the mixture and applying Pd under N2₂(dba)₃(0.030g, 0.033 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heat bath at 80 ℃ and stirred overnight. The reaction mixture was diluted with water (10mL) and 4: 1CHCl₃Isopropanol (2X 20 mL). The combined organic extracts were extracted with NaHCO₃(20mL) washed and passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. The crude oil and aqueous HCl 1N (1.5mL) in THF (3mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 8min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was diluted with methanol and then concentrated. The mixture was triturated with acetonitrile and allowed to stir for 5 minutes. The precipitate was collected by filtration and washed with diethyl ether (3X 25 mL). The solid was neutralized with 1N aqueous sodium hydroxide solution and extracted with chloroform/isopropanol (4: 1). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was diluted with ether and the precipitate was collected by filtration, washed with ether (3X 20ml) and finally with hexane. This gave N5- (2-methoxyethyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine as a tan solid (0.035g, 0.086mmol, 25.9% yield). MS (ESI cation) M/z 407(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.06(s，1H)；9.20(s，1H)；8.60(s，1H)；8.47(s，1H)；8.12(d，1H)；7.90(d，J＝2.35Hz，1H)；6.82(d，1H)；5.42(s，1H)；3.82(s，6H)；3.58(t，J＝5.58Hz，2H)；3.26(s，3H)；2.85(s，3H)。

Example 94: N5-Ethyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

A solution of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.200g, 0.443 mmol) and ethylamine (0.553mL, 1.106mmol) (Aldrich, St. Louis, Mo.) in THF (10mL) was treated with sodium tert-butoxide (0.128g, 1.328mmol) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.030 g).Deoxidizing the mixture and adding into N₂Pd for lower use₂(dba)₃(0.041g, 0.044 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heat bath at 80 ℃ and stirred overnight. The reaction mixture was washed with NaHCO₃Saturated aqueous solution (10mL) diluted and CH₂Cl₂(2X 25 mL). The combined organic extracts were extracted with NaHCO₃(20mL) washed and passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. The crude oil and aqueous HCl 1N (1.5mL) in THF (3mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 8min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was concentrated and neutralized with SiliCycle silicon-carbonate silica gel (SiliCycle Inc., Quebec City, Candida) (0.800 g). The mixture was diluted with THF (5mL) and allowed to stir under an inert atmosphere overnight. The mixture was concentrated, diluted with DCM (10mL) and filtered. The desired product was released from the silica by washing with methanol (20 mL). The filtrate was concentrated and triturated with ether to give N5-ethyl-N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine as a tan solid (0.065g, 0.173mmol, 39.0% yield). MS (ESI cation) M/z 377(M + H) ⁺。 ¹H NMR(400MHz，CD₃OD)δ8.65(d，1H)；8.35(d，1H)；8.20(s，1H)；7.92(d，1H)；7.76(s，1H)；6.75(d，1H)；3.87(s，3H)；3.20(m，2H)；2.80(s，3H)；1.29(s，3H)。

Example 95: n5- (4-methoxybenzyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

Treatment of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-Methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.150g, 0.332mmol) and 4-methoxybenzylamine (0.108mL, 0.830mmol) (source: aldrich) in THF (10 mL). Deoxidizing the mixture and adding into N₂Pd for lower use₂(dba)₃(0.030g, 0.033 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heat bath at 80 ℃ and stirred overnight. The reaction mixture was washed with NaHCO₃Saturated aqueous solution (15mL) diluted and CH₂Cl₂(2X 25 mL). The combined organic extracts were extracted with NaHCO₃(20mL) washed and passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. The crude oil and aqueous HCl1N solution (1.5mL) in THF (2.5mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 8min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was diluted with MeOH, concentrated and neutralized with SiliCycle silicon-carbonate silica gel (SiliCycle inc., Quebec City, candida) (0.800 g). The mixture was diluted with THF/DCM (1: 1mL) and allowed to stir under an inert atmosphere overnight. The mixture was filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography via RediSep Teledyne ISCO, Lincoln, NE, pre-packed silica gel column (40g) and purified by elution with a gradient of 1% to 15% isopropanol in dichloromethane to give N5- (4-methoxybenzyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine as a tan solid (0.020g, 0.043mmol, 12.86% yield). MS (ESI cation) M/z 469(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.58(s，1H)；12.06(s，1H)；9.26(s，1H)；8.59-8.65(m，1H)；8.44(d，J＝2.15Hz，1H)；8.09(dd，J＝8.80，2.35Hz，1H)；7.81(d，J＝2.54Hz，1H)；7.38(d，J＝8.41Hz，2H)；6.88(d，J＝8.61Hz，2H)；6.78(d，J＝8.80Hz，1H)；5.75(s，1H)；4.26(s，2H)；3.76-3.88(m，3H)；3.71(s，3H)；2.80-2.90(m，3H)。

Example 96: n5- (3-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine

A solution of 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.230g, 0.509mmol) and 3-methoxyaniline (0.142mL, 1.272mmol) (Aldrich, St.Louis, Mo.) in THF (10mL) was treated with sodium tert-butoxide (0.147g, 1.527mmol) and 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.040 g). Deoxidizing the mixture and adding into N₂Pd for lower use₂(dba)₃(0.030g, 0.033 mmol). The flask was fitted with a reflux condenser, which was then placed in a pre-heat bath at 80 ℃ and stirred overnight. The reaction mixture was washed with NaHCO₃Saturated aqueous solution (15mL) diluted and CH₂Cl₂(2X 25 mL). The combined organic extracts were extracted with NaHCO ₃(20mL) washed and passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan oil. The crude oil and aqueous HCl 1N (1.5mL) in THF (2.5mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 8min (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was diluted with MeOH, concentrated and triturated with THF. The precipitate was collected by filtration and washed with diethyl ether (3X 25 mL). The solid (0.178g) was neutralized with a mixture of SiliCycle silicon-carbonate silica gel (SiliCycle Inc., Quebec City, Candida) (1.8g) in THF/DCM (1: 1; 10mL) and allowed to stir under an inert atmosphere overnight. The mixture was filtered through a fine sintered funnel. The desired material, still attached to the silica-polymer, was released by washing the silica with methanol (2x10mL) and concentrating. The residue was triturated with ether and the precipitate was collected by filtration to give N5- (3-methoxyphenyl) -N2- (6-methoxypyridin-3-yl) -one as a tan solid3- (2-methyl-9H-purin-6-yl) pyridine-2, 5-diamine (0.040g, 0.088mmol, 17.29% yield). MS (ESI cation) M/z 456(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.50(s，1H)；9.75(s，1H)；8.54(s，2H)；8.17(s，2H)；8.08(s，1H)；7.08(s，1H)；6.83(d，J＝8.80Hz，1H)；6.51-6.59(m，2H)；6.32(s，1H)；3.84(s，3H)；3.71(s，3H)；2.86(s，3H)。

Example 97: n- (3- (2-methyl-9H-purin-6-yl) -5-morpholinopyridin-2-yl) -1H-indazol-4-amine

Di-bromo-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (0.310g, 0.625mmol) (example 64 intermediate), morpholine (0.054g, 0.625mmol) (Aldrich, St.Louis, MO), sodium tert-butoxide (0.090g, 0.937mmol) (Aldrich, St.Louis, MO), tris (dibenzylideneacetone) dipalladium (0) (0.011g, 0.012mmol) (Aldrich, St.Louis, MO) and 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (0.022g, 0.037mmol) (Strem Chemicals, Inc, Newburyp, MA)A mixture of alkanes (100mL, 941mmol) was deoxygenated and heated at 95-100 deg.C under N₂Stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water (3 ×). The organic layer was concentrated, adsorbed onto a silica gel packed column and passed through RediSepTeledyne ISCO, Lincoln, NE, silica gel column pre-packed (120g), chromatographed on a gradient of 10% to 50% ethyl acetate in hexanes to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5-morpholinopyridin-2-amine (0.105g, 33% yield). The residue was purified with trifluoroacetic acid (Aldrich, Louis, MO) and dichloromethane to give N- (3- (2-methyl-9H-purin-6-yl) -5-morpholinopyridin-2-yl) -1H-indazol-4-amine. MS (ESI cation) M/z 419(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.46((br.s.，1H)；9.56((br.s.，1H)；8.56(d，J＝0.39Hz，1H)；8.51-8.53(m，1H)；8.12(d，J＝1.37Hz，2H)；6.82(d，J＝9.00Hz，1H)；3.78-3.86(m，7H)；3.11(br.s.，2H)；3.12(t，J＝4.89Hz，2H)；2.84(s，3H)。

Example 98: 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-3-ol

The title compound was synthesized following a procedure similar to example 97, substituting pyrrolidin-3-ol (Aldrich) for morpholine. MS (ESI cation) M/z 419(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.57(d，J＝4.11Hz，1H)；12.13(br.s.，1H)；8.65(br.s.，1H)；8.49(br.s.，1H)；8.35(br.s.，1H)；7.80(br.s.，1H)；6.79(d，J＝9.39Hz，1H)；5.12(br.s.，1H)；4.45(d，J＝4.50Hz，1H)；3.83(d，J＝1.96Hz，3H)；3.51(dd，J＝4.60，2.84Hz，1H)；3.50(br.s.，1H)；3.41(d，J＝7.82Hz，2H)；3.15(br.s.，1H)；2.85(br.s.，3H)。

Example 99: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) piperazin-1-yl) pyridin-2-amine

The title compound was synthesized according to a procedure similar to that of example 97, substituting 1-methylsulfonylpiperazine (Apollo Chemical Company, llc., Burlington, NC) for morpholine. MS (ESI cation) m/z 496(M+H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.66(br.s.，1H)；12.35(d，J＝2.15Hz，1H)；9.63(br.s.，1H)；8.63(d，J＝2.35Hz，1H)；8.52(br.s.，1H)；8.15(d，J＝0.78Hz，2H)；6.83(d，J＝0.98Hz，1H)；3.84(d，J＝0.78Hz，3H)；3.33(d，J＝0.59Hz，3H)；3.23(d，J＝5.48Hz，3H)；2.97(br.s.，1H)；2.96(d，J＝0.78Hz，3H)；2.85(s，3H)；1.04(dd，J＝6.46，1.17Hz，1H)。

Example 100: ((2S) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-2-yl) methanol

The title compound was synthesized according to a procedure similar to example 97, substituting morpholine by (S) -pyrrolidine-2-methanol (Aldrich, st. louis, MO). MS (ESI cation) M/z433(M + H)⁺。

Example 101: ((2R) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) pyrrolidin-2-yl) methanol

The title compound was synthesized according to a procedure similar to example 97, substituting morpholine by (R) -pyrrolidine-2-methanol (Aldrich, st. louir, MO). MS (ESI cation) M/z433(M + H)⁺。

Example 102: n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

Step 1: n- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

4' -Aminoacetanilide (69.0mg, 0.460mmol, Aldrich, St. Louis, MO) and 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (120mg, 0.383mmol) in THF (5mL) were charged to a glass microwave reaction vessel and Ar bubbled for 2 minutes and the reaction sealed. The reaction mixture was cooled to 0 ℃, lithium bis (trimethylsilyl) amide (1N in THF, 1.2mL, 1.2mmol) was added dropwise, and the solution was stirred at 0 ℃ for 1 h. After warming to room temperature, the reaction mixture was taken up with saturated NH₄Cl (10mL) was diluted and extracted with EtOAc (3X). The organic extracts were washed with brine and over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo. The crude material was passed through chromatography via RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (25g) to dissolve in CH ₂Cl₂2% to 10% 2M NH₃Was eluted with a gradient to provide N- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide (115mg, 0.259mmol, 67.7% yield) as a yellow solid. MS (ESI cation) M/z 444(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.68(s，1H)；9.86(s，1H)；9.72(d，J＝8.02Hz，1H)；8.86(s，1H)；8.34(d，J＝2.15Hz，1H)；7.75(d，J＝7.82Hz，2H)；7.56(d，J＝7.63Hz，2H)；6.98(s，1H)；5.84(d，J＝10.95Hz，1H)；3.92-4.22(m，1H)；3.64-3.87(m，1H)；2.90(s，3H)；2.30-2.33(m，1H)；2.03(s，3H)；1.99-2.01(m，2H)；1.79-1.82(m，1H)；1.48-1.71(m，2H)。

Step 2: n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

N- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-yl) pyridine from step 1A solution of phenylamino) phenyl) acetamide (90mg, 0.203mmol) in DCM (5mL) was treated with trifluoroacetic acid (5mL, 67.3 mmol). The solution was stirred at room temperature for 30 minutes. The mixture was cooled to 0 ℃ and neutralized with aqueous NaOH (10N). The suspension was diluted with water and extracted with DCM (50 mL). The aqueous layer was concentrated in high vacuum to give a suspension which was filtered to provide 300mg of a yellow solid. The crude material was passed through chromatography via RediSepTeledyne ISCO, Lincoln, NE, Pre-filled silica gel column (40g) to 2% to 10% 2M NH in DCM₃Purify by eluting with a MeOH gradient to provide N- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide as a yellow solid (20mg, 0.056mmol, 27.4% yield). MS (ESI cation) M/z360(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ13.75(s，1H)；10.03(d，J＝7.43Hz，1H)；9.81(s，1H)；8.18(s，1H)；7.77(d，J＝7.82Hz，2H)；7.52(d，J＝8.22Hz，2H)；6.85-6.92(m，1H)；2.74(s，3H)；2.02(s，3H)。

Example 103: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine

Step 1: (6-Fluoropyridin-3-yl) (4- (methylthio) phenyl) methanol

Magnesium turnings (0.214g, 8.79mmol) dissolved in a very small amount of THF were treated with 1, 2-dibromoethane (50. mu.L, ca.) and the mixture was allowed to stand until bubbling was observed (1 min). A solution of 4-bromothioanisole (Aldrich) (1.705g, 8.39mmol) in THF (20mL) was added dropwise and the mixture was stirred for 2h, occasionally heating to gentle reflux with a heat gun to give a cloudy, light yellow solution. The resulting Grignard solution was added dropwise to cooled 6-fluoronicotinaldehyde (Frontier scientific) in a dry ice/acetone bath over 10minc) (1.000g, 7.99mmol) in THF (10 mL). The mixture was stirred at-78 ℃ for 30min and then quenched by dropwise addition of 2N aqueous HCl (9.0mL, 2 eq). The cooling bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was extracted from water into EtOAc and dried (MgSO)₄) And concentrated to give (6-fluoropyridin-3-yl) (4- (methylthio) phenyl) methanol as a colorless oil (1.856g, 7.44mmol, 93% yield).¹H NMR (400MHz, d 6-DMSO). delta.8.23 (s, 1H); 7.87(t, J ═ 8.22Hz, 1H); 7.32(d, J ═ 8.02Hz, 2H); 7.22(d, J ═ 7.82Hz, 2H); 7.11(d, J ═ 8.41Hz, 1H); 6.11(br.s., 1H); 5.78(s, 1H); 2.44(s, 3H). M/z (ESI, cation) 250.0(M + H) ⁺。

Step 2: 2-fluoro-5- (4- (methylthio) benzyl) pyridine

A solution of (6-fluoropyridin-3-yl) (4- (methylthio) phenyl) methanol (1.716g, 6.88mmol) in DCM (3.0mL) was treated with trifluoroacetic acid (2.56mL, 34.4mmol) to give a green solution. The mixture was stirred for 5min and then triethylsilane (3.30mL, 20.65mmol) was added dropwise. The green color quickly dissipated to give a brownish solution and a brief exotherm was observed (DCM started refluxing). The mixture was stirred for 30min and then extracted from NaHCO₃The saturated aqueous solution was extracted into DCM. The DCM extract was dried (MgSO)₄) And purified by flash chromatography (5% to 7.5% EtOAc/hexanes) to give 2-fluoro-5- (4- (methylthio) benzyl) pyridine (89% over 2 steps) as a colorless oil.¹H NMR(400MHz，d6-DMSO)δ8.15(s，1H)；7.81(t，J＝8.22Hz，1H)；7.20(s，4H)；7.10(d，J＝8.41Hz，1H)；3.94(s，2H)；2.44(s，3H)。¹⁹F NMR (376MHz, d6-DMSO) delta-72.37 (s, 1F). M/z (ESI, cation) 234.0(M + H)⁺。

And step 3: 3- (5, 5-dimethyl-1, 3, 2-diBorane-2-yl) -2-fluoro-5- (4- (methylthio) benzyl) pyridine and 2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-ylboronic acid

A solution of LiTMP was generated by adding n-BuLi (1.6M in hexane) (1.653mL, 2.65mmol) dropwise to a solution of 2, 2, 6, 6-tetramethylpiperidine (0.467mL, 2.77mmol) in THF (5.0mL) cooled in an ice bath. . The resulting yellow solution was stirred for 15 min. A solution of 2-fluoro-5- (4- (methylthio) benzyl) pyridine (561.1mg, 2.405mmol) and triisopropyl borate (1.110mL, 4.81mmol) in THF (5.0mL) was cooled in a dry ice/acetone cooling bath and treated dropwise with the above LiTMP solution over 15min to give a yellow/brown solution. The solution was stirred at-78 ℃ for 1h and then slowly warmed to 20 ℃ over 1.5 h. The solution was stirred at 20 ℃ for a further 1h, before quenching with acetic acid (159mg, 2.65 mmol). The resulting pale yellow solution was treated with 2, 2-dimethylpropane-1, 3-diol (376mg, 3.61mmol) and stirred at 20 ℃. After 1h, LCMS indicated 12% of unreacted starting material with 88% m/z corresponding to the peak of 2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-ylboronic acid. After stirring at 20 ℃ for 16h, no change was observed by LCMS. The mixture was extracted from water into EtOAc (2 ×). LCMS indicated the product was still in the aqueous layer, so the aqueous layer was acidified (2M HCl) and re-extracted with EtOAc (2 ×) (LCMS showed success). The combined organic extracts were dried (MgSO) ₄) And concentrated to give an orange oil, which was partially crystallized (about 1.1 g). The mixture was re-extracted from 2M aqueous HCl into EtOAc and dried (MgSO)₄) And concentrated to give the crude product as an orange/brown oil (775mg), which crystallized to give a waxy solid.¹H NMR and¹⁹f NMR indicated 12% unreacted SM, 63% 3- (5, 5-dimethyl-1, 3, 2-diBorane-2-yl) -2-fluoro-5- (4- (methylthio) benzyl) pyridine (yield 63.5%) and 24% 2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-ylboronic acid (yield 24.5%). The crude product was used in the next step after further purification.

3- (5, 5-dimethyl-1, 3, 2-diBorane-2-yl) -2-fluoro-5- (4- (methylthio) benzyl) pyridine:¹H NMR(400MHz，d6-DMSO)δ8.20(d，J＝2.15Hz，1H)；7.91-7.96(m，1H)；7.18-7.22(m，4H)；3.93(s，2H)；3.74(s，4H)；2.44(s，3H)；0.94(s，6H)。¹⁹F NMR(377MHz，d6-DMSO)δ-63.56(s，1F)。

2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-ylboronic acid:¹H NMR(400MHz，d6-DMSO)δ8.40(br.s.，2H)；8.11-8.14(m，1H)；7.85-7.90(m，1H)；7.20(s，4H)；3.91(s，2H)；2.44(s，3H)。¹⁹F NMR(377MHz，d6-DMSO)δ-64.21(s，1F)。

and 4, step 4: 6- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

A mixture of the mixture of borate esters from step 3(549.5 mg; ca. 1.74mmol), 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (463mg, 1.831mmol), potassium acetate (513mg, 5.23mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO) (30.9mg, 0.044mmol) was placed in N ₂Under an atmosphere, and suspended in EtOH (15mL) and water (3.0 mL). The mixture was degassed and placed in N₂Then, the mixture was heated at 80 ℃ for 2.5 hours. The mixture was cooled and extracted with NaHCO₃The saturated aqueous solution was extracted into EtOAc and dried (MgSO)₄) And concentrated. The product was purified by flash chromatography (50% EtOAc/hexanes) to give 6- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine as a white foam (532.9mg, 1.185mmol, 68.0% yield).¹H NMR(400MHz，CDCl₃)δ8.28(s，1H)；8.18(s，1H)；8.14(d，J＝8.61Hz，1H)；7.16-7.23(m，2H)；7.09-7.16(m，2H)；5.84(d，J＝10.37Hz，1H)；4.18(br.s.，1H)；4.04(s，2H)；3.82(t，J＝11.15Hz，1H)；2.88(s，3H)；2.45(s，3H)；2.05-2.22(m，3H)；1.63-1.89(m，3H).¹⁹F NMR(376MHz，CDCl₃) Delta-70.26 (s, 1F). M/z (ESI, cation) 450.0(M + H)⁺。

And 5: 6- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

A solution of 6- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (532.9mg, 1.185mmol) in DCM (10mL) was cooled in an ice bath and treated with mCPBA (Aldrich, St. Louis, Mo.; anhydrous) (532mg, 3.08mmol) added portionwise over 5 min. The mixture was stirred for 2.5h, after which time LCMS indicated completion. NaHCO with excess sodium thiosulfate (2mL) was added₃The aqueous solution was saturated and the mixture was stirred for 10 min. Subsequently, the product is isolated from NaHCO ₃The saturated aqueous solution was extracted into EtOAc and dried (MgSO)₄) And concentrated to give 6- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine as a pale yellow foam (559.7mg, 1.162mmol, 98% yield).¹H NMR(400MHz，CDCl₃)δ8.28(s，1H)；8.22(s，1H)；8.16(d，J＝8.61Hz，1H)；7.88(d，J＝7.63Hz，2H)；7.43(d，J＝7.83Hz，2H)；5.84(d，J＝10.17Hz，1H)；4.12-4.24(m，3H)；3.82(t，J＝11.35Hz，1H)；3.03(s，3H)；2.88(s，3H)；1.98-2.23(m，3H)；1.63-1.90(m，3H)。¹⁹F NMR(376MHz，CDCl₃) Delta-69.21 (s, 1F). M/z (ESI, cation) 481.9(M + H)⁺。

Step 6: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine

6-methoxy-3-aminopyridine (Aldrich) (214. mu.L, 2.00mmol) was dissolved in THF (1.80mL) and cooled in an ice bath. LiHMDS (2.00mL, 1.0M in THF, 2.0mmol) was added dropwise over 5 min. The resulting dark brown solution was stirred for 30min before use. A solution of 6- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (92.6mg, 0.192mmol) in THF (1.0mL) was cooled in an ice bath and treated dropwise with 0.85mL of the above aniline solution (0.425mmol) over 15min to give a dark red solution. In a complete reaction, 5min after completion of addition, by LCMS (21)5nm) 85% conversion to the desired product was observed. After another 30min, the reaction was checked and appeared to have stopped, so an additional 0.20mL of aniline solution was added dropwise. The mixture was stirred for 10min and then quenched by the addition of water (0.2 mL). The product is obtained from NaHCO ₃The saturated aqueous solution was extracted into EtOAc and dried (MgSO)₄) Concentrated and purified by flash chromatography (50% to 60% to 70% EtOAc/hexanes) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine (94.5mg, 0.161mmol, 84% yield) as a dark yellow foam.¹H NMR(400MHz，CDCl₃) δ 12.44(s, 1H); 9.61(d, J ═ 2.15Hz, 1H); 8.41(d, J ═ 2.74Hz, 1H); 8.25(s, 1H); 8.19(dd, J ═ 8.80, 2.74Hz, 1H); 8.14(d, J ═ 2.15Hz, 1H); 7.86(d, J ═ 8.22Hz, 2H); 7.47(d, J ═ 8.02Hz, 2H); 6.77(d, J ═ 8.80Hz, 1H); 5.86(d, J ═ 10.37Hz, 1H); 4.20(d, J ═ 11.35Hz, 1H); 4.10(s, 2H); 3.95(s, 3H); 3.77-3.85(m, 1H); 3.01(s, 3H); 2.89(s, 3H); 1.97-2.23(m, 3H); 1.62-1.91(m, 3H). M/z (ESI, cation) 586.1(M + H)⁺。

And 7: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine (94.5mg, 0.161mmol) was suspended in a mixture of 2M aqueous HCl (2.0mL) and water (6 mL). Under reflux, the mixture was heated for 1h and then allowed to cool and stand at room temperature over the weekend. The resulting solid was collected by filtration, washed with water and dried to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-amine hydrochloride as a yellow solid (75.7mg, 0.141mmol, 87% yield). ¹H NMR(400MHz，d6-DMSO)δ12.50(br.s.，1H)；9.66(br.s.，1H)；8.60(s，1H)；8.52(d，J＝2.54Hz，1H)；8.26(d，J＝1.96Hz，1H)；8.16(dd，J＝8.80，2.74Hz，1H)；7.87(d，J＝8.22Hz，2H)；7.57(d, J ═ 8.22Hz, 2H); 6.85(d, J ═ 8.80Hz, 1H); 4.13(s, 2H); 3.85(s, 3H); 3.17(s, 3H); 2.84(s, 3H). M/z (ESI, cation) 502.0(M + H)⁺。

Example 104: n- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) -1H-indazol-4-amine

Step 1: n- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine

A mixture of 6- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (78.5mg, 0.163mmol) and 1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (45.5mg, 0.209mmol) in THF (1.0mL) was cooled in an ice/salt bath and treated dropwise with LiHMDS (0.627mL of a 1.0M solution in THF). The mixture was stirred for 20min and then quenched with water (0.1 mL). The mixture was stirred for 3min and then extracted from NaHCO₃Saturated aqueous solution was extracted into EtOAc. The EtOAc extract was dried (MgSO)₄) And concentrated to give a dark yellow solid (128 mg). It was used in the next step without further purification.

Step 2: n- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) -1H-indazol-4-amine

A solution of N- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (111mg, 0.164mmol) in DCM (3.0mL) was treated with TFA (1.0mL) and allowed to stand for 2H. The mixture was concentrated, azeotroped with toluene, purified by preparative HPLC, and the pure fractions were concentrated and triturated with MeOH to give pure N- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridine as an orange crystalline solid-2-yl) -1H-indazol-4-amine trifluoroacetate (8.4mg, 0.013mmol, 8.22% yield).¹H NMR (400MHz, d 6-DMSO). delta.13.12 (br.s., 1H); 12.61(br.s., 1H); 9.68(br.s., 1H); 8.63(s, 1H); 8.36(d, J ═ 2.15Hz, 1H); 8.26(s, 1H); 8.08(d, J ═ 7.63Hz, 1H); 7.87(d, J ═ 8.22Hz, 2H); 7.59(d, J ═ 8.22Hz, 2H); 7.31(t, J ═ 8.02Hz, 1H); 7.16(d, J ═ 8.41Hz, 1H); 4.17(s, 2H); 3.16(s, 3H); 2.93(s, 3H). M/z (ESI, cation) 511.0(M + H)⁺。

Examples 105 and 106: n- (5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide (105) and N5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) pyridine-2, 5-diamine (106)

Step 1: n- (5- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide

A mixture of 6- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (59.9mg, 0.124mmol) and N- (5-aminopyridin-2-yl) acetamide (Aldrich, St. Louis, MO) (18.80mg, 0.124mmol) was dissolved/suspended in benzene (1.0mL) in a 25mL flask, frozen and freeze dried. The solid was dissolved in THF (1.0mL), cooled in an ice bath, and treated dropwise with LiHMDS (0.50mL of a 1.0M solution in THF, 0.50mmol) to give a dark red solution. The solution was stirred for 3 h. The mixture was poured into NaHCO₃Saturated aqueous solution and extracted in DCM followed by EtOAc. The combined organic extracts were dried (MgSO)₄) Filtered and concentrated to give a yellow solid (50mg) which was soluble in DCM but not readily soluble in EtOAc. The product was purified by flash column through silica gel eluting with 5% MeOH/DCM to give N- (5- (3- (2-methyl-9- (tetrahydro)) as a yellow solid-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide (24.5mg, 0.040mmol, 32.1% yield). ¹H NMR(400MHz，CDCl₃) δ 12.71(br.s., 1H); 9.64(s, 1H); 8.69(br.s., 1H); 8.13-8.31(m, 5H); 7.87(d, J ═ 7.63Hz, 2H); 7.48(d, J ═ 7.63Hz, 2H); 5.86(d, J ═ 10.37Hz, 1H); 4.20(d, J ═ 11.35Hz, 1H); 3.83(t, J ═ 11.35Hz, 1H)4.12(s, 2H); 3.02(s, 3H); 2.92(s, 3H); 2.22(s, 3H); 1.94-2.18(m, 3H); 1.60-1.91(m, 3H). M/z (ESI, cation) 613.1(M + H)⁺。

Step 2: n- (5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide and N5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) pyridine-2, 5-diamine

A solution of N- (5- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide (24.5mg, 0.040mmol) in DCM (3mL) was treated with TFA (0.5 mL). The reaction was monitored by LCMS and upon completion, some hydrolyzed acetamide was also observed. The mixture was concentrated and purified by preparative HPLC to give N5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) pyridine-2, 5-diamine bis (trifluoroacetate) (3.2mg, 4.48 μmol, yield 11.20%) followed by N- (5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide trifluoroacetate (8.4mg, 0.013mmol, yield 32.7%).

N5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-yl) pyridine-2, 5-diamine bis (trifluoroacetate):¹H NMR(400MHz，CD₃OD) δ 9.63(br.s., 1H); 8.92(br.s., 1H); 8.43(s, 1H); 8.25(br.s., 1H); 8.00(d, J ═ 9.78Hz, 1H); 7.92(d, J ═ 7.82Hz, 2H); 7.60(d, J ═ 7.83Hz, 2H); 7.07(d, J ═ 9.39Hz, 1H); 4.19(br.s., 2H); 3.11(s, 3H); 2.90(s, 3H). M/z (ESI, cation) 487.0(M + H)⁺。

N- (5- (3- (2-methyl-9H-purin-6-yl) -5- (4- (methylsulfonyl) benzyl) pyridin-2-ylamino) pyridin-2-yl) acetamide trifluoroacetate:¹h NMR (400MHz, d8-THF) δ 12.99(br.s., 1H); 12.46(br.s., 1H); 10.00(br.s., 1H); 9.61(br.s., 1H); 8.82(br.s., 1H); 8.34(s, 1H); 8.27(br.s., 3H); 7.88(d, J ═ 8.02Hz, 2H); 7.58(d, J ═ 7.82Hz, 2H); 4.17(s, 2H); 2.99(s, 3H); 2.92(s, 3H); 2.11(s, 3H). M/z (ESI, cation) 529.0(M + H)⁺。

Example 107: n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indazol-4-amine

Step 1: 6- (4-Chloropyridin-3-yl) -2-methylpyrimidin-4-amine

4-chloro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridine (239mg, 998. mu. mol, Combi-Blocks, Inc., San Diego, CA), 6-chloro-2-methylpyrimidin-4-amine (143mg, 998. mu. mol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (81mg, 100. mu. mol), cesium carbonate (160. mu.l, 1996. mu. mol) in bis (N A mixture of alkane (2mL) and water (0.5mL) was stirred for 10 min. The mixture was cooled to room temperature. The reaction mixture was washed with saturated NH₄Cl (5mL) was diluted and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄Drying, filtration, concentration in vacuo and purification of the residue by chromatography on silica gel eluting with THF afforded 6- (4-chloropyridin-3-yl) -2-methylpyrimidin-4-amine (32mg, 15% yield).¹H NMR (300MHz, MeOH) delta 8.66(s, 1H); 8.57(d, J ═ 5.41Hz, 1H); 7.66(d, J ═ 5.26Hz, 1H); 6.64(s, 1H); 2.04(s, 3H). M/z (ESI, cation) 221(M + H)⁺。

Step 2: n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indazol-4-amine

6- (4-Chloropyridin-3-yl) -2-methylpyrimidin-4-amine (22mg, 100. mu. mol), 1H-indazol-4-amine (27mg, 199. mu. mol, Bionet) and EtOH (1mL) were charged to a glass microwave reaction vessel. At 160 ℃ in a Smith SynthesizerThe reaction mixture was stirred and heated in a microwave reactor (Personal Chemistry, inc., Upssala, Sweden) for 30 min. The reaction mixture was washed with saturated NaHCO₃Diluted (2mL) and extracted with EtOAc (3X 20 mL). The organic extracts were washed with saturated NaCl (2mL) and Na₂SO₄Drying, filtering, concentrating and passing the residue through silica gel chromatography with 10% MeOH/CH ₂Cl₂/1％NH₄OH was purified to give N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indazol-4-amine (14mg, 44% yield).¹H NMR(300MHz，CD₃OD) δ 8.71(s, 1H); 8.19(d, J ═ 6.14Hz, 1H); 7.34-7.53(m, 2H); 7.29(d, J ═ 7.02Hz, 1H); 7.18(d, J ═ 6.28Hz, 1H); 6.90(s, 1H); 2.59(s, 3H). M/z (ESI, cation) 318(M + H)⁺。

Examples 108 and 109: n- (6- (4- (1H-indol-4-ylamino) pyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide (108) and N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine (109)

Step 1: n- (6-chloro-2-methylpyrimidin-4-yl) acetamide

A mixture of 6-chloro-2-methylpyrimidin-4-amine (500mg, 3483. mu. mol), pyridine (568. mu.l, 69665. mu. mol) and acetic anhydride (493. mu.l, 5224. mu. mol) was stirred at 40 ℃ for 24 h. The mixture was cooled to room temperature. Will be reversedThe mixture was taken up with saturated NaHCO₃Diluted (30mL) and extracted with EtOAc (2X 400 mL). The organic extracts were washed with saturated NaCl (ca.2 mL) and Na₂SO₄Drying, filtration, concentration in vacuo and purification of the residue by chromatography on silica eluting with 40% EtOAc/hexanes to give N- (6-chloro-2-methylpyrimidin-4-yl) acetamide (458mg, 71% yield).¹H NMR(300MHz，CDCl₃) δ 8.03(s, 1H); 7.90(s, 1H); 2.58(s, 3H); 2.23(s, 3H). M/z (ESI, cation) 186(M + H) ⁺。

Step 2: n- (6- (4-chloropyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide

N- (6-chloro-2-methylpyrimidin-4-yl) acetamide (228mg, 1228. mu. mol), 3-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (294mg, 1228. mu. mol, Combi-Blocks, Inc., San Diego, Calif.), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (100mg, 123. mu. mol), cesium carbonate (197. mu.l, 2457. mu. mol), di (p-phenylene-co-oxide), at 100 ℃A mixture of alkane (4mL) and water (0.5mL) was stirred for 30 min. The mixture was cooled to room temperature. The reaction mixture was washed with saturated NH₄Cl (5mL) was diluted and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄Drying, filtration, concentration in vacuo and purification of the residue by chromatography on silica eluting with EtOAc gave N- (6- (3-chloropyridin-4-yl) -2-methylpyrimidin-4-yl) acetamide (102mg, 31.6% yield).¹H NMR(300MHz，CDCl₃) δ 8.80(s, 1H); 8.56(d, J ═ 5.41Hz, 1H); 8.34(s, 1H); 7.94(s, 1H); 7.44(d, J ═ 5.26Hz, 1H); 2.69(s, 3H); 2.25(s, 3H). M/z (ESI, cation) 263(M + H)⁺。

And step 3: n- (6- (4- (1H-indol-4-ylamino) pyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide and N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine

At 160 deg.CAt Smith SynthesizerIn a microwave reactor (Personal Chemistry, inc., Upssala, Sweden), a mixture of N- (6- (4-chloropyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide (50mg, 190 μmol) and 4-aminoindole (50mg, 381 μmol, Alfa Aesar) in EtOH (2mL) was stirred and heated for 30 min. The reaction mixture was washed with saturated NaHCO₃Diluted (3mL) and extracted with EtOAc (3X 20 mL). The organic extracts were washed with saturated NaCl (2mL) and Na₂SO₄Drying, filtration, concentration in vacuo and purification of the residue by silica gel chromatography eluting with 10% MeOH/EtOAc afforded N- (6- (4- (1H-indol-4-ylamino) pyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide (24mg, 35% yield) and N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine (22mg, 37% yield).

N- (6- (4- (1H-indol-4-ylamino) pyridin-3-yl) -2-methylpyrimidin-4-yl) acetamide:¹H NMR(300MHz，CDCl₃) δ 11.60(s, 1H); 8.94(s, 1H); 8.56(s, 1H); 8.33(s, 1H); 8.21(d, J ═ 5.85Hz, 1H); 7.14(s, 2H); 6.60(s, 1H); 3.49(s, 2H); 2.69(s, 3H); 2.27(s, 3H). M/z (ESI, cation) 359(M + H)⁺。

N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine: ¹H NMR (300MHz, d 6-DMSO). delta.11.69 (s, 1H); 11.27(s, 1H); 8.65(s, 1H); 8.16(d, J ═ 5.85Hz, 1H); 7.38(s, 1H); 7.14-7.26(m, 2H); 7.10(t, J ═ 7.75Hz, 1H); 6.93-7.05(m, 3H); 6.45(s, 1H)6.78(s, 1H); 2.47(s, 3H). M/z (ESI, cation) 317(M + H)⁺。

Example 110: n- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) -1H-indazol-4-amine

Step 1: 6- (4-Chloropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (506mg, 2.004mmol), 4-chloro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (480mg, 2.004mmol, Combi-Blocks, Inc., San Diego, Calif.), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (164mg, 0.200mmol), and cesium carbonate (0.321mL, 4.01mmol) were combined at 100 deg.CA mixture of alkane (4mL) and water (0.5mL) was stirred for 30 min. The mixture was cooled to room temperature. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (2mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan solid. The crude material was adsorbed onto a silica gel packed column and purified by flash chromatography to dissolve in CH ₂Cl₂Was eluted with 10% MeOH to afford 6- (4-chloropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine as a pale yellow glassy material (98mg, 15% yield).¹H NMR(300MHz，CDCl₃) δ 8.83(s, 1H); 8.61(d, J ═ 5.41Hz, 1H); 8.27(s, 1H); 7.50(d, J ═ 5.41Hz, 1H); 5.87(d, J ═ 10.08Hz, 1H); 4.20(d, J ═ 11.25Hz, 1H); 3.84(t, J ═ 11.33Hz, 1H); 3.48(d, J ═ 5.41Hz, 1H); 2.90(s, 3H); 1.99-2.29(m, 3H); 1.64-1.95(m, 3H). M/z (ESI, cation) 330(M + H)⁺。

Step 2: n- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) -1H-indazol-4-amine

6- (4-Chloropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (33mg, 0.100mmol) and 1H-indazol-4-amine (26.6mg, 0.200mmol, Bionet Research, Cornwall, UK) in ethanol (1mL) and one drop of 5N HCl were charged to a glass microwave reaction vessel. Stirring in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Usssala, Sweden) at 160 deg.CThe reaction mixture was stirred and heated for 30 min. The reaction mixture was washed with saturated NaHCO₃Diluted (5mL) and extracted with EtOAc (2X 30 mL). The combined organic extracts were washed with saturated NaCl (3mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan solid. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column with 10% MeOH/CH₂Cl₂Purify by elution to provide N- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) -1H-indazol-4-amine as a yellow solid (23mg, 67% yield).¹H NMR (300MHz, d 6-DMSO). delta.13.27 (s, 1H); 12.54(s, 1H); 10.22(s, 1H); 8.64(s, 1H); 8.30(d, J ═ 5.85Hz, 1H); 8.16(s, 1H); 7.30-7.43(m, 3H); 7.18(d, J ═ 6.87Hz, 1H); 2.82(s, 3H). M/z (ESI, cation) 343(M + H)⁺。

Example 111: 6-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) pyridin-3-amine

6- (4-Chloropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (36mg, 0.109mmol) and 5-amino-2-methoxypyridine (27.1mg, 0.218mmol, Aldrich) in ethanol (1mL) and one drop of 5N HCl were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 160 ℃ for 30 min. The reaction mixture was washed with saturated NaHCO₃Diluted (5mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (3mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a tan solid. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column with 10% MeOH/CH₂Cl₂Purify by elution to provide 6-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) pyridin-3-amine as a yellow solid (21mg, 58% yield).¹H NMR(300MHz，CD₃OD) δ 9.98(s, 1H); 8.42(s, 1H); 8.07-8.24(m, 2H); 7.72(d, J ═ 8.92Hz, 1H); 6.85-7.00(m, 2H); 3.96(s, 3H); 2.83(s, 3H). M/z (ESI, cation) 334(M + H)⁺。

Example 112: n- (3- (6-amino-2-methylpyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine

Step 1: 4- (3-chloropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine

A mixture of 2, 3-dichloropyrazine (0.034mL, 0.228mmol, Aldrich, St. Louis, MO), 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine (98mg, 0.228mmol), and tetrakis (triphenylphosphine) palladium (26.4mg, 0.023mmol, Strem Chemicals, Inc., Newburyport, MA) in toluene (2mL) was stirred at 110 ℃ for 48 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel with 20% EtOAc/CH₂Cl₂Purification by elution was carried out to give 4- (3-chloropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine (12mg, yield 21%). ¹H NMR(300MHz，CDCl₃) δ 8.63(d, J ═ 2.05Hz, 1H); 8.47(d, J ═ 2.19Hz, 1H); 7.44(s, 1H); 2.77(s, 3H); 2.56(s, 3H). M/z (ESI, cation) 253(M + H)⁺。

Step 2: n- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine

4- (3-Chloropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine (60mg, 0.237mmol) and 1H-indazol-4-amine (63.2mg, 0.475mmol, Bionet) dissolved in ethanol (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys optizer microwave reactor (Personal Chemistry, Biotange AB, inc., Upssanlan, Sweden) for 30min at 160 ℃. The reaction mixture was washed with saturated NaHCO₃Diluted (5mL) and extracted with EtOAc (2X 30 mL). Will be provided withThe combined organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, through a silica gel column, eluting with 40% EtOAc/hexanes to provide N- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine (38mg, 46% yield) as a yellow solid.¹H NMR (300MHz, d8-dioxane) delta 12.49(s, 1H); 11.68(s, 1H); 10.69(s, 1H); 8.24(s, 2H); 8.10(d, J ═ 7.60Hz, 1H); 8.02(s, 1H); 7.23(t, J ═ 7.97Hz, 1H); 7.07(d, J ═ 8.18Hz, 1H); 2.83(s, 3H); 2.53(s, 3H). M/z (ESI, cation) 350(M + H) ⁺。

And step 3: n- (3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine

N- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine (20mg, 0.057mmol) and 3-chloroperoxybenzoic acid (14.82mg, 0.086mmol, Aldrich, St. Louis, MO-77%) were combined at room temperature in two portionsThe mixture of alkanes (1mL) was stirred for 2 h. LCMS showed no starting material remaining. The reaction mixture was used in the next step of the reaction without purification.

And 4, step 4: n- (3- (6-amino-2-methylpyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine

The mixture from step 3 was treated with ammonia (30% in water) in a sealed tube. The mixture was stirred at 100 ℃ overnight. The solvent was removed in vacuo and the residue was chromatographed on silica gel at 50% THF/CH₂Cl₂Purify by elution to give N- (3- (6-amino-2-methylpyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine as a yellow solid (7mg, 39% yield).¹H NMR(300MHz，d6-DMSO)δ13.17(s，1H)；12.95(s，1H)；8.37(d，J＝2.05Hz，1H)；8.25(s，1H)；8.18(d，J＝2.05Hz，1H)；8.10(d，J＝7.75Hz，1H)；7.45(s，1H)；7.33(t，J ═ 8.11Hz, 1H); 7.19(d, J ═ 7.31Hz, 1H); 2.65(s, 3H). M/z (ESI, cation) 319(M + H)⁺。

Example 113: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) quinolin-2-amine

Step 1: 2-chloro-3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) quinoline

Di-N-layers of 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.55g, 2.18mmol), 2-chloroquinolin-3-ylboronic acid (0.90g, 4.35mmol, Aldrich, St. Louis, MO) and tetrakis (triphenylphosphine) palladium (0) (0.13g, 0.11mmol, Strem Chemicals, Inc., Newburyport, MA)The mixture of alkane (3mL) and water (1mL) was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90 ℃ for 6h and then allowed to cool to room temperature. The organic phase was removed and the solvent was removed in vacuo. The crude reaction mixture was chromatographed on silica gel (0 to 3% MeOH/CH)₂Cl₂) Purification of (a) provided the title compound as an orange solid. M/z (ESI, cation) 380(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) quinolin-2-amine

Treatment of 5-amino-2-methoxypyridine (50mg, 0.41mmol, Aldrich, St. Louis, MO) and 2-chloro-3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) quinoline (77mg, 0.20mmol) with LiHMDS (1M in THF, 0.51mL, 0.51mmol) at 0 deg.CAlkane (4mL) solution. The reaction mixture was stirred at 0 ℃ for 1 h and at room temperature 1And 8 h. Subsequently, an additional amount of LiHMDS (1M in THF, 0.51mL, 0.51mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of MeOH (2mL) and the solvent was removed in vacuo. The crude reaction mixture was chromatographed on silica gel (2 to 3% MeOH/CH) ₂Cl₂) Purification of (a) provided the title compound as a dark orange solid. M/z (ESI, cation) 468(M + H)⁺。

And step 3: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) quinolin-2-amine

A solution of N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) quinolin-2-amine (21mg, 0.045mmol) in DCM (1mL) and TFA (1mL) was stirred at room temperature for 30 min. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution (2 ×), water and brine. Subjecting the organic layer to Na₂SO₄And (5) drying. The crude material was adsorbed onto a silica gel packed column and chromatographed on silica gel (1 to 4% MeOH/CH)₂Cl₂) And (5) purifying. The title compound was obtained as a yellow solid. M/z (ESI, cation) 384(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ13.71(s，1H)；12.73(s，1H)；10.24(s，1H)；8.86(s，1H)；8.71(s，1H)；8.40(d，J＝7.0Hz，1H)；7.92(d，J＝7.8Hz，1H)；7.71(br.s.，2H)；7.37(b r.s.，1H)；6.92(d，J＝8.6Hz，1H)；3.88(s，3H)；2.91(s，3H)。

Example 114: 4- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 2-iodo-4-methyl-6- (methylthio) -1, 3, 5-triazine

At room temperature, 2-chloro-4-methyl-6- (methylthio) -1, 3, 5-triazine (2110mg, 12.01mmol) and 67% hydriodic acid solution (2.260mL, 30.0mmol)CH (A) of₂Cl₂The mixture was stirred (4mL) for 3 h. The solid was filtered off and washed with CH₂Cl₂And (6) washing. The solid is treated with NaHCO₃Treated with saturated aqueous solution (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude product as a yellow solid. This crude product was chromatographed on silica gel with 50% CH₂Cl₂Hexane/hexane to give 2-iodo-4-methyl-6- (methylthio) -1, 3, 5-triazine (2.1g, 7.86mmol, 65.4% yield).¹H NMR(300MHz，CDCl₃) δ 2.53(s, 3H); 2.51(s, 3H). M/z (ESI, cation) 267.8(M + H)⁺。

Step 2: 2-fluoro-3- (tributylstannyl) pyrazines

N-butyllithium (1.6M in hexane, 0.920mL, 10.99mmol) was added to 2, 2, 6, 6-tetramethylpiperidine (2.024mL, 11.99mmol) in THF (50mL) at-50 ℃. After the addition, the mixture was stirred at 0 ℃ for 20min and subsequently cooled down to-100 ℃. 2-Fluopyrazine (980mg, 9.99mmol) in THF (5mL) was then added dropwise. After 5min, tributyltin chloride (3.25mL, 11.99mmol) dissolved in THF (5mL) was added dropwise and stirring continued for 1 h. The reaction was quenched with 35% aqueous HCl, ethanol, THF (1: 4: 5) and allowed to warm to 20 ℃. The reaction mixture was washed with NaHCO₃A saturated aqueous solution (30mL) was diluted and extracted with EtOAc (2X 50 mL). The organic extracts were washed with saturated aqueous NaCl solution (30mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column with 50% CH ₂Cl₂Purified by elution with hexanes to provide 2-fluoro-3- (tributylstannyl) pyrazine (2980mg, 7.70mmol, 77% yield) as a colorless oil.¹H NMR(300MHz，CDCl₃)δ8.63(s，1H)；8.02(s，1H)；1.46-1.68(m，6H)；1.12-1.42(m，12H)；0.88(t，J＝7.23Hz，9H)。

And step 3: 2- (3-Fluoropyrazin-2-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine

A mixture of 2-iodo-4-methyl-6- (methylthio) -1, 3, 5-triazine (100mg, 0.374mmol), 2-fluoro-3- (tributylstannyl) pyrazine (145mg, 0.374mmol), and tetrakis (triphenylphosphine) palladium (0) (43.3mg, 0.037mmol) in toluene (2mL) was stirred at 110 deg.C for 18 h. The mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes, to give 2- (3-fluoropyrazin-2-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (42mg, 0.177mmol, 47.3% yield).¹H NMR (300MHz, CDCl3) delta 8.73(s, 1H); 8.42(s, 1H); 2.73(s, 3H); 2.65(s, 3H). M/z (ESI, cation) 238.0(M + H)⁺。

And 4, step 4: n- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrazin-2-amine

Will dissolve in II2- (3-Fluoropyrazin-2-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (61mg, 0.257mmol), 5-amino-2-methoxypyridine (0.038mL, 0.309mmol), copper (I) iodide (5mg, 0.026mmol) and N, N-diisopropylethylamine (0.089mL, 0.514mmol) in an alkane (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 24 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel with 20% EtOAc/CH ₂Cl₂Purify by elution to give N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrazin-2-amine as a yellow solid (67mg, 0.196mmol, 76% yield).¹H NMR(300MHz，CDCl₃) δ 11.34(s, 1H); 8.36(d, J ═ 1.90Hz, 1H); 8.26(s, 2H); 8.00(dd, J ═ 8.99, 2.56Hz, 1H); 6.80(d, J ═ 8.77Hz, 1H); 3.96(s, 3H); 2.77(s, 3H); 2.68(s, 3H). M/z (ESI, cation) 342.0(M + H)⁺。

And 5: 4- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -6-methyl-1, 3, 5-triazin-2-amine

Will dissolve in IIN- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrazin-2-amine (44mg, 0.129mmol) in an alkane (1mL) and aqueous ammonia (1mL, 37% in water) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc, to give 4- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -6-methyl-1, 3, 5-triazin-2-amine (34mg, 0.110mmol, 85% yield) as a yellow solid.¹H NMR(300MHz，CDCl₃) δ 11.83(s, 1H); 8.37(d, J ═ 2.05Hz, 1H); 8.24(s, 1H); 8.20(s, 1H); 8.04(dd, J ═ 8.92, 2.48Hz, 1H); 6.80(d, J ═ 8.77Hz, 1H); 5.71(s, 2H); 3.95(s, 3H); 2.62(s, 3H). M/z (ESI, cation) 311.0(M + H) ⁺。

Example 115: 4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4-iodo-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1020mg, 2.65mmol) and 67% hydroiodic acid in CH (0.499mL, 6.63mmol) were added at room temperature₂Cl₂The mixture was stirred (10mL) for 19 h. The reaction mixture was washed with saturated NaHCO₃Diluted (30mL) and extracted with EtOAc (2X 40 mL). The organic extracts were washed with saturated NaCl (20mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to afford a solution that was lightCrude material as yellow solid. The solvent was removed in vacuo and the residue was chromatographed on silica gel with 50% CH₂Cl₂Hexane elution to give 4-iodo-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a mixture of product and starting material (3: 1) (826mg, 1.734mmol, 65.4% yield).

Step 2: 4- (3-Chloropyridin-4-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-iodo-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (306mg, 0.642mmol), 3-cyclopyridine-4-boronic acid (101mg, 0.642mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (52.4mg, 0.064mmol) and cesium carbonate (251mg, 0.770mmol) in bis (S-bis-p-toluenesulfonate, bis (N-methylbenzyl) ammonium salt at 90 deg.C A mixture of alkane (6mL) and water (1mL) was stirred for 1 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow glass. The crude product was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give the product as a glass.¹H NMR(300MHz，CDCl₃) δ 8.69(s, 1H); 8.58(d, J ═ 4.97Hz, 1H); 7.71(d, J ═ 4.82Hz, 1H); 7.10-7.26(m, 4H); 6.86(t, J ═ 8.77Hz, 4H); 4.80(s, 4H); 3.81(s, 3H); 3.80(s, 3H); 2.56(s, 3H). M/z (ESI, cation) 462.0(M + H)⁺。

And step 3: n, N-bis (4-methoxybenzyl) -4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (3-Chloropyridin-4-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (32mg, 0.069mmol), 5-amino-2-methoxypyridine (0.017mL, 0.139mmol), Brett pre-catalyst ((SP-4-4) - [2- [2- (amino-. kappa.N) ethyl]Phenyl-kappa C]Chloro [ di ] sCyclohexyl [3, 6-dimethoxy-2 ', 4', 6 '-tris (1-methylethyl) [1, 1' -biphenyl ] ]-2-yl]Phosphine-kappa P]Palladium) (2mg) and sodium 2-methylpropan-2-olate (16.64mg, 0.173mmol) and bisAlkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 16h at 100 ℃. The reaction mixture was washed with saturated NH₄Cl (10mL) was diluted and extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was chromatographed on silica gel at 20% THF/CH₂Cl₂Purification by elution to give N, N-bis (4-methoxybenzyl) -4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine (9mg, 0.016mmol, 24% yield).¹H NMR(300MHz，CDCl₃) δ 10.32(s, 1H); 8.49-8.68(m, 1H); 8.33(s, 1H); 8.24(d, J ═ 5.12Hz, 2H); 8.03(d, J ═ 5.12Hz, 2H); 7.95(d, J ═ 1.61Hz, 1H); 7.38(dd, J ═ 8.70, 2.41Hz, 2H); 7.21(d, J ═ 8.33Hz, 2H); 7.14(d, J ═ 8.33Hz, 2H); 6.98(s, 1H); 6.87(d, J ═ 8.33Hz, 2H); 6.79(d, J ═ 8.33Hz, 2H); 6.72(d, J ═ 8.77Hz, 1H); 4.86(s, 2H); 4.79(s, 2H); 3.81(s, 3H); 3.76(s, 3H); 2.56(s, 3H). M/z (ESI, cation) 550.0(M + H) ⁺。

And 4, step 4: 4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine.

N, N-bis (4-methoxybenzyl) -4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine (7mg, 0.013mmol) and triflic acid (3.38. mu.L, 0.038mmol) in TFA (0.1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 2h at room temperature. The reaction mixture was washed with saturated NaHCO₃Diluted (5mL) and extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄Drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow solid. The crude product was purified by silica gel chromatography eluting with EtOAc to give 4- (3- (6-methoxypyridin-3-ylamino) pyridin-4-yl) -6-methyl-1, 3, 5-triazin-2-amine (3.2mg, 10.35 μmol, 81% yield).¹H NMR(300MHz，CDCl₃) δ 10.38(s, 1H); 8.38(s, 1H); 8.24(d, J ═ 5.12Hz, 1H); 8.13(s, 1H); 8.07(d, J ═ 4.97Hz, 1H); 7.58(dd, J ═ 8.77, 2.05Hz, 1H); 6.81(d, J ═ 8.77Hz, 1H); 5.41(s, 2H); 3.96(s, 3H); 2.54(s, 3H). M/z (ESI, cation) 310.0(M + H) ⁺。

Example 116: 6- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -2-methylpyrimidin-4-amine

Step 1: 4- (3-Fluoropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine

4-iodo-2-methyl-6- (methylthio) pyrimidine (266mg, 1.000mmol), 2-fluoro-3- (tributylstannyl) pyrazine (387mg, 1.000mmol), and tetrakis (triphenylphosphine) palladium (0) (116mg, 0.100mmol) in toluene (3mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys optizer microwave reactor (Personal Chemistry, Biotange AB, inc., Upssanlan, Sweden) at 140 ℃ for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes, to give 4- (3-fluoropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine (28mg, 0.119mmol, 12% yield).¹H NMR(300MHz，CDCl₃) δ 8.68(s, 1H); 8.32(s, 1H); 7.67(s, 1H); 2.79(s, 3H); 2.63(s, 3H). M/z (ESI, cation) 237.1(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine

Will dissolve in II4- (3-Fluoropyrazin-2-yl) -2-methyl-6- (methylthio) pyrimidine (21mg, 0.089mmol), 5-amino-2-methoxypyridine (0.022mL, 0.178mmol), copper (I) iodide (2mg, 8.89. mu. mol) and N-ethyl-N-isopropylpropan-2-amine (22.97mg, 0.178mmol) in an alkane (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 24h at 100 ℃. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (5mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow solid. The crude product was purified by silica gel chromatography eluting with 30% EtOAc/hexanes to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (14mg, 0.041mmol yield 46.3%).¹H NMR(300MHz，CDCl₃) δ 12.20(s, 1H); 8.42(d, J ═ 2.05Hz, 1H); 8.22(s, 1H); 8.18(s, 1H); 8.09(dd, J ═ 8.92, 2.63Hz, 1H); 8.02(d, J ═ 1.90Hz, 1H); 6.79(d, J ═ 8.77Hz, 1H); 3.95(s, 3H); 2.78(s, 3H); 2.63(s, 3H). M/z (ESI, cation) 341.0(M + H)⁺。

And step 3: n- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) pyrazin-2-amine

Will dissolve in IIN- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (11mg, 0.032mmol) and 3-chloroperoxybenzoic acid (11.15mg, 0.065mmol) in an alkane (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was used for the next step without purification.

And 4, step 4: 6- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -2-methylpyrimidin-4-amine

Will dissolve in II N- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) pyrazin-2-amine (11.40mg, 0.032mmol) (crude product from the previous step) in an alkane (1mL) and ammonium hydroxide, 28.0-30.0% (0.5mL, 12.84mmol) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 2h at 100 ℃. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes, to give 6- (3- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) -2-methylpyrimidin-4-amine (8.2mg, 0.027mmol, 83% yield).¹H NMR(300MHz，CDCl₃) δ 12.46(s, 1H); 8.42(s, 1H); 8.15(s, 1H); 8.10(dd, J ═ 8.77, 2.48Hz, 1H); 7.98(d, J ═ 1.32Hz, 1H); 7.47(s, 1H); 6.78(d, J ═ 8.62Hz, 1H); 4.95(s, 2H); 3.95(s, 3H); 2.64(s, 3H). M/z (ESI, cation) 310.1(M + H)⁺

Example 117: 4- (4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5-bromo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine

A mixture of 5-bromopyrimidin-4-amine (344mg, 1.977mmol), 6-methoxypyridin-3-ylboronic acid (907mg, 5.93mmol), N-diisopropylethylamine (1.376mL, 7.91mmol) and anhydrous copper (II) acetate (539mg, 2.97mmol) in dichloromethane (2mL) was stirred at room temperature overnight. The solid was filtered off and washed with CH ₂Cl₂And (6) washing. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes, to give 5-bromo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (36mg, 0.128mmol, 6.48% yield).¹H NMR(300MHz，CDCl₃)δ8.55(s，1H)；8.46(s，1H)；8.28(s, 1H); 7.85(dd, J ═ 8.77, 2.48Hz, 1H); 6.98(s, 1H); 6.80(d, J ═ 8.92Hz, 1H); 3.95(s, 3H). M/z (ESI, cation) 281.0(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine

5-bromo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (23mg, 0.082mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (35.2mg, 0.082mmol), copper (I) iodide (15mg, 0.082mmol), cesium fluoride (206mg, 0.82mmol) and tetrakis (triphenylphosphine) palladium (0) (9.45mg, 8.18. mu. mol) and THF (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude product as a pale yellow solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (15mg, 0.044mmol, 53.7% yield). ¹H NMR(300MHz，CDCl₃) δ 11.58(s, 1H); 9.65(s, 1H); 8.74(s, 1H); 8.35(d, J ═ 2.19Hz, l H); 8.07(dd, J ═ 8.84, 2.56Hz, 1H); 6.82(d, J ═ 8.92Hz, 1H); 3.96(s, 3H); 2.67(s, 3H); 2.65(s, 3H). M/z (ESI, cation) 342.0(M + H)⁺。

And step 3: 4- (4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (14mg, 0.041mmol), ammonium hydroxide, 28.0-30.0% (0.5mL, 12.84mmol) and diAlkane (1 m)L) are placed in a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 1h under reflux. The solid formed was filtered off and washed with EtOAc to give 4- (4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine (10mg, 0.032mmol, 79% yield).¹H NMR (300MHz, d 6-DMSO). delta.11.78 (s, 1H); 9.37(s, 1H); 8.65(s, 1H); 8.48(s, 1H); 8.10(d, J ═ 8.33Hz, 1H); 7.94(s, 1H); 7.79(s, 1H); 6.88(d, J ═ 8.77Hz, 1H); 3.87(s, 3H); 2.43(s, 3H). M/z (ESI, cation) 311.1(M + H)⁺。

Example 118: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine

Step 1: 2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine

Di (2, 4-dichloro-5-iodopyrimidine (274mg, 0.997mmol), 5-amino-2-methoxypyridine (0.247mL, 1.994mmol), N-diisopropylethylamine (0.347mL, 1.994mmol) and copper (I) iodide (38mg, 0.199mmol) were added at 100 deg.CThe mixture of alkanes (2mL) was stirred for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (242mg, 0.667mmol, 67.0% yield).¹H NMR(300MHz，CDCl₃)δ 8.44(s，1H)；8.28(d，J＝1.90Hz，1H)；7.83(dd，J＝8.84，2.56Hz，1H)；7.01(s，1H)；6.81(d，J＝8.77Hz，1H)；3.96(s, 3H). M/z (ESI, cation) 362.9(M + H)⁺。

Step 2: 2-chloro-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (181mg, 0.499mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (215mg, 0.499mmol), copper (I) iodide (19mg, 0.100mmol), cesium fluoride (250mg, 0.998mmol) and tetrakis (triphenylphosphine) palladium (0) (57.7mg, 0.050mmol) and bis (triphenylphosphine) were added Alkane (3mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 2-chloro-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (87mg, 0.231mmol, 46.4% yield).¹H NMR(300MHz，CDCl₃) δ 11.82(s, 1H); 9.48(s, 1H); 8.37(s, 1H); 8.08(dd, J ═ 9.28, 1.97Hz, 1H); 6.83(d, J ═ 9.06Hz, 1H); 3.96(s, 3H); 2.67(s, 3H); 2.64(s, 3H). M/z (ESI, cation) 376.0(M + H)⁺。

And step 3: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine

2-chloro-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (32mg, 0.085mmol), aqueous ammonia (0.5mL, 23.11mmol) (30% in water) and di Alkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 16h at 100 ℃. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 5% MeOH/EtOAc, to give 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine (21mg, 0.065mmol, 76% yield).¹H NMR (300MHz, d 6-DMSO). delta.11.87 (s, 1H); 9.09(s, 1H); 8.74(s, 1H); 8.20(d, J ═ 9.35Hz, 1H); 7.61(s, 1H); 7.46(s, 1H); 7.01(s, 2H); 6.81(d, J ═ 8.04Hz, 1H); 3.85(s, 3H); 2.35(s, 3H). M/z (ESI, cation) 326.1(M + H)⁺。

Example 119: 4- (2-methoxy-4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5-iodo-2-methoxy-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (181mg, 0.499mmol), sodium methoxide (0.5M solution in methanol, 0.043mL, 0.749mmol), and methanol (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an EmryOptimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 15 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (5mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-iodo-2-methoxy-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (162mg, 0.452mmol, 91% yield).¹H NMR(300MHz，CDCl₃)δ8.35(s，1H)；8.26(d，J＝2.05Hz，1H)；7.83(dd，J＝8.84, 2.56Hz, 1H); 6.87(s, 1H); 6.78(d, J ═ 8.77Hz, 1H); 3.94(s, 3H); 3.89(s, 3H). M/z (ESI, cation) 359.0(M + H)⁺。

Step 2: 2-methoxy-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine

5-iodo-2-methoxy-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (120mg, 0.335mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (144mg, 0.335mmol), copper (I) iodide (13mg, 0.067mmol), cesium fluoride (102mg, 0.670mmol) and tetrakis (triphenylphosphine) palladium (0) (38.7mg, 0.034mmol) and bisAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give 2-methoxy-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (86mg, 0.232mmol, 69.1% yield).¹H NMR(300MHz，CDCl₃) δ 11.78(s, 1H); 9.53(s, 1H); 8.39(s, 1H); 8.06(dd, J ═ 8.77, 1.90Hz, 1H); 6.80(d, J ═ 8.92Hz, 1H); 4.01(s, 3H); 3.96(s, 3H); 2.63(s, 6H). M/z (ESI, cation) 372.0(M + H)⁺。

And step 3: 4- (2-methoxy-4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

2-methoxy-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (41mg, 0.110mmol), aqueous ammonia (0.5mL, 23.22mmol) (dissolved in water)30%) and twoAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 16h at 100 ℃. The solid formed was filtered off and washed with EtOAc to give 4- (2-methoxy-4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine (28mg, 0.082mmol, 74.5% yield). ¹H NMR (300MHz, d 6-DMSO). delta.11.98 (s, 1H); 9.25(s, 1H); 8.53(s, 1H); 8.16(dd, J ═ 8.84, 2.56Hz, 1H); 7.84(s, 1H); 7.68(s, 1H); 6.88(d, J ═ 8.77Hz, 1H); 5.76(s, 1H); 3.89(s, 3H); 3.86(s, 3H); 2.40(s, 3H). M/z (ESI, cation) 341.0(M + H)⁺。

Example 120: 4- (4- (6-methoxypyridin-3-ylamino) -2-morpholinylpyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5-iodo-N- (6-methoxypyridin-3-yl) -2-morpholinylpyrimidin-4-amine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (160mg, 0.441mmol), morpholine (0.077mL, 0.883mmol), and ethanol (3mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 20 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an off-white solid. The crude product was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-iodo-N- (6-methoxypyridin-3-yl) -2-morpholinopyrimidin-4-amine (162mg, 0.392mmol, 89% yield). ¹H NMR(300MHz，CDCl₃)δ8.26(d，J＝1.90Hz, 1H); 8.20(s, 1H); 7.72(dd, J ═ 8.77, 2.34Hz, 1H); 6.75(d, J ═ 8.92Hz, 1H); 6.67(s, 1H); 3.95(s, 3H); 3.68(d, J ═ 5.26Hz, 8H). M/z (ESI, cation) 414.0(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2-morpholinopyrimidin-4-amine

5-iodo-N- (6-methoxypyridin-3-yl) -2-morpholinopyrimidin-4-amine (118mg, 0.286mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (123mg, 0.286mmol), copper (I) iodide (11mg, 0.057mmol), cesium fluoride (87mg, 0.571mmol), tetrakis (triphenylphosphine) palladium (0) (33.0mg, 0.029mmol) and bis (triphenylphosphine) were addedAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2-morpholinopyrimidin-4-amine (43mg, 0.101mmol, 35.3% yield). ¹H NMR(300MHz，CDCl₃) δ 11.63(s, 1H); 9.41(s, 1H); 8.38(d, J ═ 1.90Hz, 1H); 7.90(dd, J ═ 8.77, 2.34Hz, 1H); 6.78(d, J ═ 8.77Hz, 1H); 3.96(s, 3H); 3.88(s, 4H); 3.65-3.81(m, 4H); 2.60(s, 3H); 2.58(s, 3H). M/z (ESI, cation) 427.1(M + H)⁺。

And step 3: 4- (4- (6-methoxypyridin-3-ylamino) -2-morpholinylpyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1,3, 5-triazin-2-yl) -2-morpholinylpyrimidin-4-amine (34mg, 0.080mmol), aqueous ammonia (0.5mL, 23.11mmol) (30% in water) and bisAlkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 16h at 100 ℃. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc, to give 4- (4- (6-methoxypyridin-3-ylamino) -2-morpholinopyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine (22mg, 0.056mmol, 69.8% yield).¹H NMR (300MHz, d 6-DMSO). delta.11.91 (s, 1H); 9.16(s, 1H); 8.50(s, 1H); 8.08(d, J ═ 4.97Hz, 1H); 7.67(s, 1H); 7.51(s, 1H); 6.85(d, J ═ 8.77Hz, 1H); 3.85(s, 3H); 3.74(s, 4H); 3.66(s, 4H); 2.36(s, 3H). M/z (ESI, cation) 396.0(M + H) ⁺。

Example 121: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine

Step 1: 5-iodo-N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (150mg, 0.414mmol), dimethylamine (a 2.0M solution in tetrahydrofuran) (0.044mL, 0.827mmol), and ethanol (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes, to give 5-iodo-N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine (123mg, 0.331mmol, 80% yield).¹H NMR(300MHz，CDCl₃) δ 8.30(s, 1H); 8.18(s, 1H); 7.84(dd, J ═ 8.92, 2.48Hz, 1H); 6.75(d, J ═ 8.92Hz, 1H); 6.65(s, 1H); 3.94(s, 3H); 3.09(s, 6H). M/z (ESI, cation) 371.9(M + H)⁺。

Step 2: n4- (6-methoxypyridin-3-yl) -N2, N2-dimethyl-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine

5-iodo-N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine (98mg, 0.264mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (114mg, 0.264mmol), cesium fluoride (80mg, 0.528mmol), copper (I) iodide (10mg, 0.053mmol), tetrakis (triphenylphosphine) palladium (0) (30.5mg, 0.026mmol) and bis (triphenylphosphine) palladium (0)Alkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N4- (6-methoxypyridin-3-yl) -N2, N2-dimethyl-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine (32mg, 0.083mmol, 31.5% yield).¹H NMR(300MHz，CDCl₃) δ 11.66(s, 1H); 9.43(s, 1H); 8.42(s, 1H); 8.05(dd, J ═ 8.70, 2.27Hz, 1H); 6.77(d, J ═ 8.92Hz, 1H); 3.95(s, 3H); 3.25(s, 6H); 2.59(s, 3H); 2.57(s, 3H). M/z (ESI, cation) 385.1(M + H) ⁺。

And step 3: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine

Reacting N4- (6-methoxypyridin-3-yl)) N2, N2-dimethyl-5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine (16mg, 0.042mmol), aqueous ammonia (0.5mL, 23.11mmol) (30% in water) and bisAlkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 16h at 100 ℃. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 5% MeOH/EtOAc, to give 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N4- (6-methoxypyridin-3-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine (11mg, 0.031mmol, 74.8% yield).¹H NMR(300MHz，CDCl₃) δ 11.94(s, 1H); 9.29(s, 1H); 8.42(s, 1H); 8.07(dd, J ═ 8.92, 2.34Hz, 1H); 6.76(d, J ═ 8.77Hz, 1H); 5.29(s, 2H); 3.95(s, 3H); 3.23(s, 6H); 2.48(s, 3H). M/z (ESI, cation) 354.0(M + H)⁺。

Example 122: 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyrrolidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5-iodo-N- (6-methoxypyridin-3-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (181mg, 0.499mmol), pyrrolidine (0.084mL, 0.998mmol) and ethanol (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 20 min. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2X 40 mL). The organic extracts were washed with saturated NaCl (20mL) and Na2SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product is passed through a silica gel colorChromatography, eluting with 50% EtOAc in hexanes to afford 5-iodo-N- (6-methoxypyridin-3-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine (172mg, 0.433mmol, 87% yield).¹H NMR(300MHz，CDCl₃) δ 8.19(s, 1H); 7.89(dd, J ═ 8.33, 2.34Hz, 1H); 6.74(d, J ═ 8.92Hz, 1H); 6.67(s, 1H); 3.94(s, 3H); 3.50(s, 4H); 1.95(s, 4H). M/z (ESI, cation) 398.0(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine

5-iodo-N- (6-methoxypyridin-3-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine (141mg, 0.355mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (153mg, 0.355mmol), copper (I) iodide (14mg, 0.071mmol), cesium fluoride (108mg, 0.710mmol), tetrakis (triphenylphosphine) palladium (0) (41.0mg, 0.035mmol) and bis (triphenylphosphine) were added Alkane (3mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a brown oil. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine (28mg, 0.068mmol, 19.22% yield).¹H NMR(300MHz，CDCl₃) δ 11.74(s, 1H); 9.45(s, 1H); 8.49(s, 1H); 8.13(dd, J ═ 8.92, 2.34Hz, 1H); 6.77(d, J ═ 8.77Hz, 1H); 3.95(s, 3H); 3.58-3.76(m, 4H); 2.59(s, 3H); 2.57(s, 3H); 1.93-2.09(m, 4H). M/z (ESI, cation) 411.0(M + H)⁺。

And step 3: 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyrrolidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyrrolidin-1-yl) pyrimidin-4-amine (18mg, 0.044mmol), aqueous ammonia (0.5mL, 23.11mmol) (30% in water) and bis Alkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath at 100 ℃ for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc, to give 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyrrolidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine (12mg, 0.032mmol, 72.1% yield).¹H NMR(300MHz，CDCl₃) δ 12.03(s, 1H); 9.30(s, 1H); 8.48(s, 1H); 8.15(dd, J ═ 8.92, 2.48 Hz, 1H); 6.76(d, J ═ 9.06Hz, 1H); 5.24(s, 2H); 3.95(s, 3H); 3.66(dd, J ═ 5.85, 4.09Hz, 4H); 2.49(s, 3H); 2.00(t, J ═ 6.43Hz, 4H). M/z (ESI, cation) 380.1(M + H)⁺。

Example 123: 4- (4- (6-methoxypyridin-3-ylamino) -2- (piperidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5-iodo-N- (6-methoxypyridin-3-yl) -2- (piperidin-1-yl) pyrimidin-4-amine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (181mg, 0.499mmol), piperidine (0.099mL, 0.998mmol), and ethanol (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 20 min. The reaction mixture was diluted with water (20mL) Released and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 5-iodo-N- (6-methoxypyridin-3-yl) -2- (piperidin-1-yl) pyrimidin-4-amine (189mg, 0.460mmol, 92% yield).¹H NMR(300MHz，CDCl₃) δ 8.24(s, 1H); 8.17(s, 1H); 7.79(dd, J ═ 8.84, 2.56Hz, 1H); 6.75(d, J ═ 8.77Hz, 1H); 6.63(s, 1H); 3.94(s, 3H); 3.57-3.73(m, 4H); 1.47-1.69(m, J ═ 4.68Hz, 6H). M/z (ESI, cation) 412.0(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (piperidin-1-yl) pyrimidin-4-amine

5-iodo-N- (6-methoxypyridin-3-yl) -2- (piperidin-1-yl) pyrimidin-4-amine (161mg, 0.391mmol), 2-methyl-4- (methylthio) -6- (tributylstannanyl) -1, 3, 5-triazine (168 mg, 0.391mmol), cesium fluoride (119mg, 0.783mmol), copper (I) iodide (15mg, 0.078mmol), tetrakis (triphenylphosphine) palladium (0) (45.2mg, 0.039mmol) and bisAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (piperidin-1-yl) pyrimidin-4-amine (36mg, 0.085mmol, 21.66% yield).¹H NMR(300MHz，CDCl₃)δ11.61(s，1H)；9.41(s，1H)；7.99(d，J＝8.48Hz，1H)；6.77(d，J ═ 8.77Hz, 1H); 3.95(s, 3H); 3.78-3.91(m, 4H); 2.59(s, 3H); 2.56(s, 3H); 1.56-1.78(m, J ═ 2.63Hz, 6H). M/z (ESI, cation) 425.0(M + H)⁺。

And step 3: 4- (4- (6-methoxypyridin-3-ylamino) -2- (piperidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (piperidin-1-yl) pyrimidin-4-amine (22mg, 0.052mmol), aqueous ammonia (0.5mL, 30% in water) and bisAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath at 100 ℃ for 23 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc, to give 4- (4- (6-methoxypyridin-3-ylamino) -2- (piperidin-1-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine (18mg, 0.046mmol, 88% yield). ¹H NMR(300MHz，CDCl₃) δ 11.88(s, 1H); 9.27(s, 1H); 8.35(s, 1H); 7.97-8.06(m, J ═ 8.18, 1.46Hz, 1H); 6.76(d, J ═ 8.92Hz, 1H); 5.21(s, 2H); 3.95(s, 3H); 3.83(s, 4H); 2.48(s, 3H); 1.57-1.76(m, 6H). M/z (ESI, cation) 394.1(M + H)⁺。

Example 124: 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyridin-4-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyridin-4-yl) pyrimidin-4-amine

2-chloro-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4 at 100 deg.CDi (38mg, 0.101mmol) of amine, pyridine-4-boronic acid (14.91mg, 0.121mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (8.26mg, 10.11. mu. mol) and cesium carbonate (39mg, 0.121mmol)The mixture of alkanes (1mL) was stirred for 1 h. The mixture was cooled to room temperature. The reaction mixture was washed with saturated NH₄Cl (10mL) was diluted and extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude product as an orange solid. The crude product was purified by silica gel chromatography eluting with 10% MeOH in EtOAc to give N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyridin-4-yl) pyrimidin-4-amine (11mg, 0.026mmol, 26.0% yield). ¹H NMR(300MHz，CDCl₃) δ 11.69(s, 1H); 9.78(s, 1H); 8.62-9.02(m, 2H); 8.46(s, 1H); 8.29-8.43(m, 1H); 8.24(d, J ═ 4.53Hz, 1H); 8.04-8.14(m, 1H); 6.79-6.93(m, 1H); 5.30(s, 2H); 4.00(s, 3H); 2.69(s, 3H); 2.67(s, 3H). M/z (ESI, cation) 419.1(M + H)⁺。

Step 2: 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyridin-4-yl) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -2- (pyridin-4-yl) pyrimidin-4-amine (8mg, 0.019mmol), aqueous ammonia (0.5mL, 23.11mmol) (30% in water) and bisAlkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 100 ℃ for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc, to give 4- (4- (6-methoxypyridin-3-ylamino) -2- (pyridin-4-yl) pyrimidin-5-yl) -6-methyl-1,3, 5-triazin-2-amine (4mg, 10.33. mu. mol, 54.0% yield).¹H NMR (300MHz, d 6-DMSO). delta.11.96 (s, 1H); 8.77(d, J ═ 5.12Hz, 1H); 8.59(s, 1H); 8.21(dd, J ═ 9.06, 2.34Hz, 1H); 8.15(d, J ═ 5.12Hz, 1H); 7.99(s, 1H); 7.82(s, 1H); 6.96(d, J ═ 8.77Hz, 1H); 3.90(s, 2H); 2.45(s, 3H). M/z (ESI, cation) 388.1(M + H) ⁺。

Example 125: 4- (2- (4-fluorophenyl) -4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 2- (4-fluorophenyl) -N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine

Di (38mg, 0.101mmol) of 2-chloro-N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine, 4-fluorobenzeneboronic acid (16.98mg, 0.121mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (8.26mg, 10.11. mu. mol) and cesium carbonate (66mg, 0.202mmol) at 100 deg.CA mixture of alkane (3mL) and water (0.5mL) was stirred for 1 h. The mixture was cooled to room temperature. The reaction mixture was washed with saturated NH₄Cl (5mL) was diluted and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 30% EtOAc/hexanes to give 2- (4-fluorophenyl) -N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (23mg, 0.053mmol, 52.2% yield).¹H NMR(300MHz，CDCl₃)δ11.64(s，1H)；9.73(s， 1H)；8.39-8.50(m，3H)；8.11(dd，J＝8.77，2.48Hz，1H) (ii) a 7.16(t, J ═ 8.62Hz, 2H); 6.87(d, J ═ 8.92Hz, 1H); 4.00(s, 3H); 2.67(d, J ═ 4.38Hz, 6H). M/z (ESI, cation) 436.1(M + H) ⁺。

Step 2: 4- (2- (4-fluorophenyl) -4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine

2- (4-fluorophenyl) -N- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidin-4-amine (12mg, 0.028mmol), aqueous ammonia (0.5mL, 30% in water) and bisAlkane (1mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath at 100 ℃ for 17 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes, to give 4- (2- (4-fluorophenyl) -4- (6-methoxypyridin-3-ylamino) pyrimidin-5-yl) -6-methyl-1, 3, 5-triazin-2-amine.¹H NMR(300MHz，CDCl₃) δ 9.60(s, 1H); 8.35-8.54(m, 3H); 8.12(dd, J ═ 8.84, 2.41Hz, 1H); 7.15(t, J ═ 8.62Hz, 2H); 6.86(d, J ═ 8.92Hz, 1H); 5.44(s, 2H); 3.99(s, 3H); 2.56(s, 3H). M/z (ESI, cation) 405.0(M + H)⁺。

Example 126: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine

Step 1: N2-cyclopentyl-5-iodo-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine

2-chloro-5-iodo-N- (6-methoxypyridin-3-yl) pyrimidin-4-amine (181mg, 0.499mmol), cyclopentylamine (85mg, 0.998mmol), and ethanol (3mL) were charged to a glass microwave reaction vessel. Microwave reaction at 140 ℃ in an Emrys Optimizer The reaction mixture was stirred and heated in a vessel (Personal Chemistry, Biotage AB, inc., Upssala, Sweden) for 30 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes, to give N2-cyclopentyl-5-iodo-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine (188mg, 0.457mmol, 92% yield).¹H NMR(300MHz，CDCl₃) δ 8.30(s, 1H); 8.14(s, 1H); 7.82(d, J ═ 10.38Hz, 1H); 6.75(d, J ═ 8.92Hz, 1H); 6.66(s, 1H); 4.79-4.96(m, 1H); 4.10(dd, J ═ 13.15, 4.53Hz, 1H); 3.94(s, 3H); 1.97(dd, J ═ 11.62, 5.19Hz, 2H); 1.56-1.78(m, 4H); 1.35-1.50(m, 2H). M/z (ESI, cation) 412.0(M + H)⁺。

Step 2: N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine

N2-cyclopentyl-5-iodo-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine (145mg, 0.353mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) -1, 3, 5-triazine (152mg, 0.353mmol), copper (I) iodide (14mg, 0.071mmol), cesium fluoride (107mg, 0.705mmol), tetrakis (triphenylphosphine) palladium (0) (40.7mg, 0.035mmol) and bisAlkane (3mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 20 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a black solid. The crude product was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine as a white solid (52mg, 0.122mmol, 34.7% yield).¹H NMR(300MHz，CDCl3)δ11.46-11.87(m，1H)；9.15-962(m, 1H); 8.26-8.63(m, 1H); 7.84-8.26(m, 1H); 6.77(d, J ═ 8.77Hz, 1H); 5.11-5.52(m, 1H); 4.12-4.56(m, 1H); 3.95(s, 3H); 2.59(d, J ═ 6.87Hz, 6H); 1.87-2.21(m, 2H); 1.56-1.87(m, 4H). M/z (ESI, cation) 425.1(M + H)⁺。

And step 3: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine

N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) -5- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) pyrimidine-2, 4-diamine (36mg, 0.085mmol), aqueous ammonia (0.5mL, 23.11mmol) and bisAlkane (2mL) was charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath for 24h at 100 ℃. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc, to give 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N2-cyclopentyl-N4- (6-methoxypyridin-3-yl) pyrimidine-2, 4-diamine (28mg, 0.071mmol, 84% yield). ¹H NMR(300MHz，CDCl₃) δ 11.99(s, 1H); 9.21(s, 1H); 8.29-8.56(m, 1H); 8.19(s, 1H); 6.76(d, J ═ 8.92Hz, 1H); 5.26(s, 3H); 4.25(s, 1H); 3.95(s, 3H); 2.49(s, 3H); 2.04(s, 2H); 1.34-1.87(m, 6H). M/z (ESI, cation) 394.1(M + H)⁺。

Example 127: 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

The title compound was prepared following the procedure described for example 62, with deprotection of the purine performed as follows. Dissolving 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) in THF (2ml)Pyridin-2-amine (0.100g, 0.221mmol) and 1.0M hydrochloric acid (1.106mL, 1.106mmol) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated at 100 ℃ for 10 minutes (100 watts, enabling the Powermax feature) in a Discover-type microwave reactor (CEM, Matthews, NC). The mixture was diluted with DCM, made basic with 1N NaOH (pH about 12) and the mixture was stirred for 10 min. The precipitate was collected by filtration and washed with diethyl ether to give 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine (0.060g, 0.163mmol, 73.7% yield) as a yellow solid. ¹H NMR (400MHz, d 6-DMSO). delta.13.83 (s, 1H); 10.24(s, 1H); 8.54(s, 1H); 8.18(s, 2H); 8.06(s, 1H); 3.85(s, 3H); 2.73(s, 3H); 1.62(s, 2H). M/z (ESI, cation) 367.9(M + H)⁺。

Example 128: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d] Azole-5-amines

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.496g, 6.49mmol), 5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (2.000g, 5.90mmol), potassium acetate (1.777g, 18.10mmol), Am-Phos (0.403g, 0.649mmol), di (N-methyl-l-amino-phenyl) acetic acid (N-methyl-phenyl) ethyl acetate, di (N-methyl-phenyl) ethyl-4-chloro-N, N-bis (4-methoxybenzyl) -6Alkane (20mL) and water (3.00mL, 167mmol) were charged to a microwave vial (80 mL). The vials were heated in a CEM Voyager microwave (large scale apparatus) at 120 ℃ for 25 minutes,while supplying 100 watts of energy via Powermax (a simultaneous heating and cooling technique). The reaction mixture was diluted with water (15mL) and extracted with chloroform (3X 50 mL). Combining the organic extracts over Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was adsorbed onto a silica gel packed column and purified by chromatography, pre-filled with silica gel column (220g) via SiliCycle siliasaep, with 10% to 100% ethyl acetate/hexanes, over 45min to give tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (3.000g, 4.66mmol, 79% yield) as a yellow oil.¹H NMR (400MHz, d6-DMSO) δ 8.50(dd, J ═ 9.39, 2.35Hz, 1H); 8.28(d, J ═ 1.37Hz, 1H); 7.25(d, J ═ 8.61Hz, 4H); 6.89(dd, J ═ 11.15, 8.61Hz, 4H); 6.70-6.81(m, 1H); 4.77(d, J ═ 4.69Hz, 4H); 3.65-3.82(m, 6H); 3.58(s, 2H); 3.24-3.37(m, 4H); 2.47(s, 3H); 2.28-2.38(m, 4H); 1.33-1.50(m, 9H). M/z (ESI, cation) 644.2(M + H)⁺。

Step 2: 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (3.000g, 4.66mmol) and trifluoroacetic acid (5.39mL, 69.9mmol) dissolved in 1, 2-dichloroethane (20mL) were charged to a glass microwave reaction vessel (80 mL). The reaction mixture was stirred and heated at 80 ℃ for 5min in a CEM Voyager type (large apparatus) microwave (100 Watts, enabling Powermax characteristics). The mixture was concentrated in vacuo to remove as much residual TFA as possible. The crude mixture (3.4g) was dissolved in THF (30mL), cooled to-20 deg.C, and sodium carbonate (4.94g, 46.6mmol) was added to the mixture. After 10min, methanesulfonyl chloride (3.63mL, 46.6mmol) was added dropwise. After addition, the mixture was allowed to warm slowly to ambient temperature overnight. The mixture was diluted with DCM and water (30 ml). Reacting the mixture with CH ₂Cl₂(3×20mL) was extracted. The combined organic extracts are passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude product as a tan oil. This crude product was purified by chromatography, pre-packed with a silica gel column (120 g) via a SiliCycle SiliaSep, eluting with a 30min gradient of 10% to 100% EtOAc in hexanes, followed by a 20 min gradient of 1% to 15% MeOH in DCM to give 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.702g, 2.74mmol, 58.7% yield) as a pale yellow solid.¹H NMR(400MHz，CDCl₃) δ 8.46(dd, J ═ 9.00, 2.15Hz, 1H); 8.24(d, J ═ 1.37Hz, 1H); 7.23(dd, J ═ 8.51, 6.94Hz, 4H); 6.86(t, J ═ 8.71Hz, 4H); 4.81(d, J ═ 1.96Hz, 4H); 3.81(d, J ═ 6.26Hz, 6H); 3.60(s, 2H); 3.23(s, 4H); 2.74-2.80(m, 3H); 2.56-2.61(m, 4H); 2.55(s, 3H). M/z (ESI, cation) 622.1(M + H)⁺。

And step 3: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d] Azole-5-amines

4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.900g, 1.448mmol) and benzo [ d [ -methyl ] amino ] A mixture of oxazol-5-amine (0.388g, 2.90mmol) in THF (20mL) was cooled to-20 deg.C and treated with 1.0M lithium bis (trimethylsilyl) amide dissolved in THF (5.07mL, 5.07mmol) added dropwise. The mixture was allowed to warm slowly to ambient temperature. The reaction mixture was diluted with water (15mL) and CH₂Cl₂(3X 50 mL). The combined organic extracts are passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated to give the crude product as a tan solid. The crude product is producedThe material was pre-filled with silica gel column (120 g) by chromatography via SiliCycle SiliaSep to dissolve in CH₂Cl₂To give N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] d as a tan oil, eluting with a 30min gradient of 0% to 10% MeOH] Oxazol-5-amine. This material was treated with trifluoromethanesulfonic acid (0.916mL, 10.32mmol) dissolved in trifluoroacetic acid (7.75mL, 101mmol) and heated at 70 ℃ for 20 min. The mixture was cooled to ambient temperature and concentrated in vacuo. The crude residue was diluted with DCM (20mL) and neutralized with sodium bicarbonate (10 g). The mixture was stirred vigorously for 10 min. Subsequently, water (10mL) was added dropwise and stirred for 5 min. The mixture was filtered through a fine sintered funnel. The collected solid was washed with water to wash out sodium bicarbonate. The yellow solid was washed with diethyl ether and recrystallized from hot DMF to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] as a pale yellow solid ] Azole-5-amine (0.300g, 0.605mmol, 46.9% yield).¹H NMR (400MHz, d 6-DMSO). delta.12.11 (s, 1H); 8.68(s, 2H); 8.50(s, 1H); 8.29(s, 1H); 7.90(s, 1H); 7.72(d, J ═ 11.35Hz, 3H); 3.51(s, 2H); 3.12(s, 4H); 2.87(s, 3H); 2.50(m, 7H). M/z (ESI, cation) 496.1(M + H)⁺。

Example 129: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Step 1: 5- (bromomethyl) -2-fluoropyridines

A mixture of 2-fluoro-5-methyl-pyridine (15.00mL, 135mmol), N-bromosuccinimide (24.03g, 135mmol) and benzoyl peroxide (1.635g, 6.75mmol) in carbon tetrachloride (100mL) was heated at reflux for 2.5 h. The mixture was cooled and filtered through a medium fritted funnel. The solid was washed with DCM (3X 50 ml). The filtrate was concentrated to give 5- (bromomethyl) -2-fluoropyridine (25.7g, 135mmol, 100% yield) as an orange oil. M/z (ESI, cation) 191.9(M + H)⁺. The mixture was sent to the next step of the synthesis without further purification.

Step 2: 4- ((6-Fluoropyridin-3-Yl) methyl) morpholine

A solution of 5- (bromomethyl) -2-fluoropyridine (26.000g, 137mmol) in THF (30mL) was cooled to-30 deg.C and morpholine (17.88mL, 205mmol) was added slowly. After 5min, triethylamine (57.2mL, 410mmol) was added slowly. After addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 30min, the mixture was filtered through a fine sinter funnel and the filtrate was concentrated to give an orange oil. The crude material was purified by chromatography, via Thompson Instruments pre-packed silica gel (330 g) column, eluting with a 50min gradient of 0% to 100% EtOAc in hexanes to give 4- ((6-fluoropyridin-3-yl) methyl) morpholine as an orange oil (15.767g, 80mmol, 58.7% yield). ¹H NMR(400MHz，CDCl₃) δ 8.13(s, 1H); 7.79(td, J ═ 8.07, 2.45Hz, 1H); 6.90(dd, J ═ 8.31, 2.84Hz, 1H); 3.67-3.72(m, 4H); 3.49(s, 2H); 2.39-2.48(m, 4H). M/z (ESI, cation) 197.1(M + H)⁺。

And step 3: 2-fluoro-5- (morpholinomethyl) pyridin-3-ylboronic acid

A solution of diisopropylamine (13.51mL, 96mmol) in tetrahydrofuran (66mL) was treated with 2.0M n-butyllithium dissolved in hexane (48.2mL, 96mmol) at-40 deg.C and stirred for 1 h. The resulting LDA solution was cooled to-78 ℃ and a solution of 4- ((6-fluoropyridin-3-yl) methyl) morpholine (15.767g, 80mmol) in THF (50mL) was added over 20min via cannula. The dark red mixture was stirred at-78 ℃ for 1.5 h. Slow downA solution of triisopropyl borate (27.7mL, 121mmol) in THF (22mL) was added. The resulting mixture was stirred at-78 ℃ for 30min, and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture is treated with 1N NaOH_(aq)Quench (50mL) and stir. The aqueous layer was separated and the organic layer was extracted with 1N NaOH (2X 20 mL). The combined aqueous layers were carefully acidified with 5N HCl until acidic (pH 5 to about 6) and the resulting cloudy mixture was extracted with EtOAc (3 × 100 mL). The aqueous layer was freeze-dried. The resulting residue was diluted with 1: 1 MeOH/DCM and placed in a sonicator for 5 min. The mixture was filtered through a fine sintered funnel. The filtrate was concentrated to give 2-fluoro-5- (morpholinomethyl) pyridin-3-ylboronic acid (19.000g, 79mmol, 99% yield) as a brown yellow oil. ¹H NMR (400MHz, d4-MeOH) delta 8.46(s, 1H); 8.32(d, J ═ 6.06Hz, 1H); 4.42(s, 2H); 3.82-4.00(m, 4H); 3.23-3.36(m, 4H); 2.01(s, 1H). M/z (ESI, cation) 241.1(M + H)⁺。

And 4, step 4: 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (8.82g, 22.91mmol), 2-fluoro-5- (morpholinomethyl) pyridin-3-ylboronic acid (5.000g, 20.83mmol), potassium acetate (6.28g, 63.9mmol) and Am-Phos (1.036g, 1.666mmol) in a CEM Voyager microwave (Large Scale apparatus) at 120 deg.CThe mixture of alkane (40mL) and water (3.00mL, 167mmol) was heated for 25min while supplying 100 watts of energy via Powermax (simultaneous heating and cooling technique). The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50mL) and CHCl₃(3X 100 mL). Combining the organic extracts over Na₂SO₄And (5) drying. The solution was filtered and concentrated to give the crude product as a yellow oil. This crude product was purified by chromatography, pre-filled with a silica gel column (330 g) via a SiliCycle SiliaSep using a 40min gradient of 0-100% ethyl acetate/hexane followed by 1- Gradient purification with 20% methanol in dichloromethane for 30min to give a tan oil. The oil was triturated with DCM and ether and the mixture was filtered. The filtrate was concentrated to give 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.615g, 4.80mmol, 23% yield) as a pale yellow oil.¹H NMR(400MHz，CDCl₃) δ 8.13(d, J ═ 1.56Hz, 1H); 7.79(td, J ═ 7.97, 2.05Hz, 1H); 7.22(dd, J ═ 8.61, 7.04Hz, 4H); 6.81-6.92(m, 4H); 4.82(d, J ═ 3.33Hz, 2H); 3.76-3.86(m, 4H); 3.70(ddd, J ═ 9.54, 4.99, 4.84Hz, 4H); 3.45-3.57(m, 6H); 2.55(s, 3H); 2.46(dq, J ═ 12.79, 4.41Hz, 4H). M/z (ESI, cation) 545.2(M + H)⁺。

And 5: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.500g, 0.918mmol) and benzo [ d [ -methyl ] amino acid]A mixture of thiazol-5-amine (0.276g, 1.836mmol) in THF (10mL) was cooled to-20 deg.C and treated dropwise with 1.0M lithium bis (trimethylsilyl) amide dissolved in THF (3.21mL, 3.21 mmol). The mixture was slowly warmed to ambient temperature while stirring under an inert atmosphere for 1 h. The reaction mixture was diluted with water (50mL) and CHCl ₃(3X 50 mL). The combined organic extracts are passed over Na₂SO₄And (5) drying. The solution was filtered and concentrated to give the crude product as a tan solid. This crude product was purified by chromatography, pre-packed with a silica gel column (80 g) via a SiliCycle SiliaSep, with a 30 min gradient of 10% to 100% EtOAc in hexanes, followed by a 25min gradient of 1-20% MeOH/DCM to give the bis-PMB protected material as a tan oil (0.437 g). This material was treated with a mixture of trifluoroacetic acid (1.8mL, 23.36mmol) and trifluoromethanesulfonic acid (0.2mL, 2.252mmol) and the resulting solution was heated at 70 ℃ for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. The mixture was dissolved in DCM (10mL) and stirred for 5min, withSodium carbonate (2.5 g) was then added slowly to the mixture and stirred vigorously for 20 min. The solid was collected by filtration and washed with dichloromethane (2X 30mL) followed by water (3X 20 mL). Drying the solid to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-yl) benzo [ d ] as a tan solid]Thiazol-5-amine (0.155g, 0.357mmol, 38.9% yield).¹H NMR (400MHz, d 6-DMSO). delta.12.25 (s, 1H); 9.36(s, 1H); 8.91(s, 1H); 8.76(s, 1H); 8.33(s, 1H); 8.06(d, J ═ 8.80Hz, 1H); 7.94(s, 1H); 7.80(s, 2H); 3.58(s, 4H); 3.46(s, 2H); 2.44-2.54(m, 3H); 2.39(s, 4H). M/z (ESI, cation) 435(M + H) ⁺。

Example 130: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.500g, 0.918mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.261g, 1.836mmol) in THF (20mL) was cooled to-20 deg.C and treated dropwise with a 1.0M lithium bis (trimethylsilyl) amide solution (3.21mL, 3.21 mmol). The mixture was allowed to warm slowly to ambient temperature over 1 h. The reaction mixture was diluted with water (50mL) and CH₂Cl₂(3X 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude product as a tan solid. This crude product was purified by chromatography, pre-packed with a silica gel column (80 g) via a SiliCycle SiliaSep, eluting with a gradient of 0% to 100% EtOAc in hexanes over 30min to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.095g) as a tan oil. This material was treated with trifluoroacetic acid (1.8mL, 23.36mmol) and trifluoromethanesulfonic acid (0.2 m) L, 2.252mmol) and heated at 70 ℃ for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. This brown oil was dissolved in DCM (10mL) and stirred for 5min, then sodium carbonate (1.6g) was added slowly to the mixture and stirred vigorously for 20 min. The mixture was filtered and concentrated. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was diluted with ether (20mL) and placed in a sonicator for 2 min. The precipitate was collected by filtration. The solid was recrystallized from hot ethyl acetate to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.025g, 0.059mmol, 6.39% yield) as a tan solid.¹H NMR (400MHz, d 6-DMSO). delta.11.94 (s, 1H); 8.72(s, 1H); 8.41(s, 1H); 8.36(d, J ═ 12.91Hz, 1H); 8.24(s, 1H); 7.90(s, 1H); 7.75(s, 1H); 3.93(s, 3H); 3.57(s, 4H); 3.43(s, 2H); 2.44(s, 7H). M/z (ESI, cation) 427(M + H)⁺。

Example 131: 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) -2, 2-dimethylpropan-1-ol

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (95.0mg, 0.213mmol) was dissolved in THF (2.5mL) and the flask was cooled in an ice-water bath. Subsequently, tert-butylmagnesium chloride (1.0M solution in tetrahydrofuran, 0.60mL, 0.60mmol) was added via syringe to turn the reaction red. The reaction was stirred under nitrogen while warming to room temperature, and after 70min, the reaction was treated with MeOH (1.0mL) and 5N HCl (0.50 mL). The flask was fitted with a reflux condenser and placed in a pre-heated oil bath (about 50 ℃) and stirring was continued for 1 h. Subsequently, the reaction was cooled to room temperature, diluted with MeOH, concentrated and purified by preparative HPLC (10% to 100% MeCN/with0.1% TFA in water, total flow rate 100mL/min) over 28 minutes to give 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) -2, 2-dimethylpropan-1-ol (45.9mg, 97.4% purity, 52% yield).¹H NMR (d6-DMSO, 400MHz) δ 12.62(br s, 1H), 9.61(s, 1H), 8.63(s, 1H), 8.53(d, J ═ 2.74Hz, 1H), 8.21-8.14(m, 2H), 6.88(d, J ═ 9.0Hz, 1H), 4.31(s, 1H), 3.86(s, 3H), 2.85(s, 3H), 0.91(s, 9H). M/z (ESI, cation) 420(M + H) ⁺。

Examples 132 and 133: (1S) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) -2, 2-dimethylpropan-1-ol and (1R) -1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) -2, 2-dimethylpropan-1-ol.

An isomeric mixture of 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) -2, 2-dimethylpropan-1-ol (example 131) was purified by chiral SFC preparative chromatography. The following conditions were used:

column: IC (250X 21mm, 5 μm). times.2

Mobile phase: 65: 35 (A: B)

A: liquid CO₂

B: methanol (0.2% DEA)

Flow rate: 50mL/min

Oven/column temperature: 40 deg.C

About 2 mg/injection

The two separate peaks containing the two enantiomers were collected, concentrated and dried under high vacuum to give the two enantiomers.

First elution peak (example 132):

¹h NMR (d6-DMSO, 400MHz) δ 12.80(s, 1H), 9.80(s, 1H), 8.54(d, J ═ 2.74Hz, 1H), 8.48(s, 1H), 8.21(dd, J ═ 8.90Hz, 2.84Hz, 1H), 8.17(d, J ═ 2.35Hz, 1H), 6.84(8.80Hz, 1H), 5.24(d, J ═ 3.72Hz, 1H), 4.29(d, J ═ 3.52Hz, 1H), 3.84(s, 3H), 2.83(s, 3H), 0.90(s, 9H). M/z (ESI, cation) 420(M + H) ⁺。

Second elution peak (example 133):

¹h NMR (d6-DMSO, 400MHz) δ 12.65(s, 1H), 9.78(s, 1H), 8.57(s, 1H), 8.54(d, J ═ 2.15Hz, 1H), 8.22(d, J ═ 2.35Hz, 1H), 8.19(s, 1H), 6.84(d, J ═ 8.80Hz, 1H), 5.26(s, 1H), 4.29(s, 1H), 3.84(s, 3H), 2.85(s, 3H), 0.90(s, 9H). M/z (ESI, cation) 420(M + H)⁺。

Chiral HPLC analysis showed ee > 99.9% for the two resolved enantiomers.

Example 134: 5- ((tert-butylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (99.5mg, 0.223mmol) was suspended in CH₂Cl₂(1.5mL) and ethanol (1.5mL) and tert-butylamine (0.075mL, 0.71mmol) and titanium tetraisopropoxide (0.20mL, 0.68mmol) were added. The reaction was stirred at room temperature for 20min under nitrogen, and then equipped with a reflux condenser and placed in a preheated oil bath (about 50 ℃) and stirred for 90 min. Subsequently, the reaction was cooled to room temperature and boron hydride was addedSodium (28.7mg, 0.759mmol) and MeOH (1.0 mL). The reaction was stirred at room temperature for 45 minutes, and then more MeOH and 5N HCl (0.50mL) were added, and stirring was continued at room temperature overnight. Subsequently, the reaction was diluted with DCM and MeOH and passed through Celite The pad was filtered and washed with DCM, MeOH, and a 1: 1 mixture of the two solvents. The filtrate was concentrated and diluted with DCM and MeOH, and passed through another CeliteThe pad was filtered and washed with DCM and MeOH. The filtrate was concentrated and purified by preparative HPLC to give 5- ((tert-butylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine as a TFA salt (51.1mg, 98.3% purity, 43% yield).¹H NMR (d6-DMSO, 400MHz) δ 12.74(br s, 1H), 9.81(br s, 1H), 8.70(s, 1H), 8.65(br s, 2H), 8.59(d, J ═ 2.74Hz, 1H), 8.42(d, J ═ 2.35Hz, 1H), 8.14(dd, J ═ 8.80Hz, 2.74Hz, 1H), 6.89(d, J ═ 8.80Hz, 1H), 4.18(br s, 2H), 3.86(s, 3H), 2.87(s, 3H), 1.39(s, 9H). M/z (ESI, cation) 419(M + H)⁺。

Example 135: 5- ((isopropylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (90.6mg, 0.203mmol) was suspended in ethanol (1.2mL) and DCM (1.2mL) and isopropylamine (0.060mL, 0.70mmol) and titanium tetraisopropoxide (0.20mL, 0.68mmol) were added. The reaction was stirred at room temperature for 75min, and then sodium borohydride (26.8mg, 0.708mmol) was added along with MeOH (1mL) and stirring continued at room temperature. After 2h, add More MeOH and 5N HCl (0.50mL) were added and stirring was continued overnight. The suspension was diluted with DCM and MeOH and passed through CeliteThe pad was filtered and washed with DCM and MeOH. The filtrate was concentrated and purified by preparative HPLC to give 5- ((isopropylamino) methyl) -N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine as a TFA salt (79.5mg, purity 97.1%, yield 76%).¹H NMR (d6-DMSO, 400MHz) δ 12.71(br s, 1H), 9.80(br s, 1H), 8.69(s, 1H), 8.65(br s, 2H), 8.58(d, J ═ 2.74Hz, 1H), 8.42(d, J ═ 2.15Hz, 1H), 8.14(dd, J ═ 9.00Hz, 2.74Hz, 1H), 6.89(d, J ═ 9.00Hz, 1H), 4.24-4.18(m, 2H), 3.86(s, 3H), 3.48-3.38(m, 1H), 2.87(s, 3H), 1.31(d, J ═ 6.46Hz, 6H). M/z (ESI, cation) 405(M + H)⁺。

Example 136: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-2-ylmethylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (73.8mg, 0.166mmol) was suspended in CH₂Cl₂(1.5mL) and EtOH (1.5mL) and 2- (aminomethyl) pyridine (0.050mL, 0.49mmol) and titanium tetraisopropoxide (0.15mL, 0.51mmol) were added via syringe. The reaction was stirred at room temperature under nitrogen for 90min, and then sodium borohydride (26.3mg, 0.695mmol) and MeOH (1.0mL) were added, and stirring was continued. After 70min, more MeOH and 5N aqueous HCl (0.50mL) were added and stirring was continued overnight. The suspension was diluted with DCM and MeOH and passed through Celite The pad was filtered and washed with DCM and MeOH.The filtrate was concentrated, treated with DMSO and TFA and purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 minutes using total flow rate 100mL/min) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-2-ylmethyl amino) methyl) pyridin-2-amine as the TFA salt (52.1mg, 55% yield).¹H NMR (d6-DMSO, 400MHz) δ 12.69(br s, 1H), 9.81(br s, 1H), 9.46(br s, 2H), 8.68(s, 1H), 8.66(d, J ═ 4.30Hz, 1H), 8.56(d, J ═ 2.74Hz, 1H), 8.41(d, J ═ 2.35Hz, 1H), 8.14(dd, J ═ 9.00Hz, 2.74Hz, 1H), 7.89(dt, J ═ 7.73Hz, 1.76Hz, 1H), 7.51(d, J ═ 7.82Hz, 1H), 7.46-7.41(m, 1H), 6.88(d, J ═ 8.80Hz, 1H), 4.41(s, 2H), 4.29.2 s, 2H), 3.86 (s, 3H). M/z (ESI, cation) 454(M + H)⁺。

Example 137: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-4-ylmethylamino) methyl) pyridin-2-amine

6- (6-Methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (102.5mg, 0.230mmol) was suspended in dichloromethane (1.3mL) and EtOH (1.3mL) and 4- (aminomethyl) pyridine (0.070mL, 0.69mmol) and titanium tetraisopropoxide (0.20mL, 0.68mmol) were added. The reaction was stirred at room temperature under nitrogen. After 50min, sodium borohydride (30.8mg, 0.814mmol) and MeOH (1mL) were added and stirring continued at room temperature. After 1h, more MeOH and 5N aqueous HCl (0.60mL) were added and stirring continued over the weekend at room temperature. Subsequently, the reaction was treated with DCM and MeOH, and passed through Celite The pad was filtered and washed with DCM and MeOH. The filtrate was concentrated and treated with DCM and TFA, and some DMSO (about 1mL) was concentrated. Dissolving the material in water and partiallyConcentration, resulting in the formation of a precipitate. The suspension was filtered and the solid was washed with MeOH. The solid was set aside. The filtrate was concentrated and filtered again. The solids were combined with the solids collected from the first filtration. The filtrate was concentrated and purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 28 min). Fractions with product were combined with the solid that had been collected, concentrated and dried first under high vacuum at about 50 ℃ and then under high vacuum at room temperature overnight to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-4-ylmethylamino) methyl) pyridin-2-amine as the TFA salt (126.6mg, 96.7% purity, 97% yield).¹H NMR(D₂O, 400MHz) δ 8.83-8.77(m, 4H), 8.43(s, 1H), 8.21(dd, J ═ 8.41Hz, 2.35Hz, 2H), 8.08-8.03(m, 3H), 7.82(dd, J ═ 9.00Hz, 2.74Hz, 1H), 6.95(dd, J ═ 9.00Hz, 1H), 4.63(s, 2H), 4.51(s, 2H), 4.42(s, 2H), 3.91(s, 3H), 2.69(s, 3H). M/z (ESI, cation) 454(M + H) ⁺。

Example 138: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-3-ylmethylamino) methyl) pyridin-2-amine

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (113.7mg, 0.255mmol) was suspended in dichloromethane (1.3mL) and ethanol (1.3mL) and 3- (aminomethyl) pyridine (0.080mL, 0.79mmol) and titanium tetraisopropoxide (0.23mL, 0.78mmol) were added. The reaction was stirred at room temperature under nitrogen. After 85min, sodium borohydride (33.8mg, 0.893mmol) and MeOH (1mL) were added and stirring continued at room temperature. After another 70min, 5N HCl (0.50mL) was added along with MeOH and stirring continued at room temperature for 3 days. More 5n hcl (0.20mL) and MeOH was added and stirring was continued at room temperature overnight. The suspension was diluted with DCM and MeOH and passed through CeliteThe pad was filtered and washed with DCM and MeOH. The filtrate was concentrated, treated with DCM, MeOH, TFA and concentrated again. The material was dissolved with water and MeOH and purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 28 minutes). The HPLC fractions with product were collected, concentrated, and dried first at 50 ℃ under high vacuum in a water bath and then at room temperature overnight under high vacuum to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((pyridin-3-ylmethylamino) methyl) pyridin-2-amine as a TFA salt (117.1mg, 81% yield). ¹H NMR(D₂O, 400MHz) δ 8.94(s, 1H), 8.92-8.87(m, 1H), 8.83(d, J ═ 5.87Hz, 1H), 8.69(d, J ═ 8.22Hz, 1H), 8.47(s, 1H), 8.37(s, 1H), 8.26(d, J ═ 2.15Hz, 1H), 8.13-8.06(m, 1H), 7.98(dd, J ═ 9.19Hz, 2.54Hz, 1H), 7.11(d, J ═ 9.19Hz, 1H), 4.61(s, 2H), 4.44(s, 2H), 3.99(s, 3H), 2.73(s, 3H). M/z (ESI, cation) 454(M + H)⁺。

Example 139: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol

Step 1: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylthio) phenyl) methanol

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (209.2mg, 0.470mmol) was suspended in THF (5.0mL) and the reaction flask was cooled in an ice-water bath under nitrogen. Subsequently, 4-thioanisole magnesium bromide (0.5M solution in tetrahydrofuran, 2.5mL, 1.3mmol) was added via syringe and the reaction was slowly warmed upAnd (4) cooling to room temperature. After 1h, the reaction was quenched with saturated ammonium chloride and diluted with water. The reaction was extracted with 10: 1 DCM/MeOH. The organic extracts were combined, concentrated, and purified on a silica gel filter (about 1 inch in a 30ml sintered filter using 50: 1 DCM/2N aqueous ammonia in MeOH to 20: 1 DCM/2N aqueous ammonia in MeOH to 5: 1 DCM/2N aqueous ammonia in MeOH). Fractions with product were collected, concentrated, and dried under high vacuum to give (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylthio) phenyl) methanol (241 mg). ¹H NMR(CDCl₃) δ 12.51(s, 1H), 9.80(s, 1H), 8.39(s, 1H), 8.26-8.18(m, 3H), 7.43-7.38(m, 2H), 7.26-7.20(m, 2H), 6.77(d, J ═ 8.41Hz, 1H), 5.90(s, 1H), 5.85(d, J ═ 10.17Hz, 1H), 4.20(d, J ═ 11.35Hz, 1H), 3.95(s, 3H), 3.83(t, J ═ 11.25Hz, 1H), 2.89(s, 3H), 2.74(s, 1H), 2.47(s, 3H), 2.17-1.65(m, 6H). M/z (ESI, cation) 570(M + H)⁺。

Step 2: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol

(6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylthio) phenyl) methanol (241mg, 0.423mmol) was dissolved in DCM (4.0mL) and the reaction flask was cooled in an ice-water bath under nitrogen. Subsequently, mCPBA (180.5mg, 1.046mmol) was added via syringe as a solution in DCM (5mL) and the reaction was warmed to room temperature and stirred. After 45min, more mCPBA (58mg, 0.34mmol) was added and stirring continued. After 25min, more mCPBA (27.3mg, 0.158mmol) was added and stirring continued. After 15 minutes, the reaction was treated with a solution of 10mL saturated sodium bicarbonate and 2mL saturated sodium thiosulfate. The mixture was stirred at room temperature for 30 min. Subsequently, the layers were separated and the aqueous phase was extracted with DCM and then 10: 1 DCM/MeOH. The organic extracts were combined, washed with brine, concentrated, and dried under high vacuum in a water bath (about 40 ℃) to give (6- (6-methoxy-6) Pyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol was used directly in the next step.¹H NMR(CDCl₃400MHz) δ 12.54(s, 1H), 9.75(s, 1H), 8.40(s, 1H), 8.27-8.21(m, 2H), 8.17(d, J ═ 8.22Hz, 1H), 7.95-7.89(m, 2H), 7.74-7.68(m, 2H), 6.78(d, J ═ 10.17Hz, 1H), 6.01(s, 1H), 5.85(d, J ═ 11.93Hz, 1H), 4.21(d, J ═ 13.11Hz, 1H), 3.95(s, 3H), 3.87-3.77(m, 1H), 3.03(s, 3H), 2.97-2.89(m, 1H), 2.89(s, 3H), 2.19-1.95(m, 3H), 1.93-1H). M/z (ESI, cation) 602(M + H)⁺。

And step 3: (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol

(6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol (crude from the previous step) was suspended in MeOH (5.0mL) and aqueous hydrochloric acid (5N, 0.50mL, 2.5mmol) was added. The reaction was stirred at room temperature for about 2h and then diluted with DCM and MeOH. After 3.5h, the suspension was filtered. HPLC showed neither the solid nor the filtrate to be > 95% pure, so they were combined, concentrated, treated with water and filtered. The solid was collected, treated with DMSO and TFA, and passed through Celite (diatomaceous earth) pad filtration. The filtrate was purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, total flow rate 100mL/min over 28 min) to give (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) (4- (methylsulfonyl) phenyl) methanol (122.4mg, 56% yield over two steps).¹H NMR (d6-DMSO, 400MHz) included δ 12.62(br s, 1H), 9.84(br s, 1H), 8.62(s, 1H), 8.52(d, J ═ 2.54Hz, 1H), 8.29(d, J ═ 2.15Hz, 1H), 8.16(dd, J ═ 8.71Hz, 2.64Hz, 1H), 7.90(d, J ═ 8.22Hz, 2H), 7.73(d, J ═ 8.22Hz, 2H), 6.84 (c), (cd, J ═ 8.80Hz, 1H), 5.91(s, 1H), 3.84(s, 3H), 3.17(s, 3H), 2.84(s, 3H). M/z (ESI, cation) 518(M + H)⁺。

Example 140: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine

Step 1: 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol

6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) nicotinaldehyde (641.5mg, 1.440mmol) was suspended in THF (14mL) and the reaction was cooled in an ice bath under nitrogen. Subsequently, methyl magnesium bromide (3.0M solution in ether, 1.65mL, 4.95mmol) was added via syringe and the reaction was allowed to warm to room temperature. After 1 hour 45 minutes, the reaction was cooled in an ice bath and treated dropwise with saturated ammonium chloride, initially observing gas evolution. Subsequently, the reaction was warmed to room temperature and diluted with water (15 mL). The layers were separated and the aqueous phase was extracted with 10: 1 DCM/MeOH. The organic layer and organic extracts were combined, concentrated, and dried under high vacuum to give 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol (725 mg). ¹H NMR(CDCl₃400MHz) δ 12.52(s, 1H), 9.81(s, 1H), 8.43(s, 1H), 8.36-8.19(m, 3H), 6.83-6.77(m, 1H), 5.88(d, J ═ 9.00Hz, 1H), 5.01(d, J ═ 5.87Hz, 1H), 4.21(d, J ═ 10.95Hz, 1H), 3.89-3.81(m, 1H), 2.91(s, 3H), 2.21-1.65(m, 6H), 1.63-1.61(m, 3H). M/z (ESI, cation) 462(M + H)⁺。

Step 2: n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine

1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol (14.2mg, 0.031mmol) was dissolved in DCM (1mL) and triethylamine (Aldrich 99.5%, 0.020mL, 0.14mmol) was added. The reaction was cooled in an ice bath under nitrogen and methanesulfonyl chloride (0.010mL, 0.13mmol) was added. The reaction was stirred at 0 ℃ for 15min under nitrogen and then 1-methanesulfonylpiperazine (35mg, 0.21mmol) was added. The reaction was warmed to room temperature and stirred further. After 90min, the reaction was diluted with MeOH (1mL) and 5N aqueous HCl (0.20mL) was added. Stirring was continued for 3.5h at room temperature. Water was also added.

Separately, 1- (6- (6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethanol (231mg, 0.501mmol) was dissolved in DCM (10mL) and triethylamine (Aldrich 99.5%, 0.28mL, 2.0mmol) was added. The reaction was cooled in an ice-water bath and methanesulfonyl chloride (0.15mL, 1.9mmol) was added. The reaction was stirred at 0 ℃ for 15min, and then 1-methanesulfonylpiperazine (474.4mg, 2.89mmol) was added, causing precipitation. The reaction was warmed to room temperature and stirred further. After 2h, the reaction was diluted with MeOH (10mL) and 5N HCl (2.0mL) was added. Stirring was continued at room temperature. After another 1 hour, this reactant was combined with the other reactant, treated with 5N NaOH and 5N HCl to adjust the pH to about 6, and allowed to stand at room temperature over the weekend. The resulting suspension was filtered and the solid was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was washed with water. The filtrate was discarded. The solid was collected and purified by preparative HPLC (10% to 100% MeCN/water with 0.1% TFA, using a total flow rate of 100mL/min over 28 minutes) to give N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine as the TFA salt (81.0mg, 24% yield). ¹H NMR(d6-DMSO，400MHz)δ12.61(br s，1H)，9.78(s，1H)，8.67(s，1H)，8.54(d，J＝2.54Hz，1H)，8.40(d，J＝2.35Hz，1H)，8.16(dd，J＝9.0Hz，2.74Hz，1H)，6.87(d, J ═ 8.80Hz, 1H), 4.69(br, s, 1H), 3.85(s, 3H), 3.45-3.00(m, 6H), 2.98(s, 3H), 2.86(s, 3H), 1.76(d, J ═ 7.04Hz, 3H). M/z (ESI, cation) 524(M + H)⁺。

Example 141: 4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.37g, 6.15mmol), 2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-ylboronic acid (1.89g, 6.83mmol), Am-Phos (224mg, 0.316mmol) and potassium acetate (2.72g, 27.7mmol) were suspended in EtOH (30mL) and water (7.5 mL). Nitrogen was bubbled through the suspension for about 20 seconds, and then the flask was fitted with a reflux condenser and placed into a preheated oil bath (80 ℃ -88 ℃) and the reaction was stirred under nitrogen for 2 hours 45 minutes. Subsequently, the reaction was cooled to room temperature, treated with water (90mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated. The residue was washed with hexane, but the hexane purge still contained product. Thus, these rinses were combined with the residue and concentrated. The material was purified on a silica gel filter (600 mL sintered filter funnel with about 3 inches of silica; 5: 1 DCM/hexane to DCM to 40: 1 DCM/MeOH to 30: 1 DCM/MeOH) to give 4- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.843 g). ¹H NMR(CDCl₃，400MHz)δ8.32(dd，J＝9.00Hz，2.35Hz，1H)，8.14(dd，J＝1.56Hz，1H)，7.24-7.18(m，6H)，7.13-7.09(m，2H)，6.90-6.83(m，4H)，4.81(s，2H)，4.78(s，2H)，3.99(s，2H)，3.82(s，3H)，3.80(s，3H)，2.53(s，3H) 2.46(s, 3H). M/z (ESI, cation) 582(M + H)⁺。

Step 2: 4- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (4- (methylthio) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (624.5 mg.1.074mmol) was dissolved in DCM (11mL) and the flask cooled in an ice-water bath. Subsequently, mCPBA (557mg, 3.23mmol) was added as a solution in DCM (17.5mL) and the reaction was warmed to room temperature and stirred under nitrogen. After 35min, the reaction was treated with a mixture of saturated sodium bicarbonate (25mL) and saturated sodium thiosulfate (6mL) and stirring was continued at room temperature. After 50 min, the layers were separated and the aqueous phase was extracted with DCM. The organic phase was dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (30 mL sintered filter with about 1 inch of silica gel; DCM to 50: 1 DCM/MeOH) to give 4- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (539.6mg, 75% yield calculated as 91% purity).¹H NMR(CDCl₃400MHz) δ 8.34(dd, J ═ 8.90Hz, 2.45Hz, 1H), 8.16(d, J ═ 1.76Hz, 1H), 7.89(d, J ═ 8.41Hz, 2H), 7.40(d, J ═ 8.22Hz, 2H), 7.21(d, J ═ 8.61Hz, 4H), 6.90-6.82(m, 4H), 4.82(s, 2H), 4.79(s, 2H), 4.13(s, 2H), 3.82(s, 3H), 3.80(s, 3H), 3.03(s, 3H), 2.54(s, 3H). M/z (ESI, cation) M/z 614(M + H) ⁺。

And step 3: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (503mg, 0.820mmol) and 5-amino-2-methoxypyridine (112mg, 0.905mmol) were dissolved in THF (8.0mL) and the flask was cooled in an ice-water bath while the reaction was stirred under nitrogen. Subsequently, add the bis via syringeLithium (trimethylsilyl) amide (1.0M solution in tetrahydrofuran, 2.5mL, 2.500mmol) and the reaction stirred for 40 min. Subsequently, the reaction was treated with ice water (0.60mL) and the reaction was diluted with DCM, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica; DCM to 100: 1 DCM/MeOH to 50: 1 DCM/MeOH). The pure fractions were set aside while the impure fractions were collected, concentrated and purified on another silica filter (30 mL sintered filter with about 1 inch of silica; DCM to 100: 1/MeOH). The fractions with product were combined with the pure fractions from the first column and concentrated to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (412 mg). ¹H NMR(CDCl₃400MHz δ 11.58(s, 1H), 8.61(d, J ═ 2.35Hz, 1H), 8.26(d, J ═ 2.54Hz, 1H), 8.13(d, J ═ 2.35Hz, 1H), 7.87(dd, J ═ 8.90Hz, 2.64Hz, 1H), 7.81(d, J ═ 8.22Hz, 2H), 7.37(d, J ═ 8.22Hz, 2H), 7.21(d, J ═ 8.61Hz, 2H), 7.15(d, J ═ 8.61Hz, 2H), 6.87(d, J ═ 8.61Hz, 2H), 6.82(d, J ═ 8.41Hz, 2H), 6.70(d, J ═ 8.80, 1H), 4.85H (s, 4.85H), 3.3.3H, 3.3H, 3H), 3.93H, 3.7H, 3H, and. M/z (ESI, cation) 718(M + H)⁺

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (412mg, 0.574mmol) was suspended in trifluoroacetic acid (Aldrich redistilled 99 +%, 6.0mL, 78mmol) and the flask was fitted with a reflux condenser and placed in a pre-heated oil bath (75 deg.C) and the reaction stirred overnight. Subsequently, the reaction was cooled to room temperature and concentrated, and diluted with saturated sodium bicarbonate followed by 5N NaOH to raise the pH to about 8-9. The suspension was filtered and the solid was washed with water. Will be provided with The filtrate was discarded, and the solid was collected with DCM and MeOH, concentrated, treated with MeOH and filtered. The solid was washed with MeOH. The solid was not > 95% pure by HPLC, so the filtrate and solid were combined, concentrated and purified on a silica gel column (30: 1 to 20: 1 DCM/MeOH). Fractions with product were collected, concentrated, treated with MeOH and filtered. The yellow solid was washed with MeOH, collected, and dried at room temperature under high vacuum overnight to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (126.1mg, 46% yield) as a yellow powder.¹H NMR(CDCl₃400MHz) δ 11.64(s, 1H), 8.65(d, J ═ 2.15Hz, 1H), 8.36(d, J ═ 2.35Hz, 1H), 8.17(d, J ═ 1.56Hz, 1H), 8.11(dd, J ═ 8.90Hz, 2.25Hz, 1H), 7.88(d, J ═ 8.22Hz, 2H), 7.42(d, J ═ 7.82Hz, 2H), 6.78(d, J ═ 8.80Hz, 1H), 5.36(br s, 2H), 4.04(s, 2H), 3.95(s, 3H), 3.04(s, 3H), 2.56(s, 3H). M/z (ESI, cation) 478(M + H)⁺。

Example 142: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (602.4mg, 0.9816mmol) and 5-fluoro-6-methoxypyridin-3-amine (159.0mg, 1.119mmol) were dissolved in THF (10mL) and the reaction flask was cooled in an ice-water bath. Subsequently, lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran, 3.0mL, 3.0mmol) was added via syringe and the reaction stirred under nitrogen for 35 min. Followed byThe reaction was diluted with water (20mL) and then extracted with DCM. Brine was added to the biphasic mixture and extraction with DCM was continued. Water and MeOH was also added to the aqueous phase to help break the emulsion. The organic extracts (total about 350mL) were combined and washed with brine (50 mL). The brine layer was extracted with DCM and all organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered funnel with about 2 inches of silica; 100: 1 DCM/MeOH) to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (384.7 mg). ¹H NMR(CDCl₃400MHz) δ 11.82(br s, 1H), 8.63(d, J ═ 1.96Hz, 1H), 8.17(d, J ═ 2.15Hz, 1H), 8.00(d, J ═ 12.32Hz, 1H), 7.95(d, J ═ 2.15Hz, 1H), 7.82(d, J ═ 8.02Hz, 2H), 7.37(d, J ═ 8.22Hz, 2H), 7.21(d, J ═ 8.41, 2H), 7.15(d, J ═ 8.41Hz, 2H), 6.90-6.81(m, 4H), 4.86(s, 2H), 4.77(s, 2H), 4.01(s, 5H), 3.82(s, 3H), 3.80(s, 3H), 2.96(s, 3H), 2.58(s, 3H), 3.58H). M/z (ESI, cation) 736(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (384.7mg, 0.5228mmol) was dissolved in trifluoroacetic acid (Aldrich redistilled 99 +%, 5.0mL, 65mmol) and the reaction flask was fitted with a reflux condenser and placed in a pre-heated oil bath (75 ℃ C.) and stirred overnight. Subsequently, the reaction was cooled to room temperature, concentrated and treated with saturated sodium bicarbonate and 5N naoh and then with 5N HCl to adjust the pH to 6. Subsequently, DCM was added and the layers were separated. The aqueous phase was filtered and the collected solids were combined with the organic phase. The aqueous phase was extracted with DCM and these organic extracts were combined with the organic phase, concentrated and purified on a silica gel column (30: 1 DCM/2N aqueous ammonia in MeOH to 10: 1 DCM/2N aqueous ammonia in MeOH). Eluting the large part After separation of the product, the polarity of the solvent increases. Fractions with product were collected, concentrated, treated with MeOH and filtered. The solid was washed with MeOH, collected and dried under high vacuum. The material was < 95% pure by HPLC, so the solid was washed with EtOAc, filtered, collected and dried in a water bath (40 ℃) under high vacuum and then at room temperature overnight under high vacuum to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (4- (methylsulfonyl) benzyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (61.3mg, 24% yield) as a yellow powder.¹H NMR (d6-DMSO, 400MHz) δ 11.89(s, 1H), 8.65(d, J ═ 2.15Hz, 1H), 8.40(d, J ═ 2.15Hz, 1H), 8.38-8.30(m, 2H), 7.86(d, J ═ 8.22Hz, 2H), 7.90-7.84(m, 1H), 7.74(br s, 1H), 7.53(d, J ═ 8.22Hz, 2H), 4.09(s, 2H), 3.93(s, 3H), 3.17(s, 3H), 2.41(s, 3H). M/z (ESI, cation) 496(M + H)⁺。

Example 143: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 51; 2.102g, 5.462mmol), 5- (1, 3-dioxolan-2-yl) -2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridine (example 234; 1.901g, 6.442mmol), Am-Phos (200.6mg, 0.2833mmol) and potassium acetate (1.51g, 15.4mmol) were suspended in water (4mL) and 1, 4-bisAlkane (20mL) and nitrogen was bubbled through the suspension for 30 s. Subsequently, the flask was equipped with a reflux condenserAnd placed in a preheated oil bath (100 ℃) and stirred under nitrogen for 4 h. Subsequently, the reaction was cooled to room temperature, treated with water (40mL) and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and passed through CeliteThe (celite) pad was filtered and concentrated. The crude material was purified on a silica gel filter (600 mL sintered funnel with about 3 inches of silica; DCM to 100: 1 DCM/MeOH to 50: 1 DCM/MeOH) to give 4- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.175 g).¹H NMR(CDCl₃400MHz) δ 8.65(dd, J ═ 8.90Hz, 2.45Hz, 1H), 8.42(d, J ═ 1.37Hz, 1H), 7.23(dd, J ═ 8.41Hz, 5.87Hz, 4H), 6.87(dd, J ═ 10.27Hz, 8.71Hz, 4H), 5.93(s, 1H), 4.83(s, 2H), 4.81(s, 2H), 4.17-4.04(m, 4H), 3.82(s, 3H), 3.80(s, 3H), 2.55(s, 3H). M/z (ESI, cation) 518(M + H) ⁺。

Step 2: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde

4- (5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.688g, 3.262mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.477g, 3.36mmol) were dissolved in THF (28mL) and the reaction flask cooled in an ice-water bath under nitrogen. Subsequently, lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran, 9.5mL, 9.5mmol) was added and the reaction stirred under nitrogen for 35 min. Subsequently, aqueous HCl (5.0M, 4.5mL, 22.50mmol) and MeOH (5.8mL) were added, and the reaction was warmed to room temperature and stirred. After 10min, the reaction was treated with water (20mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica gel; DCM to 100: 1 DCM/MeOH). The fractions with product were collected, concentrated and dried under high vacuum. LCMS showed almost product, but was also presentIn some unhydrolyzed acetonides. The material was dissolved in THF (20mL) and MeOH (4.0mL) and aqueous HCl (5.0M, 2.0mL, 10mmol) was added and the solution was stirred at room temperature. After 25min, the reaction was diluted with water (20mL) and DCM. The layers were separated and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and dried under high vacuum overnight to give 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (1.098 g). ¹H NMR (CDCl3, 400MHz) δ 12.58(s, 1H), 9.92(s, 1H), 9.25(d, J ═ 2.35Hz, 1H), 8.75(d, J ═ 2.15Hz, 1H), 8.03-7.97(m, 2H), 7.21(dd, J ═ 15.06Hz, 8.41Hz, 4H), 6.87(dd, J ═ 11.15Hz, 8.61Hz, 4H), 4.89(s, 2H), 4.85(s, 2H), 4.04(s, 3H), 3.82(s, 3H), 3.79(s, 3H), 2.61(s, 3H). M/z (ESI, cation) 596(M + H)⁺。

And step 3: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (1.0538g, 1.769mmol) was suspended in THF (16mL) and the reaction flask was cooled in an ice-water bath. Subsequently, methyl magnesium bromide (3.0M in ether, 1.80mL, 5.40mmol) was added via syringe and the reaction was stirred at 0 ℃ for 25 min. Subsequently, the reaction was treated with saturated ammonium chloride (3mL, dropwise, gas evolution initially observed) and water (20 mL). The reaction was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica gel; 100: 1 DCM/MeOH (to elute non-polar impurities) to 40: 1 (to elute product)) to give 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (893.8 mg). ¹H NMR(400MHz，CDCl₃)δ11.86(s，1H)，8.83(d，J＝2.35Hz，1H) 8.32(d, J ═ 2.35Hz, 1H), 8.01(dd, J ═ 12.13Hz, 2.15Hz, 1H), 7.96(d, J ═ 2.35Hz, 1H), 7.21(dd, J ═ 10.76Hz, 8.61Hz, 4H), 6.87(dd, J ═ 12.13Hz, 8.80Hz, 4H), 4.94-4.81(m, 5H), 4.02(s, 3H), 3.82(s, 3H), 3.79(s, 3H), 2.59(s, 3H), 1.73(d, J ═ 3.72Hz, 1H), 1.53(d, J ═ 6.46Hz, 3H). M/z (ESI, cation) 612(M + H)⁺。

And 4, step 4: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (867.1mg, 1.418mmol) was dissolved in DCM (22mL) and the flask was cooled in an ice-water bath. Triethylamine (0.90mL, 6.5mmol) and methanesulfonyl chloride (0.41mL, 5.3mmol) were then added and the reaction stirred under nitrogen. After 20min, the reaction was diluted with DCM (125mL) and treated with water (25 mL). The layers were separated and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and dissolved in DCM (15 mL). Triethylamine (0.90mL, 6.5mmol) and 1-methanesulfonylpiperazine (753.9mg, 4.591mmol) were added and the reaction was stirred at room temperature under nitrogen overnight. Subsequently, the reaction was treated with water (20mL) and diluted with DCM. The layers were separated and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica; DCM to 50: 1 DCM/MeOH to 30: 1 DCM/2N aqueous ammonia in MeOH to 15: 1 DCM/2N aqueous ammonia in MeOH to 10: 1 DCM/2N aqueous ammonia in MeOH). The product was eluted with 50: 1 DCM/MeOH. The fractions with product were collected, concentrated and repurified on a silica gel filter (150 mL sintered filter with about 2 inches silica; 100: 1 DCM/MeOH to elute impurities to 40: 1 DCM/MeOH to elute product) to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methylbenzyl) -5-methyl Yl-1, 3, 5-triazin-2-amine (456.7 mg).¹H NMR(CDCl₃400MHz) δ 11.87(s, 1H), 8.72(d, J ═ 2.35Hz, 1H), 8.25(d, J ═ 2.35Hz, 1H), 8.07(d, J ═ 12.32Hz, 2.15Hz, 1H), 7.97(d, J ═ 2.35Hz, 1H), 7.22(t, J ═ 8.51Hz, 4H), 6.91-6.82(m, 4H), 4.93-4.76(m, 4H), 4.02(s, 3H), 3.82(s, 3H), 3.79(s, 3H), 3.55(q, J ═ 6.78Hz, 1H), 3.16(t, J ═ 4.60Hz, 4H), 2.69(s, 3H), 2.60(s, 3H), 2.58-6.49H, 1H), 49 (d, 3H). M/z (ESI, cation) 758(M + H)⁺。

And 5: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (456.7mg, 0.6026mmol) was dissolved in trifluoroacetic acid (9.5mL) and the reaction flask was fitted with a reflux condenser and placed in a pre-heated oil bath (75-77 ℃ C.) and stirred for 16 h. The reaction was cooled to room temperature and concentrated. The reaction was diluted with DCM (40mL) and treated with saturated sodium bicarbonate and 5N NaOH to raise the pH of the aqueous phase to about 8. Subsequently, the layers were separated and the aqueous phase was extracted with DCM and 10: 1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, treated with MeOH and filtered. The solid was washed with MeOH. The solids were not > 95% pure by HPLC, so the filtrate and solids were combined, concentrated, and purified on a silica gel column according to the procedure described by Still et al (journal of Organic Chemistry, 1978, 43, 2923-: 30: 1 DCM/2N aqueous ammonia in MeOH to 20: 1 DCM/2N aqueous ammonia in MeOH to 15: 1 DCM/2N aqueous ammonia in MeOH to 5: 1 DCM/2N aqueous ammonia in MeOH. Fractions with product were collected, concentrated, treated with MeOH and filtered. The solid was washed with MeOH, collected and dried under high vacuum to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6- Methyl-1, 3, 5-triazin-2-amine (194.7mg, 62% yield).¹HNMR(CDCl₃400MHz) δ 11.93(s, 1H), 8.71(d, J ═ 2.54Hz, 1H), 8.31(t, J ═ 2.25Hz, 1H), 8.27(d, J ═ 2.35Hz, 1H), 8.05(d, J ═ 2.15Hz, 1H), 5.42(br s, 2H), 4.04(s, 3H), 3.56 (quartz, J ═ 6.65Hz, 1H), 3.24(t, J ═ 4.69Hz, 4H), 2.78(s, 3H), 2.68-2.54(m, 7H), 1.44(t, J ═ 6.85Hz, 3H). M/z (ESI, cation) 518(M + H)⁺。

Example 144: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde

A stock solution of 4- (5- (1, 3-dioxolan-2-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 143, step 1) (5.85g, 11.30mmol) in benzene (50mL) contained in a 250mL round bottom flask with a stir bar was frozen and freeze dried overnight (to give a pale yellow solid). Flask to N₂Opened and THF (50mL) was added followed by 6-methoxypyridin-3-amine (1.332mL, 12.43 mmol). The solution was cooled in an ice bath and LiHMDS (44mL of a 1.0M solution in THF, 44mmol) was added. The mixture was stirred for 40min and then quenched with water (3mL) and concentrated to dryness. The residue was taken up in a mixture of DCM and 2N aqueous HCl and stirred for 30 min. The product was extracted from 2N HCl into DCM and NaHCO ₃Washed with saturated aqueous solution and dried (MgSO)₄) And concentrated to give a brown solid. This solid was dissolved in DCM and purified by flash chromatography (30% EtOAc, 10% DCM, 60% hexane) to give 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazine-2-one as a yellow solidYl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (3.98g, 6.89mmol, 61.0% yield). 1H NMR (400MHz, d 6-DMSO). delta.12.09 (s, 1H); 9.90(s, 1H); 9.14(d, J ═ 2.35Hz, 1H); 8.77(d, J ═ 2.35Hz, 1H); 8.31(d, J ═ 2.74Hz, 1H); 7.87(dd, J ═ 8.80, 2.74Hz, 1H); 7.28(d, J ═ 8.61Hz, 2H); 7.21(d, J ═ 8.80Hz, 2H); 6.87-6.94(m, 2H); 6.78-6.87(m, 3H); 4.83(d, J ═ 7.24Hz, 4H); 3.85(s, 3H); 3.74(s, 3H); 3.69(s, 3H); 2.58(s, 3H). M/z (ESI, cation) 578(M + H)⁺。

Step 2: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (877.5 mg.1.519mmol) was suspended in THF (15mL) and methylmagnesium bromide (3.0M in ether, 1.5mL, 4.5mmol) was added. More THF (2.5mL) was added after about 10 min. After another 40min, the reaction was quenched with saturated ammonium chloride and diluted with water (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and filtered on a silica gel filter (150 mL sintered filter with about 2 inches of silica; 100: 1 DCM/MeOH to 40: 1 DCM/MeOH) to give 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (878.2 mg). ¹H NMR(CDCl₃400MHz) δ 11.62(s, 1H), 8.82(d, J ═ 2.54Hz, 1H), 8.30(d, J ═ 2.54Hz, 1H), 8.26(d, J ═ 2.74Hz, 1H), 7.88(dd, J ═ 8.80Hz, 2.74Hz, 1H), 7.21(dd, J ═ 12.91Hz, 8.61Hz, 4H), 6.90-6.82(m, 4H), 6.71(d, J ═ 8.80Hz, 1H), 4.93-4.86(m, 3H), 4.82(d, J ═ 6.26Hz, 2H), 3.93(s, 3H), 3.82(s, 3H), 3.79(s, 3H), 2.58(s, 3H), 1.72(d, 3H), 1.91 (d, 3H), 1.46H, 1H). M/z (ESI, cation) 594(M + H)⁺

And step 3: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (732.1mg, 1.233mmol) was dissolved in dichloromethane (22mL) and the reaction flask was cooled in an ice-water bath. The reaction was stirred under nitrogen and triethylamine (0.77mL, 5.5mmol) and methanesulfonyl chloride (0.37mL, 4.8mmol) were added via syringe. The reaction was stirred at 0 ℃ under nitrogen for 15min, and then diluted with dichloromethane (125mL) and treated with water (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and dissolved in dichloromethane (13 mL). To this solution was added triethylamine (0.77ml, 5.5mmol) and 1-methanesulfonylpiperazine (648mg, 3.95 mmol). The reaction was stirred at room temperature overnight under nitrogen, and then concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica; 100: 1 DCM/MeOH to elute impurities to 50: 1 DCM/MeOH to elute product). Fractions with product were collected, concentrated and washed with hexanes. The material was dried under high vacuum at room temperature to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (501.6 mg). ¹H NMR(CDCl₃400MHz δ 11.63(s, 1H), 8.70(d, J ═ 2.54Hz, 1H), 8.28(d, J ═ 2.54Hz, 1H), 8.22(d, J ═ 2.54Hz, 1H), 7.92(dd, J ═ 9.00Hz, 2.74Hz, 1H), 7.22(t, J ═ 9.29Hz, 4H), 6.86(dd, J ═ 18.58Hz, 8.61Hz, 4H), 6.72(d, J ═ 8.80Hz, 1H), 4.93-4.76(m, 4H), 3.93(s, 3H), 3.82(s, 3H), 3.79(s, 3H), 3.54 (quatet, J ═ 6.78Hz, 1H), 3.16(t, 4.68H), 3.49 (d, 3.49H), 3.49H (d, J ═ 6.78Hz, 1H). M/z (ESI, cation) 740(M + H)⁺。

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (499.0mg, 0.6744mmol) was dissolved in trifluoroacetic acid (10.4mL, 140mmol) and the flask was fitted with a reflux condenser, placed in a pre-heated oil bath (75 ℃) and stirred overnight. Subsequently, the reaction was cooled to room temperature, concentrated, diluted with DCM (40mL) and treated with saturated sodium bicarbonate, water and 5N NaOH until the pH of the aqueous phase was about 7. Subsequently, the layers were separated and the aqueous phase was extracted with DCM and 10: 1 DCM/MeOH. During these extractions, 5N NaOH was added to the aqueous phase to raise the pH from about 5 to about 11. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and on a silica gel filter (150 mL sintered filter with about 2 inches of silica gel; 75: 1 DCM/MeOH to 50: 1 DCM/MeOH to 35: 1 DCM/2N aqueous ammonia dissolved in MeOH to 20: 1 DCM/2N aqueous ammonia dissolved in MeOH to 10: 1 DCM/2N aqueous ammonia dissolved in MeOH) to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow powder (241.9mg, 72% yield). ¹H NMR(CDCl₃400MHz) δ 11.68(s, 1H), 8.71(s, 1H), 8.36(d, J ═ 2.74Hz, 1H), 8.27(d, J ═ 2.35Hz, 1H), 8.13(dd, J ═ 8.80Hz, 2.74Hz, 1H), 6.79(d, J ═ 8.80Hz, 1H), 5.42(br s, 2H), 3.95(s, 3H), 3.60-3.52(m, 1H), 3.30-3.20(m, 4H), 2.77(s, 3H), 2.70-2.53(m, 7H), 1.45(d, J ═ 6.06Hz, 3H). M/z (ESI, cation) 500(M + H)⁺。

Examples 145 and 146: (S) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 145) and (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 146)

The isomeric mixture of 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 144) (235mg) was purified using chiral SFC preparative chromatography. The following conditions were used:

column: chiralcel OJ-H (250X 21mm, 5 μm)

Mobile phase: 76: 24 (A: B)

A: supercritical CO₂

B: methanol (with about 0.2% diethylamine)

Flow rate: 70mL/min

Oven/column temperature: 40 deg.C

The two resulting peaks were collected separately, concentrated in vacuo, and dried under high vacuum to give the two enantiomers. In thatThe absolute stereochemistry of the enantiomer was determined by X-ray crystallographic analysis of the compound from the second eluting peak in the complex (example 146) with PI3K γ.

(S) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (from the first eluting peak) was isolated as a yellow powder.¹H NMR(CDCl₃400MHz) δ 11.66(s, 1H), 8.70(d, J ═ 2.35Hz, 1H), 8.36(d, J ═ 2.54Hz, 1H), 8.27(d, J ═ 2.35Hz, 1H), 8.13(dd, J ═ 8.80Hz, 2.74Hz, 1H), 6.79(d, J ═ 8.80Hz, 1H), 5.38(br s, 2H), 3.95(s, 3H), 3.55(q, J ═ 6.78Hz, 1H), 3.23(t, J ═ 4.89Hz, 4H), 2.77(s, 3H), 2.66-2.54(m, 4H), 2.58(s, 3H), 1.44(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 500(M + H)⁺。

(R)-4-(2-(6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (from the second eluting peak) was isolated as a yellow powder. ¹H NMR(CDCl₃400MHz) δ 11.66(s, 1H), 8.70(d, J ═ 2.35Hz, 1H), 8.36(d, J ═ 2.54Hz, 1H), 8.27(d, J ═ 2.35Hz, 1H), 8.13(dd, J ═ 8.80Hz, 2.74Hz, 1H), 6.79(d, J ═ 8.80Hz, 1H), 5.38(br s, 2H), 3.95(s, 3H), 3.55(q, J ═ 6.78Hz, 1H), 3.23(t, J ═ 4.89Hz, 4H), 2.77(s, 3H), 2.66-2.54(m, 4H), 2.58(s, 3H), 1.44(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 500(M + H)⁺。

Example 146 was also prepared by the following sequence of reaction conditions:

step 1: 1- (6-Fluoropyridin-3-yl) ethanol

A clear solution of 6-fluoronicotinaldehyde (Frontier Scientific, Logan, UT; 9.88g, 79mmol) in THF (100mL), prepared by filtering a slightly turbid suspension, was added dropwise to a solution of methylmagnesium bromide (3.0M in ether; 31.6mL, 95mmol) in THF (280mL) at-6 deg.C via an addition funnel. (addition was complete in about 20 min; during addition, the temperature of the reactants was kept below-5 ℃). MeOH (10mL) was then added (dropwise) followed by NH₄Saturated aqueous Cl (300mL) and sufficient water to dissolve the precipitate. EtOAc (200mL) was then added and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 150mL) and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford 1- (6-fluoropyridin-3-yl) ethanol as a pale yellow oil (10.55g, 95% yield). ¹H NMR(400MHz，CDCl₃)δ8.18(d，J＝2.0Hz，1H)7.85(td，J＝8.1，2.5Hz，1H)6.92(dd，J＝8.5，2.8Hz，1H)4.98(q，J＝6.5Hz，1H)2.21(br.s.，1H)1.53(d，J＝6.5Hz，3H)。

Step 2: 5- (1-bromoethyl) -2-fluoropyridine

Thionyl bromide (11.60mL, 149mmol) was added (dropwise over 15 min; gas evolution) to 1- (6-fluoropyridin-3-yl) ethanol (10.55g,74.7mmol) in DCM (300mL) and the resulting orange solution was stirred at 25 ℃ for 3 h. Subsequently, the excess SOBr was added at 0 ℃ with vigorous stirring₂Carefully quench with water (150mL) and then carefully add 5.0N aqueous NaOH (100mL) at 0 deg.C to neutralize HBr and SO₂. (yellow mixture obtained; final pH about 9; NaHCO if necessary₃Saturated aqueous solution adjusted to pH about 9). The resulting mixture was stirred vigorously at 0 ℃ for 5min to ensure complete quenching of the acidic species, and then the resulting mixture was stirred in DCM (200mL) with NaHCO₃The half-saturated aqueous solution was partitioned to achieve a pH of about 9(600 mL). The organic layer was separated and the aqueous layer was extracted with DCM (300 mL). The combined organic extracts were sequentially washed with NaHCO₃Saturated aqueous solution (500mL) and brine (500mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 5- (1-bromoethyl) -2-fluoropyridine (14.58g, 96% yield) (71% LCAP; M/z (ESI, cationic) 204.0(M + H) as a yellow oil⁺) It was used directly in step 3.

And step 3: 4- (1- (6-Fluoropyridin-3-yl) ethyl) piperazine-1-carboxylic acid (R) -tert-butyl ester

Tert-butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo.; 13.31g, 71.5mmol), potassium iodide (2.37g, 14.29mmol), and potassium carbonate (11.85g, 86mmol) were added sequentially to a solution of 5- (1-bromoethyl) -2-fluoropyridine (14.58g, 71.5mmol) in acetonitrile (300mL) at 25 deg.C, and the resulting mixture was heated at 80 deg.C for 1 h. Subsequently, the reaction mixture was partially concentrated in vacuo (final volume: about 80mL), diluted with EtOAc (600mL), and washed sequentially with 4: 1 water: brine (2X 600mL) and brine (600 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) afforded tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate as a yellow oil (16.9g, 73% yield over 2 steps).¹H NMR(300MHz，CDCl₃)δ8.12(d，J＝1.8Hz，1H)，7.78(td，J＝8.1，2.3Hz，1H)，6.90(dd，J＝8.4，2.9Hz，1H)，3.47(q，J＝6.7Hz，1H)，3.39(t，J＝4.8Hz，4H)，2.37-2.49(m，2H)，2.25-2.36(m，2H)，1.44(s，9H)，1.36(d，J＝6.7Hz，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-70.50 (dd, J ═ 8.0, 2.3Hz, 1F). M/z (ESI, cation) 310.3(M + H)⁺。

Tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate was separated into its constituent enantiomers by Supercritical Fluid Chromatography (SFC) using the following conditions:

column: chiralpakAD-H(250×30mm，5μm)

Mobile phase: 75: 25 (A: B)

A: supercritical CO ₂

B: methanol (+ 0.2% diethylamine)

Flow rate: 120mL/min

Oven/column temperature: 40 deg.C

Samples dissolved in methanol at 70 mg/mL; 50 mg/injection (repeat injection). Injection period: 1.2 min/injection

The first peak eluting from the column under these conditions was collected, concentrated in vacuo and dried under high vacuum to afford (R) -tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (6.86g, 22.2mmol) (> 99% ee) as a pale yellow solid.

And 4, step 4: (R) -5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid

N-butyllithium (2.5M in hexane, Aldrich; 20.0mL, 50.0mmol) was added dropwise (over 20 min) to a solution of (R) -tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (10.0g, 32.3mmol) in THF (150mL) at-78 deg.C and the resulting mixture was stirred for 20min at-78 deg.C. Triisopropylborate (15.0mL, 65.2mmol) was then added (dropwise over 10 min), followed by additional THF (20mL) to purge the solidification from the sides of the flaskTriisopropyl borate. The resulting mixture was stirred at-78 ℃ for 15min and then the cooling bath was removed. The reaction mixture was stirred for 1h, and then 1N aqueous NaOH (100mL) and water (40mL) were added in that order. The resulting mixture was stirred for 10min, and the organic layer was separated. The organic layer was extracted with 1N aqueous NaOH (40mL), and then the aqueous layers were combined and the pH was adjusted to a final pH of about 5 with 5N aqueous HCl. The resulting mixture was extracted with EtOAc (3 × 200mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (R) -5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (9.27g, 81% yield) as a white solid. ¹H NMR(400MHz，d₄-MeOH) δ 8.39(br.s., 1H), 8.26(d, J ═ 6.5Hz, 1H), 4.54-4.63(m, 1H), 3.31(br.s., 4H; masked with MeOH), 3.13(br.s., 4H), 1.80(d, J ═ 6.8Hz, 3H), 1.45(s, 9H).¹⁹F NMR(377MHz，d₄MeOH) δ -60.93(br.s., 1F). M/z (ESI, cation) 354.2(M + H)⁺。

And 5: 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylic acid (R) -tert-butyl ester

(R) -5- (1- (4- (tert-Butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (9.27g, 26.2mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 51) (11.47g, 29.8mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO) (1.820g, 2.57mmol) and potassium acetate (8.17g, 83.0mmol) were suspended in 1, 4-bisAlkane (150mL) and water (30 mL). The resulting mixture was sparged with nitrogen (about 30sec) and then stirred at 100 ℃ for 3.5 h. Subsequently, the reaction mixture was cooled to 25 ℃, water (150mL) was added, and the resulting mixture was extracted with EtOAc (3 × 300 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 3% MeOH/DCM) gave 4- (1- (5-) -colorless oil (R) -tert-butyl (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (13.63g, 79% yield).¹H NMR(400MHz，CDCl₃)δ8.44(dd，J＝9.0，2.3Hz，1H)，8.25(d，J＝1.8Hz，1H)，7.24(d，J＝5.7Hz，2H)，7.22(d，J＝5.5Hz，2H)，6.86(t，J＝8.9Hz，4H)，4.83(s，2H)，4.80(s，2H)，3.81(s，3H)，3.79(s，3H)，3.54-3.61(m，1H)，3.40(d，J＝3.7Hz，4H)，2.55(s，3H)，2.44(d，J＝2.7Hz，2H)，2.27-2.39(m，2H)，1.44(s，9H)，1.40(d，J＝6.7Hz，3H)。¹⁹F NMR(377MHz，CDCl₃) δ -67.83(d, J ═ 9.2Hz, 0.7F), -70.47(d, J ═ 5.7Hz, 0.3F). M/z (ESI, cation) 658.4(M + H)⁺。

Step 6: (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

2, 2, 2-trifluoroacetic acid (45.9mL, 596mmol) was added (within about 10 min) to a solution of (R) -tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (7.00g, 10.64mmol) in DCM (106mL) at 0 deg.C and the resulting mixture was stirred for 2h at 25 deg.C. Subsequently, the reaction mixture was concentrated in vacuo (5 torr, 25 ℃) to afford a viscous oil, which was taken up in DCM (100mL) and cooled to 0 ℃. Ice (20mL) was added followed by solid sodium bicarbonate (added portionwise to the rapidly stirred mixture until gas evolution ceased). Water (300mL) and DCM (50mL) were then added. The organic layer was separated and the aqueous layer was extracted with DCM (2X 150 mL). Subsequently, all organic extracts were combined, dried over sodium sulfate, and filtered through a 0.45 μ M ZAPCAP filter (Sigma-Aldrich corp., st. The clear filtrate fraction was concentrated in vacuo (final volume, 100mL) and cooled to 0 ℃. Triethylamine (5.93mL, 42.6mmol) and methanesulfonyl chloride (1.647mL, 21.28mmol) were then added continuously (dropwise addition) and the resulting mixture was stirred at 0 ℃ for 1 h. Adding NaHCO ₃Saturated aqueous solution (50mL), and the resulting mixture was dissolved in DCM (150mL) and water: (200 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3X 100 mL). Subsequently, all organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 20 to 100% (10% MeOH/EtOAc)/hexanes) afforded (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (6.28g, 9.88mmol, 93% yield) as a white foam.¹H NMR(400MHz， CDCl₃)δ8.45(dd，J＝9.0，2.3Hz，1H)，8.27(s，1H)，7.23(t，J＝8.0Hz，4H)，6.87(t，J＝8.6Hz，4H)，4.82(s，2H)，4.81(s，2H)，3.81(s，3H)，3.80(s，3H)，3.63(q，J＝6.8Hz，1H)，3.20(br.s.，4H)，2.73(s，3H)，2.59-2.67(m，2H)，2.55(s，3H)，2.49-2.54(m，2H)，1.41(d，J＝6.7Hz，3H)。¹⁹F NMR(377MHz，CDCl₃) δ -67.44(d, J ═ 9.2Hz, 0.92F), -70.10(br.s., 0.08F). M/z (ESI, cation) 636.2(M + H)⁺。

And 7: (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a 2-neck round-bottom flask equipped with a stir bar and dropping funnel, (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (19.64g, 30.9mmol) and 5-amino-2-methoxypyridine (4.13mL, 33.3mmol) were dissolved in THF (300 mL). A1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran/ethylbenzene (Acros; 96.0mL, 96mmol) was added via cannula to the dropping funnel, and the reaction flask was cooled in an ice-water bath under nitrogen. Subsequently, the LiHMDS solution was added dropwise to the reaction mixture over 20 min. Subsequently, the reaction mixture was stirred for 30min, and then saturated ammonium chloride (40mL) was added dropwise via a dropping funnel, followed by water (200 mL). The reaction was warmed to room temperature and diluted with EtOAc (150 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 75: 1 DCM/MeOH to 50: 1 DCM/2N aqueous ammonia in MeOH to 40: 1 DCM/2N aqueous ammonia in MeOH) afforded (R) -N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (18.47 g).

(R) -N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (18.47g, 24.96mmol) was dissolved in trifluoroacetic acid (200mL, 2596mmol) and the flask was fitted with a reflux condenser and placed in a preheated oil bath (75-85 ℃). The reaction was stirred under nitrogen overnight. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with DCM and a saturated aqueous solution of sodium bicarbonate was added, followed by aqueous 5N NaOH (to raise the pH of the aqueous phase to about 14) and then 5N HCl (to lower the pH of the aqueous solution to about 5). Finally, a saturated aqueous solution of sodium bicarbonate was added to raise the pH to about 6 to 7. The organic layer was separated and combined with the residual solids that were insoluble in the organic phase. The aqueous phase was treated with brine and extracted with 10: 1 DCM/MeOH. All organic extracts and undissolved solids were then combined and concentrated in vacuo.

The residue was taken up in DCM and filtered. The solid was washed with DCM. The filtrate was concentrated, treated with MeOH and filtered. Subsequently, the combined solids were washed with MeOH and DCM and set aside (solid a).

The combined filtrates were concentrated in vacuo and purified by column chromatography (silica gel, 50: 1 DCM/MeOH to 40: 1 DCM/MeOH to 30: 1 DCM/MeOH to 20: 1 DCM/2N aqueous ammonia in MeOH to 15: 1 DCM/2N aqueous ammonia in MeOH to 10: 1 DCM/2N aqueous ammonia in MeOH). Fractions containing product were combined and concentrated in vacuo, and the resulting solid was combined with solid a. Subsequently, the combined solids were suspended in Et ₂And O, and filtering. The collected solid was washed with Et₂O wash and discard filtrate. The solid was washed with MeOH and Et₂O wash, followed by DCM, MeOH, and Et₂O-washAnd (6) washing. The solid was set aside (solid B) and the filtrate was concentrated in vacuo and purified by column chromatography (silica gel, 100: 1 DCM/MeOH to 50: 1 DCM/MeOH to 20: 1 DCM/2N aqueous ammonia in MeOH to 15: 1 DCM/2N aqueous ammonia in MeOH to 10: 1 DCM/2N aqueous ammonia in MeOH). The product-containing fractions were combined and concentrated in vacuo, and the resulting solid was combined with solid B and dried.

The resulting solid was dissolved in DMSO (about 50mL) and partially concentrated in vacuo until a solid began to form. Sufficient DMSO was added to dissolve the precipitated solid, and the solution was poured into water (about 400 mL). Water was added to bring the final volume to about 600mL (only a small precipitate formed). Brine (100mL) was added and a yellow solid precipitated. The resulting suspension was filtered and the collected solid (solid C) was washed with water. Solid sodium chloride was added to the filtrate to give a saturated solution, which was allowed to stand overnight at room temperature to yield additional precipitated solid. This precipitate was collected by filtration, washed with water, combined with solid C and dried in vacuo. The drying was treated with water (200mL) and saturated sodium bicarbonate (50mL) and mixed for 10 min. Subsequently, the resulting suspension was filtered and washed successively with water and EtOH. Subsequently, the collected solid was dried in vacuo to give (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (8.46g, 55% over 2 steps) as a yellow solid. ¹H NMR(CDCl₃400MHz) δ 11.66(s, 1H), 8.70(d, J ═ 2.35Hz, 1H), 8.36(d, J ═ 2.54Hz, 1H), 8.27(d, J ═ 2.35Hz, 1H), 8.13(dd, J ═ 8.80Hz, 2.74Hz, 1H), 6.79(d, J ═ 8.80Hz, 1H), 5.38(br s, 2H), 3.95(s, 3H), 3.55(q, J ═ 6.78Hz, 1H), 3.23(t, J ═ 4.89Hz, 4H), 2.77(s, 3H), 2.66-2.54(m, 4H), 2.58(s, 3H), 1.44(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 500(M + H)⁺。

Examples 147 and 148: (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 147) and (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 148).

The isomeric mixture of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 143) (187mg) was purified using chiral SFC preparative chromatography. The following conditions were used:

column: chiralcel OJ-H (250X 20mm, 5 μm)

Mobile phase: 78: 22 (A: B)

A: liquid CO ₂

B: methanol (with about 1% diethylamine)

Flow rate: 70mL/min

Oven/column temperature: 40 deg.C

The two resulting peaks were collected separately, concentrated in vacuo, and dried under high vacuum to give the two enantiomers.

(S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (from the first eluting peak) was isolated as a yellow powder.¹H NMR(CDCl₃400MHz) δ 11.93(s, 1H), 8.71(d, J ═ 2.35Hz, 1H), 8.32-8.26(m, 2H), 8.05(d, J ═ 2.35Hz, 1H), 5.40(br s, 2H), 4.03(s, 3H), 3.56(q, J ═ 7.04Hz, 1H), 3.24(t, J ═ 4.89Hz, 4H), 2.78(s, 3H), 2.68-2.53(m, 4H), 2.59(s, 3H), 1.44(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 518(M + H)⁺。

(R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazineOxazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (from the second eluting peak) was isolated as a yellow powder.¹H NMR(CDCl₃400MHz) δ 11.93(s, 1H), 8.71(d, J ═ 2.35Hz, 1H), 8.32-8.26(m, 2H), 8.05(d, J ═ 2.15Hz, 1H), 5.41(br s, 2H), 4.04(s, 3H), 3.56(q, J ═ 6.39Hz, 1H), 3.24(t, J ═ 4.50Hz, 4H), 2.78(s, 3H), 2.68-2.53(m, 4H), 2.59(s, 3H), 1.44(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 518(M + H) ⁺。

Example 148 was also prepared by following the sequence of reaction conditions to confirm the absolute stereochemistry assigned to the two enantiomers described above:

step 1: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Lithium bis (trimethylsilyl) amide (1.0M in hexane; 31.9mL, 31.9mmol) was added dropwise (over 10 min) to a mixture of (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 146, step 6; 6.75g, 10.62mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, norbrth unswick, NJ; 2.264g, 15.93mmol) in THF (100mL) at 0 ℃ and the resulting solution was stirred for 1h at 0 ℃. Subsequently, with NH₄Saturated aqueous Cl (140mL) quenched excess LiHMDS and the reaction mixture was quenched in EtOAc (500mL) with NH₄The mixture was partitioned between half-saturated aqueous Cl (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 200 mL). The combined organic extracts were washed successively with brine (300mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) afforded (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (7.25g, 90% yield) as a yellow solid. ¹H NMR(400MHz，CDCl₃)δ11.88(1H，s)，8.72(1H，d，J＝2.0Hz)，8.25(1H，d，J＝2.2Hz)，8.06(1H，dd，J＝12.3，1.6Hz)，7.96(1H，d，J＝2.0Hz)，7.21(4H，t，J＝8.2Hz)，6.86(4H，dd，J＝14.1，8.4Hz)，4.70-4.96(4H，m)，4.01(3H，s)，3.81(3H，s)，3.78(3H，s)，3.55(1H，q，J＝6.7Hz)，3.15(4H，br s)，2.68(3H，s)，2.59(3H，s)，2.48-2.57(4H，m)，1.38(3H，d，J＝6.7Hz)。¹⁹F NMR(376MHz，CDCl₃) Delta-139.13 (1F, d, J ═ 13.0 Hz). M/z (ESI, cation) 758.3(M + H)⁺。

Step 2: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (9.94g, 13.12mmol) and trifluoromethanesulfonic acid (6.5mL, 73.2mmol) in TFA (65mL) was stirred at 70 ℃ for 2 h. Subsequently, the mixture was cooled to 25 ℃ and concentrated in vacuo. The residue was cooled with a 0 deg.C bath and ice (about 250g), NaOH (1N, aq; 220mL) and NaHCO were added successively₃The aqueous solution (110mL) was saturated to bring the pH of the resulting mixture to about 9. The resulting yellow-brown slurry was extracted with DCM (3 × 400mL) and the combined organic extracts were dried over sodium sulfate and concentrated on silica gel. Chromatographic purification (silica gel, 0 to 10% MeOH/EtOAc) afforded a yellow solid. This solid was passed through preparative SFC chromatography (column: Chiralcel OD-H (250X 20mm, 5 μm), mobile phase: 77: 23 (A: B), A: liquid CO₂And B: methanol (+ 1% diethylamine), flow rate: 70mL/min, oven/column temperature: purification at 40 ℃) to afford a yellow solid which was then suspended in MeOH plus 0.2% diethylamine (175 mL). The resulting mixture was sonicated for 2min, centrifuged (3000 Xg, 5min) and the clumped material collected. Subsequently, this washing process was repeated, and the collected material was then suspended in isopropanol plus 0.2% 2M NH dissolved in MeOH ₃(175 mL). The resulting mixture was sonicated for 2min, centrifuged (3000 Xg, 5min) and the pellet collectedA agglomerated material. This washing process was repeated and the collected material was then dried under vacuum to provide (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (3.50g, 52% yield).¹H NMR(400MHz，CDCl₃)δ11.90(s，1H)，8.70(d，J＝1.6Hz，1H)，8.30(d，J＝2.2Hz，1H)， 8.27(dd，J＝12.5，2.0Hz，1H)，8.04(d，J＝2.3Hz，1H)，5.41(br.s.，2H)，4.03(s，3H)，3.55(q，J＝6.4Hz，1H)，3.23(br.s.，4H)，2.77(s，3H)，2.60-2.68(m，2H)，2.58(s，5H)，1.44(d，J＝6.7Hz，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-138.85 (d, J ═ 12.6Hz, 1F). M/z (ESI, cation) 518.2(M + H)⁺。

Example 149: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (6-Fluoropyridin-3-yl) (4- (methylthio) phenyl) methanone

(6-Fluoropyridin-3-yl) (4- (methylthio) phenyl) methanol (example 103) (1.5304g, 6.1387mmol) was dissolved in DCM (60mL) and manganese (IV) oxide (Aldrich, less than 5 microns, activated, 2.546g, 29.28mmol) was added. The reaction was stirred at room temperature for 90 minutes and then more active manganese (IV) oxide (2.736g, 31.47mmol) was added. The reaction was stirred overnight and then passed through CeliteThe pad was filtered and washed with DCM. The filtrate was concentrated and dried under high vacuum to give (6-fluoropyridin-3-yl) (4- (methylthio) phenyl) methanone (1.334 g). ¹H NMR(CDCl₃，400MHz)δ8.64(d，J＝2.35Hz，1H)，8.26(td，J＝8.07Hz，2.45Hz，1H) 7.75(d, J ═ 8.61Hz, 2H), 7.33(d, J ═ 8.41Hz, 2H), 7.09(dd, J ═ 8.41Hz, 2.54Hz, 1H), 2.56(s, 3H). M/z (ESI, cation) 248(M + H)⁺。

Step 2: 1- (6-Fluoropyridin-3-yl) -1- (4- (methylthio) phenyl) ethanol

(6-Fluoropyridin-3-yl) (4- (methylthio) phenyl) methanone (1.256g, 5.079mmol) was dissolved in THF (19mL) and the flask was cooled in an ice-water bath. Subsequently, over 5min, methyl magnesium bromide (3.0M in ether, 3.40mL, 10.2mmol) was added via syringe. The reaction was stirred at 0 ℃ under nitrogen for 20min and then treated with saturated ammonium chloride (2.5mL, added dropwise, initially observing gas evolution). The reaction was quenched at 0 ℃. Subsequently, the reaction was diluted with water (15mL) and the layers were separated. The aqueous phase was extracted with DCM and the organic phases were combined, dried over sodium sulphate, filtered, concentrated and dried at room temperature under high vacuum overnight to give 1- (6-fluoropyridin-3-yl) -1- (4- (methylthio) phenyl) ethanol (1.375 g).¹H NMR(CDCl₃400MHz) δ 8.26(d, J ═ 2.35Hz, 1H), 7.82-7.76(m, 1H), 7.35-7.30(m, 2H), 7.25-7.20(m, 2H), 6.86(dd, J ═ 8.61Hz, 2.93Hz, 1H), 2.48(s, 3H), 2.30(s, 1H), 1.96(s, 3H). M/z (ESI, cation) 264(M + H) ⁺。

And step 3: 2-fluoro-5- (1- (4- (methylthio) phenyl) vinyl) pyridine

1- (6-Fluoropyridin-3-yl) -1- (4- (methylthio) phenyl) ethanol (1.261g, 4.789mmol) was dissolved in DCM (30mL) and trifluoroacetic acid (1.0mL, 13mmol) was added to turn the solution dark green. The reaction was stirred at room temperature for 45min and then treated with saturated sodium bicarbonate (15 mL). The reaction was stirred for about 5min, and then the layers were separated and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated and dried under high vacuum to give 2-fluoro-5- (1- (4- (methylthio) phenyl) vinyl) pyridine (1.183 g).¹H NMR(CDCl₃，400MHz)δ8.23(d，J＝2.35Hz，1H)，7.71(td，J＝8.12Hz，2.54Hz，1H)，7.26-7.21(m，4H)，6.91(dd，J＝8.51Hz，2.64Hz, 1H), 5.55(s, 1H), 5.43(s, 1H), 2.51(s, 3H). M/z (ESI, cation) 246(M + H)⁺。

And 4, step 4: 2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridine

2-fluoro-5- (1- (4- (methylthio) phenyl) vinyl) pyridine (992mg, 4.04mmol) was dissolved in THF (12mL) and water (4mL), and the flask was cooled in an ice-water bath under nitrogen. Ruthenium trichloride hydrate (212.4mg, 0.9422mmol) was then added and sodium borohydride (393mg, 10.4mmol) was added portionwise over about 5 min. More THF (2mL) was added and the reaction was warmed to room temperature and stirred. After 2 hours and 15 minutes, more RuCl was added ₃*H₂O (214mg, 0.951mmol), and the flask was cooled again in an ice-water bath. Subsequently, more sodium borohydride (384mg, 10.2mmol) was added and the reaction was warmed to room temperature. Stirring is continued. Gas evolution was observed. After 50min, more sodium borohydride (139mg, 3.67mmol) was added and stirring continued for 1 h. The reaction was diluted with water (20mL) and DCM (30 mL). The suspension was passed through CeliteThe pad was filtered and washed repeatedly with DCM. The biphasic mixture was treated with saturated sodium bicarbonate (50mL) and the layers were separated. The aqueous phase was extracted with DCM and all organic phases were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150mL sintered funnel with approximately 2 inches of silica; 100: 1 DCM/MeOH) to give 2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridine (875 mg).¹H NMR(CDCl₃400MHz) δ 8.10(d, J ═ 1.96Hz, 1H), 7.56(td, J ═ 8.07Hz, 2.64Hz, 1H), 7.24-7.19(m, 2H), 7.15-7.09(m, 2H), 6.84(dd, J ═ 8.41Hz, 2.93Hz, 1H), 4.15(q, J ═ 7.24Hz, 1H), 2.47(s, 3H), 1.64(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 248(M + H)⁺。

And 5: 2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-ylboronic acid

Reacting 2-fluoro-5- (1- (4- (methylthio) phenyl) ethylYl) pyridine (1.078g, 4.359mmol) and triisopropyl borate (2.50mL, 10.9mmol) were dissolved in THF (11.5 mL). In a separate flask, 2, 6, 6-tetramethylpiperidine (1.11mL, 6.54mmol) was dissolved in THF (12mL) and the flask was cooled in an ice-water bath. Subsequently, an n-butyllithium solution (1.6M in hexane, 3.8mL, 6.1mmol) was added via syringe and the yellow solution was stirred under nitrogen for 15 min. Subsequently, the contents were transferred via syringe to another flask pre-cooled in a dry ice/acetone bath. After the transfer was complete, the reaction was stirred for 1h at-78 ℃ under nitrogen. Subsequently, the reaction was allowed to slowly warm to room temperature while stirring overnight. The reaction was treated with water (30mL) and stirred for about 30 min. The layers were separated and the organic phase was extracted with 1N aqueous NaOH (15 mL). The organic phase was discarded and the aqueous phase was treated with 5N aqueous HCl to reduce the pH to about 5-6. The aqueous phase was extracted with 10: 1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to give 2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-ylboronic acid (1.2342 g).¹H NMR(400MHz，CDCl₃) δ 8.17-8.05(m, 2H), 7.25-7.19(m, 2H), 7.15-7.10(m, 2H), 4.16(q, J ═ 7.37Hz, 1H), 2.47(s, 3H), 1.66(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 292(M + H) ⁺。

Step 6: 4- (2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.4126g, 3.6704mmol), 2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-ylboronic acid (1.2342g, 4.2390mmol), Am-Phos (140.4mg, 0.1983mmol) and potassium acetate (1.531g, 15.60mmol) were suspended in 1, 4-bis (p-methoxybenzyl) amineAlkane (20mL) and water (4mL), and nitrogen was bubbled through the suspension for 15 s. Subsequently, the flask was fitted with a reflux condenser and placed in a pre-heated oil bath (100 ℃) and stirred under nitrogen overnight. Subsequently, the reaction was cooled to room temperature, diluted with water (40mL) and extracted with EtOAc. Organic extraction is carried outThe fractions were combined, dried over sodium sulfate and concentrated over CeliteThe (Celite) pad was filtered, concentrated, and purified on a silica gel filter (600 mL sintered filter with about 3 inches of silica; DCM to 100: 1 DCM/MeOH to 75: 1 DCM/MeOH). The fractions with product were collected, concentrated, and first dried at room temperature under high vacuum, and then dried under high vacuum in a water bath (about 50 ℃) to give 4- (2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.797 g). ¹H NMR(CDCl₃400MHz) δ 8.34(dd, J ═ 8.90Hz, 2.45Hz, 1H), 8.15(d, J ═ 1.96Hz, 1H), 7.24-7.17(m, 6H), 7.16-7.11(m, 2H), 6.86(dd, J ═ 10.17Hz, 8.61Hz, 4H), 4.82(s, 2H), 4.78(s, 2H), 4.20(q, J ═ 7.30Hz, 1H), 3.82(s, 3H), 3.81(s, 3H), 2.53(s, 3H), 2.45(s, 3H), 1.67(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 596(M + H)⁺。

And 7: 4- (2-fluoro-5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (1- (4- (methylthio) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.797g, 3.016mmol) was dissolved in DCM (30mL) and the reaction flask was cooled in an ice-water bath under nitrogen. Subsequently, 3-chloroperoxybenzoic acid (1.668g, 9.666mmol) was added as a solution in DCM (52mL) and the reaction was warmed to room temperature and stirred. After 30min, the reaction was cooled in an ice-water bath and treated with a mixture of saturated sodium bicarbonate (50mL) and saturated sodium thiosulfate (15 mL). The biphasic mixture was warmed to room temperature and stirred. After 1h, the layers were separated and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica; DCM to 100: 1 DCM/MeOH to 50: 1 DCM/MeOH). Fractions with product were collected, concentrated, and dried under high vacuum to give 4- (2-fluoro-5- (1- (4- (methylsulfonyl) ate) Acyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.517 g).¹H NMR(CDCl₃400MHz) δ 8.34(dd, J ═ 8.90Hz, 2.45Hz, 1H), 8.17(s, 1H), 7.88(d, J ═ 8.41Hz, 2H), 7.42(d, J ═ 8.22Hz, 2H), 7.21(d, J ═ 8.02 Hz, 4H), 6.86(t, J ═ 8.90Hz, 4H), 4.82(s, 2H), 4.78(s, 2H), 4.34(q, J ═ 7.69Hz, 1H), 3.82(s, 3H), 3.81(s, 3H), 3.02(s, 3H), 2.54(s, 3H), 1.74(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 628(M + H)⁺。

And 8: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (764.7mg, 1.218mmol) and 5-amino-2-methoxypyridine (162.9mg, 1.312mmol) were dissolved in THF (12mL) and the flask was cooled in an ice-water bath while stirring under nitrogen. Subsequently, lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran/ethylbenzene, 3.6mL, 3.6mmol) was added via syringe and the reaction was stirred at 0 ℃. After 40min, the reaction was treated with ice water (1.5mL), diluted with DCM, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150 mL sintered funnel with about 2 inches of silica; DCM to 100: 1 DCM/MeOH to 75: 1 DCM/MeOH to 40: 1 DCM/MeOH). The fractions with product were collected, concentrated and dried in a water bath (about 40 ℃) under high vacuum to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (459.4 mg). ¹H NMR(CDCl₃，400MHz)δ11.57(s，1H)，8.65(d，J＝2.35Hz，1H)，8.25(d，J＝2.35Hz，1H)，8.14(d，J＝2.35Hz，1H)，7.89(dd，J＝8.71Hz，2.45Hz，1H)，7.81(d，J＝8.22Hz，2H)，7.40(d，J＝8.02Hz，2H)，7.24-7.14(m，4H)，6.90-6.81(m，4H)，6.70(d，J＝8.80Hz，1H)，4.87(d，J4.89Hz, 2H), 4.77(d, J ═ 5.09Hz, 2H), 4.23-4.16(m, 1H), 3.92(s, 3H), 3.82(s, 3H), 3.80(s, 3H), 2.98(s, 3H), 2.57(s, 3H), 1.66(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 732(M + H)⁺。

And step 9: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (459.4mg, 0.6277mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99 +%, 7.5mL) and the flask was fitted with a reflux condenser and placed in a preheated oil bath (75 deg.C) and stirred overnight. Subsequently, the reaction was cooled to room temperature, concentrated, diluted with DCM, and treated with saturated sodium bicarbonate and 5N NaOH to raise the pH of the aqueous phase to about 6. The layers were separated and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel column (25: 1 DCM/MeOH to 20: 1 DCM/MeOH). Fractions with product were collected, concentrated, treated with MeOH and filtered. The solid was washed with MeOH, but was still not 95% pure by HPLC. Thus, the filtrate and solid were combined, concentrated, treated with EtOAc and acetone (combined to dissolve the compound), concentrated, and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min; total flow rate 100mL/min) to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (192.4 mg). ¹H NMR(CDCl₃400MHz) δ 8.87(s, 1H), 8.48(s, 1H), 8.16(d, J ═ 1.57Hz, 1H), 8.07(d, J ═ 8.02Hz, 1H), 7.91(d, J ═ 8.22Hz, 2H), 7.45(d, J ═ 8.22Hz, 2H), 6.93(d, J ═ 9.00Hz, 1H), 4.28(q, J ═ 7.56Hz, 1H), 4.03(s, 3H), 3.06(s, 3H), 2.63(s, 3H), 1.74(d, J ═ 7.04Hz, 3H). M/z (ESI, cation) 492(M + H)⁺。

Example 150: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2-fluoro-5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (752mg, 1.20mmol) and 5-fluoro-6-methoxypyridin-3-amine (175.0mg, 1.231mmol) were dissolved in THF (12.0mL) and the flask cooled in an ice-water bath under nitrogen. Subsequently, lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran/ethylbenzene, 3.6mL, 3.6mmol) was added via syringe and the reaction was stirred under nitrogen. After 15min, the reaction was treated with ice water (1.5mL) and diluted with DCM (150 mL). The solution was dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (150mL sintered filter with about 2 inches silica; DCM to 100: 1 DCM/MeOH to 50: 1 DCM/MeOH). Fractions with product were collected, concentrated, and dried under high vacuum to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (744.3 mg). ¹H NMR(CDCl₃400MHz δ 11.82(s, 1H), 8.66(d, J ═ 2.35Hz, 1H), 8.17(d, J ═ 2.54Hz, 1H), 8.03(dd, J ═ 12.13Hz, 2.15Hz, 1H), 7.95(d, J ═ 2.15Hz, 1H), 7.81(d, J ═ 8.41Hz, 2H), 7.40(d, J ═ 8.41Hz, 2H), 7.24-7.14(m, 4H), 7.90-7.81(m, 4H), 4.87(d, J ═ 5.09Hz, 2H), 4.77(d, J ═ 5.48Hz, 2H), 4.21(q, J ═ 7.04, 1H), 4.01(s, 3H), 3.82(s, 3H), 3.81 (d, 3.58H), 3.58 (s, 3H), 3.58 (d, 3H). M/z (ESI, cation) 750(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (744mg, 0.992mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99 +%, 10mL) and the flask was fitted with a reflux condenser and placed in a preheated oil bath (75 ℃ C.) and stirred overnight. Subsequently, the reaction was cooled to room temperature, concentrated, diluted with DCM (30mL) and treated with saturated sodium bicarbonate (30mL) and with 5N NaOH to raise the pH of the aqueous phase to about 7. The layers were separated and the aqueous phase was extracted with DCM and with 10: 1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL sintered filter with about 2 inches of silica; 100: 1 DCM/MeOH to 75: 1 DCM/MeOH to 50: 1 DCM/MeOH). Subsequently, the fractions with product were collected, concentrated, and purified by HPLC (10% to 100% MeCN in water with 0.1% TFA over 28 minutes using a total flow rate of 100mL/min) to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) phenyl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (187.7mg, 36% yield). ¹H NMR(CDCl₃400 MHZ) δ 11.60(s, 1H), 8.73(d, J ═ 2.35Hz, 1H), 8.24(d, J ═ 2.74Hz, 1H), 8.06(dd, J ═ 11.93Hz, 1.76Hz, 1H), 8.01(d, J ═ 2.35Hz, 1H), 7.90(d, J ═ 8.41Hz, 2H), 7.45(d, J ═ 8.22Hz, 2H), 4.30-4.23(m, 1H), 4.04(s, 3H), 3.06(s, 3H), 2.64(s, 3H), 1.74(d, J ═ 7.24Hz, 3H). M/z (ESI, cation) 510(M + H)⁺。

Example 151: 4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinecarboxaldehyde (0.127g, 0.220mmol) in THF (2.00mL) was treated with sodium cyanide (10.77mg, 0.220mmol), morpholine (0.096mL, 1.099mmol) and manganese (IV) oxide (0.287g, 3.30mmol) at ambient temperature. After 30min more manganese (IV) oxide (0.287g, 3.30mmol) was added and the mixture was stirred at ambient temperature overnight. Passing the mixture through Celite (celite) filtration and the organic layer was washed with water followed by saturated NaCl (aq) and then over anhydrous Na₂SO₄Dried, filtered and concentrated to give N, N-bis (4-methoxybenzyl) -4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine (0.128g, 0.193mmol, 88% yield) as a brown foam.¹H NMR(400MHz，CDCl₃) δ 11.95(s, 1H); 8.90(d, J ═ 2.54Hz, 1H); 8.39(d, J ═ 2.35Hz, 1H); 8.28(d, J ═ 2.74Hz, 1H); 7.89(dd, J ═ 8.80, 2.74Hz, 1H); 7.13-7.24(m, 4H); 6.81-6.90(m, 4H); 6.73(d, J ═ 8.80Hz, 1H); 4.85(s, 2H); 4.82(s, 2H); 3.94(s, 3H); 3.81(s, 3H); 3.78(s, 3H); 3.57-3.69(m, 8H); 2.59(s, 3H). M/z (ESI, cation) 663.2(M + H)⁺。

Step 2: 4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine (0.128g, 0.193mmol) in TFA (2.00mL) is treated with trifluoromethanesulfonic acid at ambient temperatureAcid (0.051mL, 0.579mmol) and heated at 80 ℃ for 4 h. The reaction mixture was concentrated without reaching dryness. Adding ice cubes and adding saturated NaHCO ₃(aqueous solution) until the pH is about 7. The solid was collected by filtration, water and CH₂Cl₂Washed and dried in vacuo to give 4- (2- ((6-methoxy-3-pyridinyl) amino) -5- (4-morpholinylcarbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine as a brown solid (0.056g, 0.133mmol, 68.6% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.92 (s, 1H); 8.87(s, 1H); 8.52(s, 1H); 8.38(s, 1H); 8.11-8.22(m, 1H); 7.92(br.s., 1H); 7.78(br.s., 1H); 6.85(d, J ═ 8.80Hz, 1H); 3.84(s, 3H); 3.54-3.65(m, 8H); 2.44(s, 3H). M/z (ESI, cation) 423.1(M + H)⁺。

Example 152: 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) carbonyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner to that described in example 151 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinecarbaldehyde and 1-methanesulfonylpiperazine (Oakwood Products, West Columbia, SC) and the desired product, 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((4- (methylsulfonyl) -1-piperazinyl) carbonyl) -3-pyridinyl) -6-methyl-1, the 3, 5-triazin-2-amine was isolated as a yellow solid (52%, two steps). ¹H NMR (400MHz, d6-DMSO) δ 12.11(s, 1H)8.85-8.93(m, 1H)8.45(dd, J ═ 2.15, 0.39Hz, 1H)8.42(d, J ═ 2.35Hz, 1H)8.30-8.39(m, 1H)7.95(br.s., 1H)7.83(br.s., 1H)3.95(s, 3H)3.61-3.73(m, 4H)3.19(t, 4H)2.91(s, 3H)2.45(s, 3H). M/z (ESI, cation) 518.0(M + H)⁺。

Example 153: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (2-methoxyethyl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinecarboxamide

The title compound was prepared in analogy to the procedure described for example 151 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinecarbaldehyde and 2-methoxyethylamine (Sigma-Aldrich, st. louis, MO) and the desired product 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (2-methoxyethyl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinecarboxamide was isolated as yellow solid (8%, two steps).¹H NMR(400MHz，CDCl₃) δ 12.08(s, 1H); 9.19(d, J ═ 2.54Hz, 1H); 8.78(d, J ═ 2.54Hz, 1H); 8.35(d, J ═ 2.54Hz, 1H); 8.12(dd, J ═ 8.80, 2.74Hz, 1H); 6.79(d, J ═ 8.80Hz, 1H); 6.72-6.76(m, 1H); 3.95(s, 3H); 3.66-3.72(m, 2H); 3.63(q, J ═ 4.56Hz, 2H); 3.38(s, 3H); 2.55(s, 3H). M/z (ESI, cation) 411.0(M + H) ⁺。

Example 154: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone

Step 1: n- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -2-chloro N- (2-hydroxyethyl) acetamide

At ambient temperature, 2- (((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) amino)A mixture of ethanol (example 225, step 1; 0.118g, 0.189mmol), chloroacetyl chloride (0.023mL, 0.284mmol) and triethylamine (0.040mL, 0.284mmol) in THF (1mL) was stirred for 2 h. 2M K was added₂CO₃(0.2mL, aq.) and MeOH (1 mL). After 1h, water was added to the mixture and it was extracted with EtOAc (3 ×). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give N- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -2-chloro-N- (2-hydroxyethyl) acetamide (0.110g, 0.157mmol, 83% yield). M/z (ESI, cation) 699.2(M + H)⁺.

Step 2: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone

Sodium hydride (60% in mineral oil) (0.014g, 0.346mmol) was added to a mixture of N- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -2-chloro-N- (2-hydroxyethyl) acetamide (0.110g, 0.157mmol) in 3mL THF at 0 ℃. The reaction mixture was allowed to warm to ambient temperature. After 1h, water was added and the mixture was extracted with EtOAc (3 ×). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone (0.101g, 0.152mmol, 97% yield) as a yellow foam.¹H NMR(400MHz，CDCl₃) δ 11.66(s, 1H); 8.71(d, J ═ 2.54Hz, 1H); 8.23-8.27(m, 1H); 8.20(d, J ═ 2.54Hz, 1H); 7.89(dd, J ═ 8.80, 2.74Hz, 1H); 7.15-7.24(m, 4H); 6.80-6.90(m, 4H); 6.70(d, J ═ 8.80Hz, 1H); 4.86(s, 2H); 4.81(s, 2H); 4.55(s, 2H); 4.10(s, 2H); 3.92(s, 3H); 3.81(s, 3H); 3.78(s, 3H); 3.74-3.77(m, 2H); 3.23-3.28(m, 2H); 2.57(s, 3H). M/z (ESI, cation) 663.2(M + H) ⁺。

And step 3: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone

Several drops of trifluoromethanesulfonic acid were added to a solution of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone (0.115g, 0.174mmol) in 2mL of TFA at room temperature. The mixture was heated to 80 ℃ for 1 h. The reaction was cooled and concentrated without reaching dryness. Adding ice cubes and adding saturated NaHCO₃(aqueous solution) until pH 7. The yellow solid is mixed with water and CH₂Cl₂MeOH and Et₂The O is washed and filtered and collected and dried in vacuum. The aqueous layer was washed with 3/1 CHCl₃n-BuOH (3X) extraction. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and pre-filled with silica gel column (4g) by chromatography via Redi-Sep to dissolve in CH₂Cl₂Gradient elution from 0% to 10% MeOH. This material was combined with the yellow solid collected above to provide 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -3-morpholinone (0.040g, 0.095mmol, 54.6% yield) as a yellow solid. ¹H NMR (400MHz, d 6-DMSO). delta.11.76 (s, 1H); 8.70(dd, J ═ 2.15, 0.39Hz, 1H); 8.53(dd, J ═ 2.54, 0.39Hz, 1H); 8.24(dd, J ═ 2.05, 0.49Hz, 1H); 8.13-8.19(m, 1H); 7.88(br.s., 1H); 7.72(br.s., 1H); 6.82(d, J ═ 8.80Hz, 1H); 4.52(s, 2H); 4.10(s, 2H); 3.84(s, 3H); 3.79-3.83(m, 2H); 3.27-3.32(m, 2H); 2.43(s, 3H). M/z (ESI, cation) 423.2(M + H)⁺。

Example 155: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi Block, Inc., 2.507g, 14.30mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (5.24g, 13.62mmol), Amphos (bis 4- (di-tert-butylphosphinyl) -N, N-dimethylaniline-dichloropalladium, 0.482g, 0.681mmol) and potassium acetate (4.10g, 41.8mmol) in ethanol (100mL) and water (10mL) was purged with argon and heated at 100 ℃ overnight. The reaction mixture was cooled, concentrated to remove EtOH, and partitioned between water (50mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by ISCO chromatography (hexane/EtOAc, 15 to 50%) to give 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.62g, 7.54mmol, 55.4% yield) as a colorless viscous solid. M/z (ESI, cation) 481.0(M + H) ⁺。

Step 2: 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 6-methoxypyridin-3-amine (Sigma-Aldrich inc., 1.405g, 11.31mmol) and 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.62g, 7.54mmol) in THF (15.00mL) was cooled to 0 ℃ in an ice bath and treated with 1.0M LiHMDS in THF (22.63mL, 22.63 mmol). The reaction mixture is washed with NH at 0 DEG C₄A saturated solution of Cl was quenched and extracted with EtOAc (50mL) over MgSO₄Dried, filtered and concentrated. The crude residue was re-diluted with DCM and SiO₂Concentrated and chromatographed via a Redi-Sep pre-packed silica gel column (40g column, 20 → 100% EtOAc in hexane) on ISCO to give 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) as a bright yellow crystalline solidYl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.77g, 6.45mmol, 86% yield). M/z (ESI, cation) 584.1(M + H)⁺。

And step 3: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-methylenepiperidine-1-carboxylate (0.117g, 0.592mmol) was treated with 9-BBN (0.5M in THF, 1.183mL, 0.592mmol) and the mixture was heated at reflux for 4 h. After cooling, the resulting solution was transferred to 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.288g, 0.493mmol), Pd₂(dba)₃(0.023g, 0.025mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (0.024g, 0.049mmol) and Na₂CO₃(0.131g, 1.233mmol) of 1, 4-bisAlkane (1.0mL) and water (0.25 mL). The mixture was sealed and heated with a microwave at 140 ℃ for 30 min. After cooling, the mixture was passed through CeliteThe short column was washed with EtOAc (3X 10 mL). The combined organic phases were concentrated and purified by flash chromatography (short column, SiO)₂Pure hexane → 30% EtOAc in hexane) to give tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidine-1-carboxylate (0.261g, 0.349mmol, 70.9% yield) as a viscous yellow slime. M/z (ESI, cation) 747.2(M + H) ⁺。

And 4, step 4: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

TFA (4.00mL, 51.9mmol) was added slowly to a stirred solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidine-1-carboxylate (0.2611g, 0.350mmol) in DCM (5.00mL, 78mmol) with gentle cooling and the mixture stirred at room temperature for 1 h. The mixture was concentrated (concentrated in vacuo to remove as much TFA as possible). The viscous residue was taken up in DCM (10.00mL) and TEA (0.487mL, 3.50mmol), followed by slow addition of methanesulfonyl chloride (0.082mL, 1.049mmol) at 0 ℃. The mixture was stirred for 1h and then concentrated. The crude product was washed with 1N NaOH_(aq)Partition between DCM (20 mL each). The separated aqueous layer was extracted with DCM (2X 20mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% to 50% ethyl acetate in hexanes) to give the desired product N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.1923g, 0.265mmol, 76% yield) as a yellow film. M/z (ESI, cation) 725.2(M + H) ⁺。

And 5: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A suspension of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.1923g, 0.265mmol) in TFA (1.022mL, 13.26mmol) was treated with a few drops of methanesulfonic acid (0.017mL, 0.265mmol) and the yellow solution was heated at 80 ℃ overnight. The volatile material was removed and the residue carefully replaced with 5% 2M NH in MeOH/DCM₃And (6) diluting. Using SiO for the solution₂Concentrated and pre-filled with silica gel via Redi-Sep (pure DCM → 10% MeOH w/NH in DCM)₃) And (4) performing chromatographic separation. After concentration of the eluent, the resulting yellow solid was washed with IPAWashing gave 4- (2- (6-methoxypyridin-3-ylamino) -5- ((1- (methylsulfonyl) piperidin-4-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (88mg, 0.182mmol, 68.5% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.11.66 (s, 1H); 8.60(d, J ═ 2.54Hz, 1H); 8.54(d, J ═ 2.54Hz, 1H); 8.17(dd, J ═ 8.90, 2.64Hz, 1H); 8.14(d, J ═ 2.15Hz, 1H); 7.84(br.s., 1H); 7.71(br.s., 1H); 6.81(d, J ═ 8.80Hz, 1H); 3.84(s, 3H); 3.45-3.62(m, 2H); 2.82(s, 3H); 2.61-2.72(m, 2H); 2.43(s, 3H); 1.67-1.68(m, 2H); 1.46-1.64(m, 1H); 1.15-1.32(m, 2H). M/z (ESI, cation) 485.2(M + H) ⁺。

Example 156: 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

2-benzyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (Frontier Inc., 90mg, 0.411mmol), 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (160mg, 0.274mmol), Pd₂dba₃A mixture of (12.54mg, 0.014mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 ', -triisopropyl-1, 1' -biphenyl (X-Phos, 13.06mg, 0.027mmol) (Strem Co.) was purged with argon and then with bisAlkane (2.50mL), water (0.25mL), and sodium carbonate (72.6mg, 0.685mmol) were treated and heated under microwave irradiation at 140 ℃ for 30 min. Passing the mixture through CeliteShort pad column filtered (celite), washed with EtOAc (× 3) and concentrated. The crude product was adsorbed onto a silica gel packed column and chromatographed via a Redi-Sep pre-packed silica gel column (pure hexane to 30% EtOAc in hexane) to give 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (110mg, 62.8%) as a yellow slime. M/z (ESI, cation) 640.0(M + H) ⁺。

Step 2: 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (110mg, 0.172mmol) in TFA (265. mu.L, 3.44mmol) was treated with a few drops of trifluoromethanesulfonic acid (15.27. mu.L, 0.172mmol) and the mixture was heated at 80 ℃ overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% MeOH/DCM and adsorbed onto a silica gel packed column and pre-filled with silica gel via Redi-Sep (pure DCM to 3% MeOH, w/NH in DCM)₃) Chromatography gave 4- (5-benzyl-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (15mg, 0.038mmol, 21.84% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.11.68 (s, 1H); 8.61(d, J ═ 2.15Hz, 1H); 8.53(d, J ═ 2.54Hz, 1H); 8.23(d, J ═ 2.15Hz, 1H); 8.16(dd, J ═ 8.80, 2.74Hz, 1H); 7.83(br.s., 1H); 7.69(br.s., 1H); 7.11-7.45(m, 5H); 6.81(d, J ═ 8.80Hz, 1H); 3.94(s, 2H); 3.84(s, 3H); 2.41(s, 3H). M/z (ESI, cation) 400.0(M + H) ⁺。

Example 157: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (160mg, 0.274mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 ', -triisopropyl-1, 1' -biphenyl (X-Phos, 13.06mg, 0.027mmol), cesium carbonate (268mg, 0.822mmol), potassium trimethylpiperazine 1-methyl-4-trifluoroborate (Frontier Scientific Co., 66.3mg, 0.301mmol) and palladium acetate (3.08mg, 0.014mmol) were purged with argon. The mixture was then treated with THF (1.0mL) and water (0.1mL) and heated under microwave irradiation at 140 ℃ for 30 min. Passing the mixture through CeliteShort column filtration (celite), washing with EtOAc (× 3) and concentration. The crude product was adsorbed onto a silica gel packed column and chromatographed over a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM) to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow slime (161mg, 0.243mmol, 89% yield). M/z (ESI, cation) 662.0(M + H) ⁺。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared from N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine in analogy to the procedure described in example 156, step 2 and was isolated (96%) as a yellow solid.¹H NMR(400MHz，d6-DMSO)δ11.74(s，1H)；8.69(d，J＝2.15Hz，1H)；8.54(d，J＝2.74Hz，1H)；8.00-8.33(m，2H)；7.86(br.s.，1H)；7.71(br.s., 1H); 6.82(d, J ═ 8.80Hz, 1H); 3.84(s, 3H); 3.49-3.81(m, 4H); 3.40(s, 2H); 2.44(s, 3H); 2.35(m, 4H); 2.14(s, 3H). M/z (ESI, cation) 422.1(M + H)⁺。

Example 158: (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (R) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) potassium trifluoroborate.

A mixture of potassium (bromomethyl) trifluoroborate (1.20g, 5.38mmol) and (R) -4-N-Boc-2-methyl-piperazine (1.166g, 5.65mmol) in THF (7.00mL) was heated at 80 ℃ under nitrogen for 24 h. After cooling, the mixture was concentrated, redissolved in acetone (125mL) and washed with K₂CO₃(1 equivalent) treatment. The suspension was stirred for 30min and passed through Celite (celite) short packed column filtration, washing with additional acetone and the combined organic phases were concentrated to give potassium (R) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) trifluoroborate as a pale yellow foam (1.627g, 94%).¹⁹F-NMR (377MHz, d 6-acetone) delta-141.36.

Step 2: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester

In a similar manner to that described in example 157, step 1, above, potassium (R) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) trifluoroborate and 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazine were used-2-amine the title compound was prepared to give 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester as a yellow slime (188mg, 0.247mmol, 74.3% yield). M/z (ESI, cation) 761.7(M + H)⁺。

And step 3: (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a similar manner to that described in example 155 (step 4 to step 5), the material isolated above from step 1 was subjected to a series of transformations involving: (1) deprotection of the BOC group; (2) n-piperazine sulfonamide formation; and (3) deprotection of the bis-PMB group on the aminotriazine to give (R) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (38mg, 0.076mmol, 85% yield). M/z (ESI, cation) 499.9(M + H)⁺. Example 159 and example 160: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide (example 159) and 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-hydroxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide (example 160).

Step 1: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

In a similar manner to that described in example 155, step 2, 5-fluoro-6-methoxypyridin-3-amine and 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-tris-methyl) -amino) -were used Oxazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester. Tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate was isolated as a yellow solid (90%). M/z (ESI, cation) 765.8(M + H)⁺。

Step 2: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide

A slightly cooled stirred solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate (8.77g, 11.45mmol) in DCM (25.00mL, 389mmol) was treated with TFA (15.00mL, 195mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residual viscous material was taken up in DCM (100mL) and carefully diluted with saturated NaHCO_3(aq)Quench until slightly basic. The aqueous layer was extracted with DCM (2X 100mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid. A portion of this solid (0.349g, 0.524mmol) was dissolved in DCM (5.00mL, 78mmol) and Et at-15 deg.C ₃N (0.365mL, 2.62 mmol). The mixture was treated slowly with dimethylcarbamoyl chloride (0.169g, 1.573mmol) and stirred for 1h, after which it was allowed to warm to room temperature overnight. The reaction mixture was concentrated, the crude product was adsorbed onto a silica gel packed column and chromatographed via a Redi-Sep pre-packed silica gel column (10 to 100% EtOAc in hexane) to give 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide (0.3555g 92%) (ESI, cation) 736.7(M + H) as a yellow solid⁺。

And step 3: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide and 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-hydroxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide

A stirred mixture of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide (0.3555g, 0.482mmol) in TFA (1.859mL, 24.12mmol) was treated with methanesulfonic acid (0.031mL, 0.482mmol) and the solution was heated at 85 ℃. After cooling, the residue was carefully concentrated and washed with 5% MeOH/DCM w/NH ₃And (6) diluting. Using SiO for the solution₂Concentrated and chromatographed via a predi-Sep pre-packed silica gel column (pure DCM to 10% MeOH in DCM) to give 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide (88mg, 0.177mmol, 36.7% yield).¹H NMR (400MHz, d 6-DMSO). delta.12.04 (s, 1H); 8.92(br.s., 1H); 8.45(s, 1H); 8.40(br.s., 1H); 8.33(d, J ═ 11.35Hz, 1H); 7.96(br.s., 1H); 7.87(br.s., 1H); 4.40(br.s., 2H); 3.95(s, 3H); 3.64(d, J ═ 14.87Hz, 2H); 3.25-3.35(m, 2H); 2.88-3.15(m, 4H); 2.78(s, 6H); 2.44(s, 3H). M/z (ESI, cation) 497.1(M + H)⁺。

The column was further eluted with 20% MeOH in DCM and NH₃Elution gave 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-hydroxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-carboxamide as a yellow solid as a by-product (51mg, 0.106mmol, 21.91% yield).¹H NMR(400MHz，d6-DMSO)δ11.94(br.s.，1H)；11.39(s，1H)；8.69(s，1H)；8.20(s，1H)；7.92(br.s.，1H)；7.85-7.91(m，1H)；7.80(d，J＝12.32Hz，1H)；7.72(br.s.，1H)；3.44(s，2H)；3.09(br.s.，4H)；2.72(s，6H)；2.42(s，3H)；2.30-2.40(m，4H)。M/z (ESI, cation) 483.1(M + H)⁺。

Example 161: 5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) -3-fluoropyridin-2-ol

During the final step of example 40, the title compound was isolated as a by-product (yellow solid).¹H NMR (400MHz, d 6-DMSO). delta.11.99 (br.s., 1H); 11.39(br.s., 1H); 8.70(br.s., 1H); 8.20(br.s., 1H); 7.91(br.s., 2H); 7.80(d, J ═ 11.35Hz, 1H); 7.73(br.s., 1H); 3.48(br.s., 2H); 3.10(br.s., 4H); 2.86(s, 3H); 2.44-2.49(m, 4H); 2.42(s, 3H). M/z (ESI, cation) 489.8(M + H)⁺。

Example 162: 4- (2- (5-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A stirred solution of 2- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -4-methyl-6- (methylthio) -1, 3, 5-triazine (200mg, 0.485mmol) and 5-methoxypyridin-3-amine (Astatech, inc., 90mg, 0.727mmol) in DMF (5.00mL, 1.000mmol) was treated with 1.0M LiHMDS in THF (1.939mL, 1.939mmol) at 0 ℃ and the mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL each) and ethyl acetate (15 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL), and the combined organic layers were washed with brine, over Na₂SO₄Dried, and concentrated to give a crude residue which was combined with IPA (3.00mL, 6.00mmol) of 2.0M aqueous ammonia was heated overnight. After cooling, the mixture was adsorbed onto a silica gel packed column and chromatographed via a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM) to give 4- (2- (5-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (44mg, 0.091mmol, 18.69% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.12.13 (s, 1H); 8.74(s, 1H); 8.55(s, 1H); 8.31(s, 1H); 8.19(br.s., 1H); 7.93(br.s., 2H); 7.78(br.s., 1H); 3.86(s, 3H); 3.52(s, 2H); 3.11(br.s., 4H); 2.87(s, 3H); 2.46-2.50(m, 4H); 2.46(s, 3H). M/z (ESI, cation) 486.1(M + H)⁺。

Example 163: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, 6-dimethyl-1, 3, 5-triazin-2-amine

Methylamine was bubbled through a mixture of N- (6-methoxypyridin-3-yl) -3- (4-methyl-6- (methylthio) -1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine (33mg, 0.064mmol) in IPA (1.50mL, 19.47mmol) for 15min and then allowed to stand overnight. The resulting precipitate was collected by filtration and washed with a minimal amount of IPA to give 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, 6-dimethyl-1, 3, 5-triazin-2-amine (17.1mg, 1.761mmol, 54.7% yield) as a yellow solid. ¹H NMR (400MHz, d6-DMSO) rotamer mixture, delta 11.26-12.03(m, 1H); 8.73(d, J ═ 13.69Hz, 1H); 8.38-8.63(m, 1H); 7.96-8.38(m, 3H); 6.83(d, J ═ 8.41Hz, 1H); 3.84(br.s., 3H); 3.50(d, J ═ 12.72Hz, 2H); 3.11(br.s., 4H); 2.90-3.03(m, 3H); 2.86(br.s., 3H); 2.47-2.50(m, 4H); 2.44(br.s., 3H). M/z (ESI, cation) 500.1(M + H)⁺。

Example 164: 4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 3- (difluoromethoxy) aniline (0.038mL, 0.303mmol) (Aldrich) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.090g, 0.202mmol) in THF (3.0mL) was treated dropwise with 1.0M LiHMDS dissolved in THF (0.606mL, 0.606mmol) (Aldrich) at 0 deg.C. The solution was stirred at 0 ℃ for 1.5h, and then at 0 ℃ with NH₄A saturated solution of Cl was quenched. The mixture was extracted with EtOAc (15mL) over MgSO₄Dried, filtered and concentrated to give 4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a brown oil (0.121g, 0.207mmol, 99% yield). ¹H NMR(400MHz，CDCl₃) δ 12.12(br.s., 1H); 8.84(d, J ═ 8.2Hz, 1H); 8.35(br.s., 1H); 7.72(br.s., 1H); 7.31(d, J ═ 8.4Hz, 1H); 7.20(d, J ═ 7.8Hz, 5H); 7.11(t, J ═ 8.0Hz, 4H); 6.84-6.90(m, 4H); 6.80(d, J ═ 7.8Hz, 1H); 6.71(d, J ═ 8.4Hz, 1H); 6.65(br.s., 1H); 6.45-6.54(m, 10H); 6.42(br.s., 4H); 6.28(br.s., 1H); 4.84(br.s., 4H); 3.80(d, J ═ 3.5Hz, 7H); 2.60(br.s., 3H). M/z (ESI, cation) 585.1(M + H)⁺。

Step 2: 4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6 was heated at 80 deg.C using an electric furnace and a metal heating blockA solution of-methyl-1, 3, 5-triazin-2-amine (0.121g, 0.207mmol) in TFA (8.0mL) (Aldrich) was heated overnight. The crude product was dissolved in 2.5mL DMSO and purified by reverse phase chromatography (Gilson; 10-90% CH in water with TFA additive)₃CN: 0.1% v/v for each solvent). Fractions were combined and CH removed₃And (C) CN. DCM was added and NaHCO was used in its entirety₃Saturated solution (1X), brine (1X) washed over MgSO₄Dried, filtered and concentrated to give 4- (2- (3- (difluoromethoxy) phenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (24mg, 6.97 μmol, 3.37% yield) as a yellow amorphous solid. ¹H NMR(400MHz，CDCl₃)12.17(br.s., 1H); 8.80(d, J ═ 8.2Hz, 1H); 8.41(br.s., 1H); 7.97(br.s., 1H); 7.83-7.90(m, 1H); 7.78(b r.s., 1H); 7.62(d, J ═ 8.6Hz, 1H); 7.31-7.40(m, 1H); 6.93-7.01(m, 1H); 6.78(d, J ═ 8.2Hz, 1H); 2.45(br.s., 3H). M/z (ESI, cation) 345.1(M + H)⁺。

Example 165: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylbenzo [ d] Azole-5-amines

Step 1: n- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylbenzo [ d] Azole-5-amines

In a similar manner to that described in example 164, using 2-methylbenzo [ d ]] Azole-5-amine (Bionet Research Intermediates) and 4- (2-fluoropyridin-3-yl)-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine the title compound was prepared and isolated as a brown oil (100%).¹H NMR(400MHz，CDCl₃) δ 11.94(s, 1H); 8.31(br.s., 1H); 8.04(br.s., 1H); 7.31-7.42(m, 1H); 7.27-7.30(m, 2H); 7.14-7.24(m, 3H); 6.79-6.96(m, 5H); 4.84(br.s., 4H); 3.80(d, J ═ 9.6Hz, 6H); 2.62(br.s., 3H); 2.59(br.s., 4H). M/z (ESI, cation) 574.0(M + H)⁺。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylbenzo [ d ] Azole-5-amines

N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylbenzo [ d ] was reacted at 80 deg.C] A solution of oxazol-5-amine (0.116g, 0.202mmol) in TFA (8.0mL) (Aldrich) was heated overnight. TFA was removed in vacuo. The crude product was dissolved in 4mL DMSO and purified by reverse phase chromatography (Gilson; 10-90% CH in water with TFA addition)₃CN: 0.1% v/v for each solvent). Fractions were combined and CH removed₃And (C) CN. DCM was added and NaHCO was used in its entirety₃Saturated solution (1X), brine (1X) washed over MgSO₄Dried, filtered and concentrated. The compound and impurities are co-eluted. The material was purified by flash column chromatography using ISCO Combiflash company (4g column; 1-10% MeOH in DCM over 40 min). The compound and impurities are co-eluted. The crude product was dissolved in 4mL DMSO. By reverse phase chromatography (Gilson; dissolved in a solution with NH)₄10-90% CH in OH additive in water₃CN: 0.1% v/v) of each solvent followed by drying in a Genevac series II System to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylbenzo [ d ] as a yellow amorphous solid] Azol-5-amine (1.079mg, 3.24. mu. mol, 1.6% yield). ¹H NMR (400MHz, d 6-DMSO). delta.12.04 (s, 1H); 8.79(dd, J ═ 7.7, 2.1Hz, 1H); 8.37(dd, J ═ 4.7, 2.0Hz, 1H); 8.33(d, J ═ 2.0Hz, 1H); 7.86(q, J ═ 3.2Hz, 1H); 7.70-7.77(m, 1H); 7.62-7.68(m, 1H); 7.54-7.60(m, 1H); 6.91(dd, J ═ 7.8, 4.7Hz, 1H); 2.60(s, 3H); 2.45(s, 4H). M/z (ESI, cation) 334.1(M + H)⁺。

Example 166: 4- (2- (3-fluoro-4-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (3-fluoro-4-methoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 164 using 3-fluoro-4-methoxyaniline (Aldrich) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and was isolated as brown solid (100%).¹H NMR (400MHz, d 6-DMSO). delta.11.82 (br.s., 1H); 8.77(d, J ═ 7.0Hz, 1H); 8.34(br.s., 1H); 7.75(d, J ═ 14.1Hz, 1H); 7.18-7.31(m, 4H); 7.11-7.17(m, 1H); 7.05(t, J ═ 9.8Hz, 1H); 6.89(t, J ═ 7.4Hz, 5H); 4.81(d, J ═ 8.6Hz, 3H); 3.80(br.s., 3H); 3.72(d, J ═ 10.4Hz, 7H); 2.56(br.s., 3H). M/z (ESI, cation) 567.1(M + H) ⁺。

Step 2: 4- (2- (3-fluoro-4-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (3-fluoro-4-methoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.1253g, 0.221mmol) as TFA (8.0 m) was added at 80 deg.CL) (Aldrich) solution was heated overnight. TFA was removed in vacuo and the residue was taken up with NaHCO₃Treatment of the saturated solution. The mixture was extracted with DCM (3 × 15mL) and concentrated. The crude brown oil was dissolved in 2.5mL DMSO and purified by reverse phase chromatography (Gilson, dissolved in NH with water)₄10-90% CH in OH additive in water₃CN: 0.1% v/v for each solvent). The fractions were concentrated in a Genevac series II system to give 4- (2- (3-fluoro-4-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow amorphous solid (3.3mg, 10.11 μmol, 4.57% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.91 (s, 1H); 8.77(dd, J ═ 7.8, 2.0Hz, 1H); 8.35(dd, J ═ 4.7, 2.0Hz, 1H); 7.94(dd, J ═ 14.2, 2.6Hz, 1H); 7.48-7.53(m, 1H); 7.11(t, J ═ 9.4Hz, 1H); 6.90(dd, J ═ 7.8, 4.7Hz, 1H); 3.82(s, 3H); 2.43(s, 3H). M/z (ESI, cation) 327.1(M + H) ⁺。

Example 167: 4- (2- (4-fluoro-3-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (4-fluoro-3-methoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 164 using 4-fluoro-3-methoxyaniline (Combi-Blocks Inc.) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and was isolated as a brown solid (100%).¹H NMR (400MHz, d 6-DMSO). delta.11.91 (br.s., 1H); 8.80(br.s., 1H); 8.35(br.s., 1H); 7.55(br.s., 1H); 7.24(br.s., 4H); 7.11(d, J ═ 1.2Hz, 1H); 6.77-6.94(m, 6H); 4.79(br.s., 4H); 3.77(br.s., 3H); 3.72(d, J ═ 10.6Hz, 6H); 2.56(br.s., 3H). M/z (ESI, cation) 567.0(M + H)⁺。

Step 2: 4- (2- (4-fluoro-3-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (4-fluoro-3-methoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.1196g, 0.211mmol) in TFA (8.0mL) was heated overnight at 80 ℃. The solution was cooled to room temperature and TFA was removed in vacuo. The crude product is treated with NaHCO ₃The saturated solution was treated, the aqueous layer was extracted with DCM (3X 15mL), the layers were separated, and the combined organic layers were dried and concentrated. The crude brown oil was dissolved in 2.5mL DMSO and purified by reverse phase chromatography (Gilson, dissolved in NH with water)₄10-90% CH in OH additive in water₃CN: 0.1% v/v for each solvent). The fractions were concentrated in a Genevac series II system to give 4- (2- (4-fluoro-3-methoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow amorphous solid (0.0025g 7.66 μmol yield 3.63%).¹H NMR (400MHz, d 6-DMSO). delta.11.94 (s, 1H); 8.77(dd, J ═ 7.7, 1.9Hz, 1H); 8.35(dd, J ═ 4.8, 1.9Hz, 1H); 7.70-7.77(m, 1H); 7.34(s, 1H); 7.14(dd, J ═ 11.4, 8.9Hz, 1H); 6.91(dd, J ═ 7.7, 4.8Hz, 1H); 3.87(s, 3H); 2.64-2.70(m, 1H); 2.44(s, 3H). M/z (ESI, cation) 327.1(M + H)⁺。

Example 168: 4- (2- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

In a similar manner to that described in example 164, 2-difluorobenzo [ d ] was used][1，3]Dioxol-5-amine (0.055g, 0.3)20mmol) (Apollo Scientific Limited) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.095g, 0.213mmol) the title compound was prepared and isolated as a brown oil (100%).¹H NMR (400MHz, d 6-DMSO). delta.11.98 (br.s., 1H); 8.79(d, J ═ 7.6Hz, 1H); 8.35(br.s., 1H); 7.92(br.s., 1H); 7.20-7.29(m, 5H); 7.16(d, J ═ 8.4Hz, 1H); stone 83-6.97(m, 5H); 4.81(d, J ═ 7.4Hz, 4H); 3.72(d, J ═ 12.7Hz, 6H); 2.57(br.s., 3H). M/z (ESI, cation) 599.0(M + H)⁺。

Step 2: 4- (2- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (2, 2-difluorobenzo [ d ]) is reacted at 80 DEG C][1，3]Dioxolen-5-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.1352g, 0.226mmol) in TFA (8.0mL) (Aldrich) was heated overnight. The solution was cooled to room temperature and TFA was removed in vacuo. The residue is taken up in NaHCO₃The saturated solution was treated, the aqueous layer was extracted with DCM (3X 15mL), the layers were separated, and the combined organic layers were dried and concentrated. The crude brown oil was dissolved in 2.5mL DMSO and purified by reverse phase chromatography (Gilson, dissolved in NH with water) ₄10-90% CH in OH additive in water₃CN: 0.1% v/v for each solvent). The fractions were concentrated in a Genevac series II system to give 4- (2- (2, 2-difluorobenzo [ d ] as a yellow amorphous solid][1，3]Dioxol-5-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (3.1mg, 8.65. mu. mol, 3.83% yield).¹H NMR (400MHz, d 6-DMSO). delta.12.11 (s, 1H); 8.80(dd, J ═ 7.8, 2.0Hz, 1H); 8.37(dd, J ═ 4.6, 2.1Hz, 1H); 8.15(d, J ═ 2.2Hz, 1H); 7.87(br.s., 1H); 7.77(br.s., 1H); 7.55(dd, J ═ 8.8, 2.2Hz, 1H); 7.35(d, J ═ 8.8Hz, 1H); 6.95(dd, J ═ 7.9, 4.6Hz, 1H); 2.44(s, 3H). M/z (ESI, cation) 359.0(M + H)⁺。

Example 169: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine

Step 1: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine

6-methoxypyridin-3-ylboronic acid (0.039g, 0.256mmol), 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.1244g, 0.213mmol), Pd ₂dba₃A mixture of (7.80mg, 8.52. mu. mol) and dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (8.12mg, 0.017mmol) was purged with argon. Mixing the mixture with twoAlkane (2.0mL) and sodium carbonate (0.27mL, 0.53mmol) were treated and heated in a Biotage Initiator microwave at 140 ℃ for 30 min. The cooled reaction mixture was treated with 1N NaOH and extracted with EtOAc (30mL), washed with brine, over MgSO₄Dried, filtered and concentrated. The crude product was used directly in the next reaction. M/z (ESI, cation) 657.0(M + H)⁺。

Step 2: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine (0.163g, 0.249mmol) in TFA (8.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature, the mixture was concentrated, and the crude residue was taken up in 2M NH in MeOH₃Treated and dry packed with silica gel. ISCO Combiflash company (40g column; 1-20% MeOH in DCM) was usedWithin 25 min; product eluted with 10% MeOH) yielded 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6 '-methoxy-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine (0.0572g, 0.137mmol, 55.2% yield) as an orange amorphous solid. ¹H NMR (400MHz, d 6-DMSO). delta.11.81 (s, 1H); 8.98(d, J ═ 2.7Hz, 1H); 8.62(d, J ═ 2.5Hz, 1H); 8.56(d, J ═ 2.7Hz, 1H); 8.47(d, J ═ 2.3Hz, 1H); 8.20(dd, J ═ 8.8, 2.7Hz, 1H); 8.00(dd, J ═ 8.6, 2.7Hz, 1H); 7.90(br.s., 1H); 7.76(br.s., 1H); 6.94(d, J ═ 8.6Hz, 1H); 6.85(d, J ═ 8.8Hz, 1H); 3.90(s, 3H); 3.86(s, 3H); 2.46(s, 3H). M/z (ESI, cation) 417.0(M + H)⁺。

Example 170: 4- (2- (3, 4-Dimethoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (3, 4-Dimethoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 164 using 3, 4-dimethoxyaniline (Aldrich) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and was isolated as brown oil (100%).¹H NMR(400MHz，CDCl₃) δ 11.69(s, 1H); 8.82(dd, J ═ 7.8, 2.0Hz, 1H); 8.30(dd, J ═ 4.7, 1.8Hz, 1H); 7.31(d, J ═ 2.2Hz, 1H); 7.20(d, J ═ 8.2Hz, 4H); 6.98(dd, J ═ 8.6, 2.3Hz, 1H); 6.78-6.91(m, 5H); 6.72(dd, J ═ 7.8, 4.7Hz, 1H); 4.83(s, 4H); 3.86(s, 3H); 3.81(s, 6H); 3.79(s, 3H); 2.57(s, 3H). M/z (ESI, cation) 579.0(M + H) ⁺。

Step 2: 4- (2- (3, 4-Dimethoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (3, 4-dimethoxyphenylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.255g, 0.441mmol) in TFA (8.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature, the mixture was concentrated, and the crude residue was taken up in 2M NH in MeOH₃Treated and dry packed with silica gel. Purification using ISCO Combiflash company (12g column; 1-25% MeOH in DCM over 30 min; product eluted with 11% MeOH) gave an insufficiently pure material to be used for testing. The residue was suspended in MeOH, and the solid was removed by filtration to give 4- (2- (3, 4-dimethoxyphenylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a brown amorphous solid (0.017g, 0.049mmol, 11.12% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.77 (s, 1H); 8.75(dd, J ═ 7.7, 1.9Hz, 1H); 8.31(dd, J ═ 4.5, 2.0Hz, 1H); 7.79(br.s., 1H); 7.70(br.s., 1H); 7.47(d, J ═ 2.3Hz, 1H); 7.30(dd, J ═ 8.7, 2.4Hz, 1H); 6.91(d, J ═ 8.8Hz, 1H); 6.84(dd, J ═ 7.8, 4.7Hz, 1H); 3.79(s, 3H); 3.74(s, 3H); 2.44(s, 3H). M/z (ESI, cation) 339.0(M + H) ⁺。

Example 171: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylquinolin-6-amine

Step 1: n- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylquinolin-6-amine

The title compound was prepared in analogy to the procedure described for example 164 using 2-methylquinolin-6-amine (Acros Organics) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine. ISCO Combiflash company (12g column, 20-60% EtOAc in hexane, over 30min, washed with 35-45% EtOAcProduct removal) to yield the title compound as a yellow amorphous solid (49.1%).¹H NMR (400MHz, d 6-DMSO). delta.12.19 (s, 1H); 8.84(dd, J ═ 7.8, 2.0Hz, 1H); 8.45(dd, J ═ 4.7, 2.0Hz, 1H); 8.39(d, J ═ 2.2Hz, 1H); 8.08(d, J ═ 8.2Hz, 1H); 7.78-7.83(m, 1H); 7.71-7.77(m, 1H); 7.34(d, J ═ 8.4Hz, 1H); 7.26(dd, J ═ 8.6, 6.3Hz, 4H); 6.98(dd, J ═ 7.8, 4.7Hz, 1H); 6.90(t, J ═ 8.3Hz, 4H); 4.84(d, J ═ 17.6Hz, 4H); 3.72(d, J ═ 14.5Hz, 6H); 2.62(d, J ═ 2.0Hz, 6H). M/z (ESI, cation) 584.0(M + H) ⁺。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylquinolin-6-amine

A solution of N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylquinolin-6-amine (0.116g, 0.199mmol) in TFA (5.0 mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and the mixture was concentrated to about 50% of the original volume. The remaining mixture was carefully transferred to NaHCO with a pipette₃In a saturated solution, it was cooled in an ice bath. The resulting precipitate was collected by filtration and washed with water. The solid was then suspended in IPA and the precipitate was collected by filtration to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-methylquinolin-6-amine (0.0581g, 0.169mmol, 85% yield) as a yellow amorphous solid.¹H NMR (400MHz, d 6-DMSO). delta.12.30 (s, 1H); 8.83(d, J ═ 7.0Hz, 1H); 8.62(s, 1H); 8.45(d, J ═ 2.7Hz, 1H); 8.15(d, J ═ 8.4Hz, 1H); 8.03(d, J ═ 8.0Hz, 1H); 7.82-7.93(m, 2H); 7.80(br.s., 1H); 7.36(d, J ═ 8.6Hz, 1H); 6.99(dd, J ═ 7.3, 4.8Hz, 1H); 2.63(s, 3H); 2.48(br.s., 3H). M/z (ESI, cation) 344.0(M + H) ⁺。

Example 172: 5 ' - (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3 ' -bipyridin-6 ' -amine

Step 1: 5 ' - (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3 ' -bipyridin-6 ' -amine

A mixture of 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.100g, 0.171mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (4.08mg, 8.56. mu. mol), tris (dibenzylideneacetone) dipalladium (0) (7.84mg, 8.56. mu. mol) and 2- (tributylstannyl) pyridine (0.082g, 0.223mmol) (Alfa Aesar) was purged with argon and toluene (0.9mL) was added. The tube was sealed and the mixture was heated at 110 ℃. The reaction mixture was cooled to room temperature, treated with water, extracted with DCM (2X 15mL), over MgSO₄Dried, filtered and concentrated. The crude material was purified by flash chromatography using an ISCO Combiflash company (12g column, 20-50% EtOAc in hexane over 30 min; product eluted with about 30-35% EtOAc).¹H NMR(400MHz，CDCl₃) δ 11.82(s, 1H); 9.41(d, J ═ 2.5Hz, 1H); 8.93(d, J ═ 2.3Hz, 1H); 8.66(d, J ═ 4.9Hz, 1H); 8.30(d, J ═ 2.7Hz, 1H); 7.93(dd, J ═ 8.9, 2.6Hz, 1H); 7.67-7.75(m, 1H); 7.59-7.65(m, 1H); 7.15-7.24(m, 5H); 6.85(dd, J ═ 20.0, 8.6Hz, 4H); 6.72(d, J ═ 8.8Hz, 1H); 4.87(d, J ═ 17.2Hz, 4H); 3.94(s, 3H); 3.81(s, 3H); 3.76(s, 3H); 2.59(s, 3H). M/z (ESI, cation) 627.0(M + H) ⁺。

Step 2: 5 ' - (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3 ' -bipyridin-6 ' -amine

A solution of 5 ' - (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3 ' -bipyridin-6 ' -amine (0.0419g, 0.067mmol) in TFA (3.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and concentrated. Dissolving the crude residue in water2M NH in MeOH₃Treated and dry packed with silica gel. Purification on an ISCO Combiflash company (12g column, 1-15% MeOH in DCM, product eluted with 10% MeOH over 25 min) afforded 5 ' - (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3 ' -bipyridin-6 ' -amine (0.0106g, 0.027mmol, 41.0% yield) as a yellow amorphous solid.¹H NMR (400MHz, d 6-DMSO). delta.11.98 (s, 1H); 9.53(d, J ═ 2.5Hz, 1H); 9.00(d, J ═ 2.5Hz, 1H); 8.67(d, J ═ 5.3Hz, 1H); 8.58(d, J ═ 2.7Hz, 1H); 8.21(dd, J ═ 9.0, 2.9Hz, 1H); 7.96(t, J ═ 7.8Hz, 2H); 7.88(td, J ═ 7.6, 1.8Hz, 1H); 7.76(d, J ═ 2.7Hz, 1H); 7.33(s, 1H); 6.86(d, J ═ 9.0Hz, 1H); 3.86(s, 3H); 2.47(s, 3H). M/z (ESI, cation) 387.0(M + H) ⁺。

Example 173: 4- (2- (5-chloro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (5-chloro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 164 using 5-chloro-6-methoxypyridin-3-amine and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and was isolated as brown oil (100%).¹H NMR (400MHz, d 6-DMSO). delta.11.71 (s, 1H); 8.78(dd, J ═ 7.8, 2.2Hz, 1H); 8.33(dd, J ═ 4.7, 2.0Hz, 1H); 8.26(d, J ═ 2.5Hz, 1H); 8.19(d, J ═ 2.3Hz, 1H); 7.17-7.29(m, 4H); 6.82-6.96(m, 5H); 4.81(d, J ═ 6.5Hz, 4H); 3.91(s, 3H); 3.74(s, 3H); 3.70(s, 3H); 2.55-2.58(m, 3H). M/z (ESI, cation) 584.0(M + H)⁺。

Step 2: 4- (2- (5-chloro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (5-chloro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.3068g, 0.525mmol) in TFA (8.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and concentrated to about 50% of the original volume. The remaining mixture was carefully transferred to NaHCO with a pipette ₃In a saturated solution, it was cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The solid was dissolved in DCM and MeOH and the charge was dried over silica gel. Purification using ISCO Combiflash company (12g column, 1-6% MeOH in DCM over 40min eluting the product with 4% MeOH) afforded 4- (2- (5-chloro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a tan amorphous solid (0.0434g, 0.126mmol, 24.03% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.89 (s, 1H); 8.80(dd, J ═ 7.8, 2.0Hz, 1H); 8.51-8.56(m, 2H); 8.35(dd, J ═ 4.7, 2.0Hz, 1H); 7.92(br.s., 1H); 7.76(br.s., 1H); 6.94(dd, J ═ 7.8, 4.7Hz, 1H); 3.93(s, 3H); 2.43(s, 3H). M/z (ESI, cation) 344.0(M + H)⁺。

Example 174: 4-methyl-6- (2- (5-methylpyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4-methyl-6- (2- (5-methylpyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 164 using 5-methylpyridin-3-amine (0.075g, 0.690mmol) (Aldrich) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine. ISCO Combiflash company (12g column) was used 30-70% EtOAc in hexanes in 30 min; product eluted with 45% EtOAc) to afford the title compound as a yellow amorphous solid (25.7%).¹H NMR (400MHz, d 6-DMSO). delta.11.93 (s, 1H); 8.81(dd, J ═ 7.8, 1.8Hz, 1H); 8.61(d, J ═ 2.3Hz, 1H); 8.39(dd, J ═ 4.7, 2.0Hz, 1H); 8.02(s, 1H); 7.93(s, 1H); 7.25(dd, J ═ 10.2, 8.8Hz, 4H); 6.85-7.00(m, 5H); 4.82(d, J ═ 14.7Hz, 4H); 3.74(s, 3H); 3.71(s, 3H); 2.59(s, 3H); 2.26(s, 3H). M/z (ESI, cation) 534.0(M + H)⁺。

Step 2: 4-methyl-6- (2- (5-methylpyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4-methyl-6- (2- (5-methylpyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine (0.063g, 0.118mmol) in TFA (3.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and concentrated to about 50% of the original volume. The remaining mixture was carefully transferred to NaHCO with a pipette₃In a saturated solution, it was cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The material was suspended in DMSO (5mL) and water (10 drops) was added. The solid was collected by filtration to give 4-methyl-6- (2- (5-methylpyridin-3-ylamino) pyridin-3-yl) -1, 3, 5-triazin-2-amine (0.0137g, 0.047mmol, 39.6% yield) as a yellow amorphous solid. ¹H NMR (400MHz, d 6-DMSO). delta.11.96-12.04 (m, 1H); 8.81(br.s., 2H); 8.39(br.s., 1H); 8.23(br.s., 1H); 8.05(s, 1H); 7.89(br.s., 1H); 7.77(br.s., 1H); 6.96(br.s., 1H); 2.45(br.s., 3H); 2.32(s, 3H). M/z (ESI, cation) 294.0(M + H)⁺。

Example 175: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine

Step 1: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine

The title compound was prepared in analogy to the procedure described for example 164 using 5-fluoro-6-methoxypyridin-3-amine (Anichem) and 4- (6-fluoro-2, 4' -bipyridin-5-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine. Purification using ISCO Combiflash company (12g column and sample loader, 30-100% EtOAc in hexane over 20 min; product eluted with 82% EtOAc) afforded the title compound as a brown oil (39.6%).¹H NMR (400MHz, d 6-DMSO). delta.11.86 (s, 1H); 8.91(d, J ═ 8.2Hz, 1H); 8.70-8.76(m, 2H); 8.21(d, J ═ 2.2Hz, 1H); 8.09(dd, J ═ 12.4, 2.2Hz, 1H); 7.94-7.99(m, 2H); 7.66(d, J ═ 8.0Hz, 1H); 7.26(dd, J ═ 18.4, 8.6Hz, 4H); 6.89(dd, J ═ 18.7, 8.7Hz, 4H); 4.83(d, J ═ 9.2Hz, 4H); 3.95(s, 3H); 3.74(s, 3H); 3.70(s, 3H); 2.59(s, 3H). M/z (ESI, cation) 645.0(M + H) ⁺。

Step 2: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine (0.139g, 0.216mmol) in TFA (8.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and concentrated under a stream of argon to about 50% of the original volume. The remaining mixture was carefully transferred to NaHCO with a pipette₃In a saturated solution, it was cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The impure solid was suspended in IPA and the suspension was subjected to filtration. The solid was washed with DMSO, followed by water to give 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine (0.0565g, 0.140mmol, 64.8% yield).¹H NMR(400MHz，d6-DMSO)δ12.03(s，1H)；8.93(d, J ═ 8.0Hz, 1H); 8.75(d, J ═ 5.9Hz, 2H); 8.54(d, J ═ 1.8Hz, 1H); 8.32-8.38(m, 1H); 8.00(d, J ═ 5.7Hz, 2H); 7.95(br.s., 1H); 7.81(br.s., 1H); 7.67(d, J ═ 8.0Hz, 1H); 3.97(s, 3H); 2.46(s, 3H). M/z (ESI, cation) 405.0(M + H) ⁺。

Example 176: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 4' -bipyridin-6-amine

Step 1: (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) (4-hydroxypiperidin-1-yl) methanone

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (0.054g, 0.091mmol) in THF (1.0mL) was treated with sodium cyanide (4.44mg, 0.091mmol) (Sigma-Aldrich), piperidin-4-ol (0.046g, 0.453mmol) (Aldrich) and manganese (IV) oxide (0.118g, 1.360mmol) (Sigma-Aldrich) at room temperature. The mixture was stirred at room temperature. After 1h, the reaction was not complete, so several grains of NaCN and a further 15 equivalents of manganese (IV) oxide (0.118g, 1.360mmol) were added. The mixture was stirred at room temperature for 18h, then through Celite(celite) filtration. The organic layer was washed with water, then brine, over MgSO₄Dry, filter and concentrate to give the title compound as a yellow film (85%).¹H NMR(400MHz，d6-DMSO)δ11.86(s，1H)；8.77(d，J＝2.3Hz，1H)；8.38(d，J＝2.3Hz，1H)；8.02-8.11(m，2H)；7.23-7.32(m，2H)；7.19(m，J＝8.6Hz，2H)；6.91(m，2H)；6.83(d，J＝8.8Hz，2H)；4.72-4.87(m，5H)； 3.90-3.95(m，3H)；3.66-3.76(m，8H)；3.17-3.28(m，2H)；2.58(s, 3H); 1.71(br.s., 2H); 1.36(br.s., 2H). M/z (ESI, cation) 695.0(M + H) ⁺。

A solution of (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) (4-hydroxypiperidin-1-yl) methanone (0.109g, 0.157mmol) TFA (7.0mL) (Aldrich) was heated overnight at 80 ℃. The solution was cooled to room temperature and concentrated under a stream of argon to about 50% of the original volume. Several tablets of ice were added, followed by slow addition of NaHCO₃Until a pH of 7 is reached. The precipitate was isolated by filtration and the filter cake was washed with water. The solid was suspended in 3mL MeOH and 1mL THF, followed by the addition of 0.5mL 1N NaOH. The suspension was stirred at room temperature for 10 min. The solid was isolated by filtration and dried to give (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) (4-hydroxypiperidin-1-yl) methanone (0.0406g, 0.089mmol, 56.9% yield) as an amorphous yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.12.08 (s, 1H); 8.85(d, J ═ 2.3Hz, 1H); 8.41(dd, J ═ 4.8, 2.2Hz, 2H); 8.35(dd, J ═ 12.6, 2.2Hz, 1H); 7.96(br.s., 1H); 7.81(br.s., 1H); 4.79(d, J ═ 3.7Hz, 1H); 3.95(s, 3H); 3.74(s, 3H); 3.20-3.27(m, 2H); 2.44(s, 3H); 1.76(br.s., 2H); 1.40(br.s., 2H). M/z (ESI, cation) 455.0(M + H) ⁺。

Example 177: 6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine

Step 1: 6-chloro-N- (4-methoxybenzyl) -2-methylpyrimidin-4-amine

At 25 ℃, 4, 6A mixture of dichloro-2-methylpyrimidine (Aldrich) (1.45g, 8.90mmol), 4-methoxybenzylamine (Alfa Aesar) (1.278mL, 9.78mmol) and triethylamine (1.488mL, 10.67mmol) in DMF (10.0mL) was stirred for 18 h. The resulting mixture was dissolved in EtOAc (300mL) and half-saturated NaHCO₃The aqueous solution (80mL) was partitioned. The organic layer was separated, washed successively with water (2X 80mL) and brine (80mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 120g, 0 to 100% EtOAc/hexanes) afforded 6-chloro-N- (4-methoxybenzyl) -2-methylpyrimidin-4-amine (2.30g, 8.72mmol, 98% yield) as an off-white solid.¹H NMR(400MHz，CDCl₃) δ 7.23(d, J ═ 8.41Hz, 2H); 6.89(d, J ═ 8.61Hz, 2H); 6.18(s, 1H); 4.42(br.s., 2H); 3.81(s, 3H); 2.50(s, 3H). M/z (ESI, cation) 264.1(M + H)⁺。

Step 2: 6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine

Sodium hydride (60 wt% in mineral oil) (0.340g, 8.51mmol) was added in one portion to a mixture of 6-chloro-N- (4-methoxybenzyl) -2-methylpyrimidin-4-amine (1.87g, 7.09mmol) and 1- (chloromethyl) -4-methoxybenzene (1.059mL, 7.80mmol) in DMF (50mL) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 5min, and then warmed to 25 ℃ and stirred for 2 h. Water (200mL) was then added and the precipitated solid was collected by vacuum filtration, washed with water (150mL) and dried under vacuum to give 6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (2.69g, 7.01mmol, 99% yield) as a white solid. ¹H NMR(400MHz，CDCl₃) δ 7.11(d, J ═ 7.24Hz, 4H); 6.86(d, J ═ 7.24Hz, 4H); 6.26(s, 1H); 4.65(br.s., 4H); 3.80(s, 6H); 2.53(s, 3H). M/z (ESI, cation) 384.1(M + H)⁺。

Example 178: 6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine

Step 1: 4- ((5- (6- (bis (4-methoxybenzyl) amino) -2-methylpyrimidin-4-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (214.0mg, 0.557mmol), 5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -2-fluoropyridin-3-ylboronic acid (example 34, step 3) (189mg, 0.557mmol), PdCl in a mixture of ethanol (3.0mL) and water (0.300mL) was dissolved in₂(AmPhos)₂(Aldrich, St.Louis, MO) (19.74mg, 0.028mmol) and potassium acetate (164mg, 1.672mmol) were sparged with argon and then heated in a 20mL microwave vial at 100 ℃ for 20 min. Subsequently, the reaction mixture was concentrated on silica gel and chromatographed (ISCO, 24g, 0 to 100% EtOAc/hexanes) to provide tert-butyl 4- ((5- (6- (bis (4-methoxybenzyl) amino) -2-methylpyrimidin-4-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (152.0mg, 0.236mmol, 42.4% yield) as a colorless oil. ¹H NMR(400MHz，CDCl₃)δ8.44(dd，J＝9.39，2.15Hz，1H)；8.14(s，1H)；7.17(d，J＝7.82Hz，4H)；6.86(d，J＝8.61Hz，5H)；4.74(br.s.，4H)；3.79(s，6H)；3.55(s，2H)；3.42(t，J＝4.69Hz，4H)；2.62(s，3H)；2.37-2.43(m，4H)；1.45(s，9H)。¹⁹F NMR(377MHz，CDCl₃) Delta-71.01 (d, J ═ 9.16Hz, 1F). M/z (ESI, cation) 643.2(M + H)⁺。

Step 2: 6- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine

2, 2, 2-trifluoroacetic acid (0.7mL, 9.09mmol) was added dropwise to tert-butyl 4- ((5- (6- (bis (4-methoxybenzyl) amino) -2-methylpyrimidin-4-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (64.3mg, 0.100mmol) dissolved in dichloromethane (1.0mL) at 25 ℃ and the resulting solution was stirred for 30min at 25 ℃. Subsequently, the reaction mixture was concentrated in vacuo, and the residue was taken up in DCM (3.0mL) and cooled to 0 ℃. Triethylamine (0.105 mL)0.750mmol) was added to the resulting solution followed immediately by methanesulfonyl chloride (0.015mL, 0.200 mmol). The resulting mixture was stirred at 0 ℃ for 20min, and then silica gel was concentrated and chromatographed (ISCO, 4g, 0 to 100% (10% MeOH-EtOAc)/hexanes) to provide 6- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (54.5mg, 0.088mmol, 88% yield) as a colorless oil.¹H NMR(400MHz，CDCl₃)δ8.45(d，J＝9.39Hz，1H)；8.14(s，1H)；7.17(d，J＝6.85Hz，4H)；6.86(d，J＝8.80Hz，5H)；4.74(br.s.，4H)；3.79(s，6H)；3.60(s，2H)；3.25(br.s.，4H)；2.78(s，3H)；2.62(s，3H)；2.58(br.s.，4H).¹⁹F NMR(377MHz，CDCl₃) Delta-70.62 (d, J ═ 8.01Hz, 1F). M/z (ESI, cation) 621.1(M + H) ⁺。

And step 3: n, N-bis (4-methoxybenzyl) -6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine

Lithium bis (trimethylsilyl) amide (Acros, Morris Plains, NJ; 1.0M solution/ethylbenzene in THF) (0.599mL, 0.599mmol) was added dropwise to a solution of 6- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (124.0mg, 0.200mmol) and 6-methoxypyridin-3-amine (0.037mL, 0.300mmol) in THF (3.0mL) at 0 deg.C and the resulting dark brown solution was stirred at 0 deg.C for 1 h. By addition of saturated NH₄The excess LiHMDS was quenched with aqueous Cl (5mL) and the resulting mixture was washed with EtOAc (50mL) and NH₄The mixture was partitioned between half-saturated aqueous Cl (15 mL). The organic layer was separated, washed with brine (10mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 12g, 0 to 10% MeOH/DCM) gave N, N-bis (4-methoxybenzyl) -6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine (137.7mg, 0.190mmol, 95% yield) as a brown solid. ¹H NMR(400MHz，CDCl₃)δ11.67(br.s.，1H)(ii) a 8.36(d, J ═ 2.54Hz, 1H); 8.06-8.11(m, 2H); 7.54(br.s., 1H); 7.18(d, J ═ 7.43Hz, 4H); 6.84-6.90(m, 4H); 6.75(d, J ═ 8.80Hz, 1H); 6.56(s, 1H); 4.77(b r.s., 4H); 3.93(s, 3H); 3.80(s, 6H); 3.42(br.s., 2H); 3.19(br.s., 4H); 2.76(s, 3H); 2.65(s, 3H); 2.50(br.s., 4H). M/z (ESI, cationic) 561.2 (M-piperazine sulfonamide)⁺。

And 4, step 4: 6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine

A solution of N, N-bis (4-methoxybenzyl) -6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine (137.7mg, 0.190mmol) and trifluoromethanesulfonic acid (50. mu.L, 0.563mmol) in TFA (2.5mL) was stirred at 80 ℃ for 2.5 h. Subsequently, the mixture was cooled to 25 ℃ and concentrated in vacuo. NaHCO is added₃The residue was carefully added as a saturated aqueous solution (25mL) (final pH about 8). The resulting suspension was sonicated for 2min, and the precipitated solid was collected by vacuum filtration, washed with water (30mL) and air dried. The residue was taken up in MeOH, concentrated on silica gel and chromatographed (ISCO, 12g, 0 to 10% MeOH/DCM) to give 6- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -2-methylpyrimidin-4-amine (55.6mg, 0.115mmol, 60.4% yield) as a yellow solid. ¹H NMR(400MHz，CDCl₃) δ 11.80(br.s., 1H); 8.37(d, J ═ 2.74Hz, 1H); 8.14(d, J ═ 1.96Hz, 1H); 8.10(dd, J ═ 8.90, 2.84Hz, 1H); 7.86(br.s., 1H); 6.76(d, J ═ 8.80Hz, 1H); 6.70(br.s., 1H); 4.95(br.s., 2H); 3.93(s, 3H); 3.43-3.56(m, 2H); 3.26(br.s., 4H); 2.78(s, 3H); 2.63(s, 3H); 2.58(br.s., 4H). M/z (ESI, cation) 485.1(M + H)⁺。

Example 179: (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol

Step 1: (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol

Sodium borohydride (103mg, 2.72mmol) was added to a suspension of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (example 144, step 1) (522.8mg, 0.905mmol) in a mixture of methanol (5.0mL) and DCM (5.0mL) at 0 ℃. The resulting solution was stirred at 0 ℃ for 5min and then allowed to warm to 25 ℃ and stirred for 45 min. Saturated aqueous ammonium chloride (10mL) and water (20mL) were then added and the resulting mixture was extracted with DCM (2X 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol as a yellow-orange solid (504.5mg, 0.870mmol, 96% yield). M/z (ESI, cation) 580.2(M + H) ⁺。

Step 2: (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol

A solution of (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol (100.7mg, 0.174mmol) and trifluoromethanesulfonic acid (0.07mL, 0.788mmol) in 2, 2, 2-trifluoroacetic acid (3.5mL) was stirred at 75 ℃ for 1 h. Subsequently, the mixture was cooled to 25 ℃ and concentrated in vacuo. NaOH (1.0N, aq; 2.0mL) was added followed by MeOH (1.0mL) (final pH > 10), and the resulting mixture was stirred at 25 ℃ for 5 min. MeOH was removed in vacuo, and the resulting mixture was filtered in vacuo. The collected solid was washed with water (20mL) and diethyl ether (6mL) in that order and then dried in vacuo. Chromatographic purification of this solid (ISCO, 4g, 0 to 10% MeOH/DCM) gave (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridine) as a yellow solid-3-ylamino) pyridin-3-yl) methanol (41.8mg, 0.123mmol, yield 70.9%).¹H NMR (400MHz, d4-MeOH) δ 8.94(d, J ═ 2.54Hz, 1H); 8.48(d, J ═ 2.35Hz, 1H), 8.25(d, J ═ 2.54Hz, 1H); 8.07(dd, J ═ 8.80, 2.74Hz, 1H); 6.85(d, J ═ 9.00Hz, 1H); 4.60(s, 2H); 3.94(s, 3H); 3.38(s, 2H); 2.52(s, 3H). M/z (ESI, cation) 340.1(M + H) ⁺。

Example 180: 3- (6-amino-2-methylpyrimidin-4-yl) -N- (1H-indazol-4-yl) quinoxalin-2-amine

Step 1: 4-chloro-2-methyl-6- (methylthio) pyrimidine

A mixture of 4, 6-dichloro-2-methylpyrimidine (11.5g, 70.6mmol, Aldrich) and sodium thiomethoxide (5.93g, 85mmol, Aldrich) in toluene (50mL) was stirred at 25 ℃ for 24 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine and over Na₂SO₄And (5) drying. The crude product was purified by recrystallization from hexane to give 4-chloro-2-methyl-6- (methylthio) pyrimidine as white crystals (5.5g, 31.5mmol, yield 44.6%).¹H NMR(400MHz，CDCl₃) δ 7.01(s, 1H); 2.64(s, 3H); 2.56(s, 3H). M/z (ESI, cation) 175(M + H)⁺。

Step 2: 4-iodo-2-methyl-6- (methylthio) pyrimidine

A mixture of 4-chloro-2-methyl-6- (methylthio) pyrimidine (5.3g, 30.3mmol) and hydroiodic acid (67% solution, 5.71mL, 76mmol, Alfea Aesar, Avocado, Lancaster) in DCM (20mL) was stirred for 20h at room temperature and filtered. The collected solid was washed with DCM and then suspended in saturated NaHCO₃Medium and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, over Na₂SO₄Dried and concentrated to give 4-iodo-2-methyl-6- (methylthio) pyrimidine (7) as a pale yellow solid. 3g, 27.4mmol, 90% yield).¹H NMR(400MHz，CDCl₃) δ 7.43(s, 1H); 2.62(s, 3H); 2.52(s, 3H). M/z (ESI, cation) 266(M + H)⁺。

And step 3: 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine

A solution of 4-iodo-2-methyl-6- (methylthio) pyrimidine (2.35g, 8.83mmol) in THF (20mL) was cooled to-78 deg.C and treated dropwise with isopropyl magnesium chloride (2N solution in THF, 2mL, 4.0mmol, Aldrich). After 10min, tributyltin chloride (2.4mL, 8.83mmol, Aldrich) was added. The mixture was stirred at-78 ℃ for 1h, then warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by flash column chromatography using alumina, eluting with a gradient of 0-10% EtOAc in hexanes, to give 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine as a colorless oil (2.5g, 5.82mmol, 65.9% yield). This material was used as is without further purification. M/z (ESI, cation) 430(M + H)⁺。

And 4, step 4: 2-chloro-3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxaline

2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine (1.6g, 3.73mmol), 2, 3-dichloroquinoxaline (1.484g, 7.45mmol, Aldrich), and tetrakis (triphenylphosphine) palladium (0.431g, 0.373mmol, Strem Chemicals) dissolved in toluene (5mL) were charged to a glass microwave reaction vessel. Argon was bubbled for 2 min. The reaction mixture was stirred and heated at 120 ℃ for 36 h. The mixture was cooled to room temperature and passed through Celite Filter (celite), wash with 10% methanol-DCM and concentrate the filtrate. The crude product was purified by chromatography, pre-packed on a silica gel column (40g) via Redi-Sep, eluting with a gradient of 0-100% DCM-hexane to give 2-chloro-3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxaline as a white solid (0.8g, 2.64mmol, 70.9% yield).¹H NMR(400MHz，d6-DMSO)δ 8.23(dd，J＝8.02，1.56Hz, 1H); 8.13-8.19(m, 1H); 7.96-8.05(m, 2H); 7.73(s, 1H); 2.67(s, 3H); 2.61(s, 3H). M/z (ESI, cation) 303(M + H)⁺。

And 5: n- (1H-indazol-4-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxalin-2-amine

1H-indazol-4-amine (220mg, 1.651mmol, Key Organics Limited/Bionet Research, United Kingdom), 1 drop concentrated HCl, 2-chloro-3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxaline (250mg, 0.826mmol) and ethanol (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 160 ℃ for 1 h. The mixture was cooled to room temperature and then passed through 2N NH in MeOH₃Neutralized, diluted with DCM and passed through Celite(celite) filtration. The filtrate was concentrated in vacuo. The crude product was purified by chromatography, pre-filled with silica gel column (40g) via Redi-Sep, with 0% to 10% 2M NH in DCM ₃Purification was performed with a gradient elution of MeOH to give N- (1H-indazol-4-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxalin-2-amine as an orange solid (150mg, 0.375mmol, 45.5% yield).¹H NMR (400MHz, d 6-DMSO). delta.13.23 (s, 1H); 12.59(s, 1H); 8.50(d, J ═ 7.63Hz, 1H); 8.42(s, 1H); 8.31(s, 1H); 8.03(d, J ═ 8.22Hz, 1H); 7.74-7.85(m, 2H); 7.59(t, J ═ 7.43Hz, 1H); 7.41(t, J ═ 7.92Hz, 1H); 7.27(d, J ═ 8.22Hz, 1H); 2.91(s, 3H); 2.68(s, 3H). M/z (ESI, cation) 400(M + H)⁺。

Step 6: n- (1H-indazol-4-yl) -3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) quinoxalin-2-amine

N- (1H-indazol-4-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) quinoxalin-2-amine (150mg, 0.375mmol) dissolved in DCM-DMF (5: 1, 6mL) was charged to a 50mL round bottom flask. mCPBA (130mg, 0.751mmol, Aldrich) was added at 0 deg.CIn this solution, the mixture was stirred at 0 ℃ for 2h, then warmed to room temperature and saturated NaHCO was used₃And (6) diluting. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The crude material was pre-filled with silica gel column (40g) by chromatography via Redi-Sep, with 2% to 10% 2M NH in DCM ₃Purification was performed with a gradient of MeOH to give N- (1H-indazol-4-yl) -3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) quinoxalin-2-amine as an orange solid (36mg, 0.087mmol, 23% yield). M/z (ESI, cation) 416(M + H)⁺。

And 7: 3- (6-amino-2-methylpyrimidin-4-yl) -N- (1H-indazol-4-yl) quinoxalin-2-amine

Will dissolve in IIN- (1H-indazol-4-yl) -3- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) quinoxalin-2-amine (36mg, 0.087mmol) in an alkane (2mL) was charged to a glass microwave reaction vessel and ammonia was bubbled for 5 minutes. The reaction mixture was stirred and heated at 100 ℃ for 4 h. More NH is added₃Bubbling in, and the mixture was heated for an additional 2 h. The mixture was cooled to room temperature and concentrated in vacuo. Preparative TLC purification (5% MeOH in DCM as developing reagent) gave 3- (6-amino-2-methylpyrimidin-4-yl) -N- (1H-indazol-4-yl) quinoxalin-2-amine as a yellow solid (10mg, 0.027mmol, 31.3% yield).¹H NMR (400MHz, d 6-DMSO). delta.13.22 (s, 2H); 8.52(d, J ═ 7.07Hz, 1H); 8.31(s, 1H); 7.95(d, J ═ 8.09Hz, 1H); 7.82(d, J ═ 9.10Hz, 1H); 7.72-7.80(m, 1H); 7.64(s, 1H); 7.55-7.62(m, 1H); 7.34-7.46(m, 2H); 7.26(d, J ═ 9.10Hz, 1H); 2.70(s, 3H). M/z (ESI, cation) 369(M + H) ⁺。

Example 181: n- (2-chloro-4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

Step 1: n- (2-chloro-4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

6- (2-Fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (100mg, 0.319mmol) and N- (4-amino-2-chlorophenyl) acetamide (64.8mg, 0.351mmol, Aldrich) in THF (5mL) were charged to a glass microwave reaction vessel and argon was bubbled for 2min and the tube was sealed. The reaction mixture was cooled to 0 ℃ and lithium bis (trimethylsilyl) amine (1N, 1mL, 0.957mmol in THF) was added dropwise. The red solution was stirred at 0 ℃ for 1h and then warmed to room temperature. The mixture was washed with saturated NaHCO₃Diluted and extracted with EtOAc (3 ×). The organic extracts were washed with saturated NaCl and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo. The crude material was pre-filled with silica gel column (25g) by chromatography over Redi-Sep with 2% to 5% 2M NH in DCM₃Purification with MeOH gradient elution to afford N- (2-chloro-4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide as a yellow solid (120mg, 0.251mmol, 79% yield). ¹H NMR (400MHz, d 6-DMSO). delta.12.84 (s, 1H); 9.74(dd, J ═ 7.92, 1.86Hz, 1H); 9.47(s, 1H); 8.89(s, 1H); 8.42(dd, J ═ 4.70, 1.76Hz, 1H); 8.30(d, J ═ 2.35Hz, 1H); 7.55-7.63(m, 1H); 7.45-7.54(m, 1H); 7.08(dd, J ═ 7.82, 4.69Hz, 1H); 5.85(dd, J ═ 10.95, 2.15Hz, 1H); 4.01-4.10(m, 1H); 3.72-3.85(m, 1H); 2.92(s, 3H); 2.24-2.39(m, 1H); 2.08(s, 3H); 1.96-2.05(m, 2H); 1.73-1.91(m, 1H); 1.56-1.70(m, 2H). M/z (ESI, cation) 478(M + H)⁺。

Step 2: n- (2-chloro-4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide

Reacting N- (2-chloro-4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) A mixture of acetamide (100mg, 0.209mmol) in DCM (3mL) was cooled to 0 deg.C, treated with trifluoroacetic acid (3mL, 40.4mmol), and the yellow solution was stirred at 0 deg.C for 1 h. The mixture was concentrated in vacuo and the residue was taken up in 2M NH in MeOH₃Treated and concentrated in vacuo. The crude product was purified by chromatography, pre-filled with silica gel column (40g) via Redi-Sep, with 2% to 10% 2M NH in DCM₃Purification with MeOH gradient elution afforded N- (2-chloro-4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide (70mg, 0.178mmol, 58.3% yield) as a yellow solid. ¹H NMR (400MHz, d 6-DMSO). delta.13.62 (s, 1H); 13.01(s, 1H); 9.80(s, 1H); 9.47(s, 1H); 8.38-8.43(m, 1H); 8.31(d, J ═ 1.57Hz, 1H); 7.54-7.60(m, 1H); 7.47-7.52(m, 1H); 7.07(dd, J ═ 7.82, 4.69Hz, 1H); 2.88(s, 3H); 2.07(s, 3H). M/z (ESI, cation) 394(M + H)⁺。

Example 182: n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide

Step 1: n- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide

6- (2-Fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (100mg, 0.319mmol) and N- (4-aminophenyl) cyclopropylamide (56.2mg, 0.319mmol, Enamine Ltd, Ukraine) in THF (5mL) were charged to a glass microwave reaction vessel, argon bubbled for 2min and the tube sealed. The reaction mixture was cooled to 0 ℃ and lithium bis (trimethylsilyl) amine (1N, 1mL, 1mmol in THF) was added dropwise. The red solution was stirred at 0 ℃ for 1h and then warmed to room temperature. The mixture was washed with saturated NH₄Quenched with Cl and extracted with EtOAc (3 ×). The organic extracts were washed with saturated NaCl and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo. Will be provided with The crude material was chromatographed through a silica gel column (25g) pre-filled with 2% to 5% 2M NH in DCM via Redi-Sep₃Purification with MeOH gradient elution afforded N- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide (90mg, 0.192mmol, 60% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.12.69 (s, 1H); 10.12(s, 1H); 9.73(dd, J ═ 7.92, 1.86Hz, 1H); 8.87(s, 1H); 8.35(dd, J ═ 4.70, 1.76Hz, 1H); 7.76(d, J ═ 9.00Hz, 2H); 7.57(d, J ═ 8.80Hz, 2H); 6.99(dd, J ═ 7.82, 4.69Hz, 1H); 5.84(dd, J ═ 10.95, 1.76Hz, 1H); 4.04(d, J ═ 12.63Hz, 1H); 3.71-3.81(m, 1H); 2.91(s, 3H); 2.27-2.38(m, 1H); 1.97-2.07(m, 2H); 1.73-1.85(m, 2H); 1.56-1.67(m, 2H); 0.72-0.82(m, 4H). M/z (ESI, cation) 470(M + H)⁺。

Step 2: n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide

A suspension of N- (4- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide (80mg, 0.170mmol) in DCM (3mL) was cooled to 0 ℃ and treated with trifluoroacetic acid (3mL, 40.4 mmol). The yellow solution was stirred at 0 ℃ for 1 h. The mixture was concentrated in vacuo and the residue was taken up in 2M NH in MeOH ₃Neutralized and then concentrated in vacuo. The crude product was purified by chromatography, pre-filled with silica gel column (40g) via Redi-Sep, with 2% to 10% 2M NH in DCM₃Purification by MeOH gradient elution to afford N- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) cyclopropylamide (20mg, 0.052mmol, 30.5% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.13.47-13.72 (m, 1H); 12.82(s, 1H); 10.10(s, 1H); 9.78(s, 1H); 8.59(s, 1H); 8.33(d, J ═ 3.20Hz, 1H); 7.75(d, J-76.46 Hz, 2H); 7.58(d, J ═ 8.53Hz, 2H); 6.94-7.03(m, 1H); 2.87(s, 3H); 1.72-1.82(m, 1H); 0.72-0.84(m, 4H). M/z (ESI, cation) 386(M + H)⁺。

Example 183: n- (5-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

Step 1: n- (5-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine

Argon was bubbled through a glass microwave reaction vessel containing 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (100mg, 0.319mmol) and 5-methoxypyridin-3-amine (47.5mg, 0.383mmol, Astatech, Inc, Bristol, PA) dissolved in THF (5mL) for 2 min. The reaction mixture was cooled to 0 ℃ and lithium bis (trimethylsilyl) amine (1N, 1mL, 0.957mmol in THF) was added dropwise. The red solution was stirred at 0 ℃ for 1h and then warmed to room temperature. The mixture was washed with saturated NH ₄Quenched with Cl and extracted with EtOAc (3 ×). The combined organic extracts were washed with saturated NaCl and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo. The crude product was purified by chromatography, pre-filled with silica gel column (25g) via Redi-Sep, with 2% to 5% 2M NH in DCM₃Purify by MeOH gradient elution to give N- (5-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine as an orange solid (60mg, 0.144mmol, 45.0% yield). M/z (ESI, cation) 418(M + H)⁺。

Step 2: n- (5-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

A suspension of N- (5-methoxypyridin-3-yl) -3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-2-amine (60mg, 0.144mmol) in DCM (3mL) was cooled to 0 deg.C, treated with trifluoroacetic acid (3mL, 40.4mmol), and the yellow solution was stirred at 0 deg.C for 1H. The mixture was concentrated in vacuo and the residue was taken up in 2M NH in MeOH₃Neutralized and then concentrated in vacuo. Subjecting the crude product to chromatography via Redi-SepPre-filled silica gel column (40g) with 2% to 10% 2M NH in DCM₃Purify by MeOH gradient elution to give N- (5-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine as a yellow solid (30mg, 0.090mmol, 62.6% yield). ¹H NMR (400MHz, d 6-DMSO). delta.13.66 (s, 1H); 13.09(s, 1H); 9.84(dd, J ═ 7.82, 1.56Hz, 1H); 8.63(s, 1H); 8.46(d, J ═ 1.76Hz, 1H); 8.41(dd, J ═ 4.69, 1.76Hz, 1H); 8.20(s, 1H); 7.95(d, J ═ 2.54Hz, 1H); 7.10(dd, J ═ 7.82, 4.69Hz, 1H); 3.87(s, 3H); 2.89(s, 3H). M/z (ESI, cation) 334(M + H)⁺。

Example 184: 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

5-chloro-2-fluoropyridin-3-ylboronic acid (1220mg, 6.96mmol) (Asymchem Laboratories, Inc.), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2300mg, 5.98mmol) and potassium acetate (1200mg, 12.23mmol) in di under argonA mixture of alkane (10mL) -water (2.0mL) was placed in a 100mL flask. Adding A-Phos-PdCl₂(150mg, 0.212mmol) and under nitrogen, the mixture was heated to 95 ℃. After 2h, more boric acid (600mg) was added and the mixture was heated for an additional 1 h. The mixture was cooled to room temperature. Adding saturated NH₄And (4) Cl. The mixture was partitioned between water (5mL) and EtOAc (30 mL). Subjecting the organic layer to Na ₂SO₄Dried and concentrated. The residue was purified on silica gel using 10-50% EtOAc in hexanes to give the desired product as a pale yellow solid (2.3 g). LCMS (ES, cation)Sub): c₂₅H₂₃ClFN₅O₂The calculated value of (a): 479.2, respectively; measured value: 480.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.53(dd，J＝8.02，2.74Hz，1H)；8.25(d，J＝1.37Hz，1H)；7.21(d，J＝8.41Hz，4H)； 6.86(t，J＝8.22Hz，4H)；4.81(d，J＝7.24Hz，4H)；3.80(2s，6H)；2.54(s，3H)。

LiHMDS (1M in THF, 1250. mu.L, 1.250mmol) was added to a solution of 5-amino-2-methoxypyridine (123mg, 0.990mmol) and 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (190mg, 0.396mmol) in THF (5mL) at room temperature under nitrogen. A dark orange mixture formed. After 2h, HCl (5N, 0.3mL) was added. The mixture was partitioned between EtOAc-water (10 mL each). The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed 3 times with water and with NaHCO₃(saturated) washing over MgSO₄Dried and concentrated. The residue silica (10-80% EtOAc in hexanes) was purified to give a yellow oil which, upon trituration with MeOH, gave a yellow solid (110 mg). LCMS (ES, cation): c₃₁H₃₀ClN₇O₃: 583.2 calculated value; measured value: 584.1(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ11.64(s，1H)；8.73(d，J＝2.74Hz，1H)；8.25(d，J＝2.54Hz，1H)；8.19(d，J＝2.74Hz，1H)；7.83(dd，J＝9.00，2.74Hz，1H)；7.19(dd，J＝16.43，8.61Hz，4H)；6.78-6.92(m，4H)；6.70(d，J＝8.80Hz，1H)；4.86(s，2H)；4.81(s，2H)；3.92(s，3H)；3.80(d，J＝9.19Hz，6H)；2.57(s，3H)。

And step 3: 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) at 80 deg.CA solution of yl) -6-methyl-1, 3, 5-triazin-2-amine (110mg, 0.188mmol) in TFA (10mL) was heated for 16 h. The orange mixture was concentrated to a slurry with saturated NaHCO₃Diluted (5mL) and filtered. The solid was washed with water, MeOH, and (3: 1) hexanes-EtOAc to give the product as a brown solid (65 mg). LCMS (ES, cation): c₁₅H₁₄ClN₇Calculated value of O: 343.1, respectively; measured value: 344.1(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.69(br.s.，1H)；8.72(br.s.，1H)；8.50(d，J＝3.33Hz，1H)；8.31(br.s.，1H)；8.09(br.s.，1H)；7.94(br.s.，1H)；7.80(br.s.，1H)；6.84(br.s.，2H)；3.85(br.s.，3H)；2.43(br.s.，3H)。

Example 185: 4- (5-fluoro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2-chloro-5-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

2-chloro-5-fluoropyridine-3-boronic acid (470mg, 2.68mmol) (Asymchem Laboratories, Inc.), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (780mg, 2.027mmol) and potassium acetate (460mg, 4.69mmol) in bisThe mixture of alkane (10mL) -water (2.0mL) was sparged with nitrogen for 10 min. Adding Pd (Ph)₃P)₄(2342mg, 2.027 mmol). The mixture was heated at 100 ℃ for 60 min. The mixture was cooled to room temperature and diluted with EtOAc (100mL) and water (30 mL). The organic phase was washed with water (2 × 20mL) and over MgSO ₄The pad is filtered. The organic residue was loaded onto a silica gel cartridge and eluted with 1: 3 EtOAc-hexane to afford a small amount of Ph₃P product admixed (380 mg). LCMS (ES, cation): c₂₅H₂₃ClFN₅O₂The calculated value of (a): 479.2, respectively; measured value: 480.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.33(d，J＝2.93Hz，1H)；7.94(dd，J＝8.02，2.93Hz，1H)；7.20(dd，J＝15.45，8.41Hz，4H)；6.86(dd，J＝12.13，8.61Hz，4H)；4.81(d，J＝2.15Hz，4H)；3.81(s，3H)；3.80(s，3H)；2.55(s，3H)。

Step 2: 4- (2-chloro-5-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2-chloro-5-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (570mg, 1.188mmol) in TFA (10mL) was treated with TfOH (0.2mL) and the mixture was heated to 80 ℃. After 24h, the mixture was cooled to room temperature. Water (10mL) was added. The mixture was filtered and the light blue solid was washed with water (3 × 5 mL). The aqueous phase was slowly neutralized with solid LiOH until pH about 8. The resulting slurry was filtered to give a white solid (85 mg). The filtrate was saturated with NaCl and the resulting slurry was filtered to give additional product (100 mg). LCMS (ES, cation): c₉H₇ClFN₅The calculated value of (a): 239.0 of the total weight of the steel; measured value: 240.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)8.60(d，J＝2.74Hz，1H)；8.04-8.14(m，1H)；7.74(br.s.，2H)；2.37(s，3H)。

And step 3: 4- (5-fluoro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2-chloro-5-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (100mg, 0.417mmol) and 5-fluoro-6-methoxypyridin-3-amine (120mg, 0.844mmol) in THF (2.0mL) was cooled in an ice bath under nitrogen. LiHMDS (1M, 2500. mu.L, 2.500mmol in THF) in THF was added dropwise. After 5min, the cooling bath was removed. After a total of 22min, HCl (5N, 0.5mL) was added. After 5min, EtOAc (10mL) and saturated NH were added ₄Cl (10 mL). The organic layer was washed with water (2X 5 mL). The combined aqueous layers were extracted with EtOAc (2X 5 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated. The residue obtained isThe material was suspended in MeOH (5mL) and filtered. The solid was washed with MeOH (2X 2mL), DCM (3X 3mL), and EtOAc (3X 3mL) to afford the first product as a brown solid. The combined washes were concentrated and purified with silica using 0-3% MeOH in DCM. The dark blue fraction contained the second crop of the desired product (m/z 346). The combined product batches were suspended in diethyl ether (4mL) and filtered to give the final product as a green solid (60 mg). LCMS (ES, cation): c₁₅H₁₃F₂N₇Calculated value of O: 345.1; measured value: 346.2(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.78(s，1H)；8.56(dd，J＝9.78，2.93Hz，1H)；8.38(br.s.，2H)；8.28(dd，J＝12.81，1.86Hz，1H)；7.97(br.s.，1H)；7.84(br.s.，1H)；3.93(s，3H)；2.44(s，3H)。¹⁹F NMR(377MHz，d6-DMSO)δ-140.84(s，1F)；-139.70(s，1F)。

Example 186: 4- (5-fluoro-2- (5-fluoropyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2-chloro-5-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (85mg, 0.355mmol) and 3-amino-5-fluoropyridine (118mg, 1.053mmol) in THF (3mL) was cooled in an ice bath under nitrogen. After 5min, a solution of LiHMDS (1M, 2500. mu.L, 2.500mmol in THF) was added. After 10min, the cooling bath was removed. After 2h, HCl (5N, 0.5mL) was added. EtOAc (10mL) and saturated NH were added ₄Cl (10 mL). The mixture was stirred vigorously for 15 min. The resulting emulsion was filtered through a glass frit. The collected solid was dissolved in warm DMSO and purified by preparative HPLC (30-75% MeCN/water/w 0.1% TFA, over 20 min). The collected product fractions were concentrated to dryness. Adding saturated NaHCO₃(10 mL). The mixture was neutralized with HCl (5N) and filtered. Dissolving the filtrate in CHCl₃iPrOH (5%) in (3X 5 mL). The combined organic layers were passed over Na₂SO₄Drying and concentrating to obtainA yellow solid, which was filtered as an ether suspension to give the product as a yellow powder (18 mg). LCMS (ES, cation): c₁₄H₁₁F₂N₇The calculated value of (a): 315.1, respectively; measured value: 316.1(M + H)⁺.¹H NMR(400MHz，d6-DMSO)δ12.18(s，1H)；8.82(s，1H)；8.62(dd，J＝9.78，3.13Hz，1H)；8.44-8.53(m，2H)；8.18(d，J＝2.54Hz，1H)；8.04(br.s.，1H)；7.90(br.s.，1H)；2.46(s，3H)。¹⁹F NMR(377MHz，d6-DMSO)δ-139.21(s，1F)；-127.41(s，1F)。

Example 187: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (380mg, 0.638mmol) in DCM (5mL) was treated with TFA (6.0mL, 78mmol) and then TfOH (0.050mL, 0.563 mmol). The solution was heated under a condenser at 80 ℃. After 2.5h, more TfOH (0.050mL, 0.563mmol) was added. After 24h, the mixture was concentrated. The residue was azeotroped once with toluene (10 mL). The mixture was suspended in 1: 1 DMSO-water (5mL each) and filtered. Subsequently, the resulting solid was suspended in saturated NaHCO ₃For several hours and filtered. The mother liquor is discarded. The resulting residue was dissolved in hot DMSO and filtered. The filtrate was diluted with MeOH (2x v/v) and allowed to settle. The resulting suspension was filtered. The resulting solid was re-dissolved in hot DMSO and diluted with MeOH. After 3 replicates, the solid was approximately 95% pure product (50 mg). LCMS (ES, cation): c₁₆H₁₄FN₇O₂The calculated value of (a): 355.1, respectively; measured value: 356.2(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.47(br.s.，1H)；9.92(s，1H)；9.17(br.s.，1H)；8.81(br.s.，1H)；8.42(br.s.，1H)；8.32(d，J＝13.11Hz，1H)；8.01(br.s.，1H)；7.85(d，J＝0.78Hz，1H)；3.96(s，3H)；2.46(br.s.，3H)。¹⁹F NMR(377MHz，d6-DMSO)δ-139.31(d，J＝11.44Hz，1F)。

Example 188: 4- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of tetrahydro-2H-pyran-4-amine (130mg, 1.285mmol), 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (345mg, 0.719mmol) and cesium carbonate (165mg, 0.506mmol) in THF (2.5mL) was heated under microwave irradiation (100 deg.C, 15 min; 120 deg.C, 2X 15 min). The mixture was partitioned between EtOAc (10mL) and water (5 mL). The organic layer was washed with water and saturated NH₄Cl washed with Na₂SO₄Dried and concentrated. The resulting solid was triturated with hot MeOH (10mL) to give a yellow solid (300 mg). LCMS (ES, cation): c ₃₀H₃₃ClN₆O₃The calculated value of (a): 560.2; measured value: 561.2(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ9.48(d，J＝7.24Hz，1H)；8.67(d，J＝2.54Hz，1H)；8.13(d，J＝2.54Hz，1H)；7.18(t，J＝9.10Hz，4H)；6.87(d，J＝8.61Hz，4H)；4.82(s，2H)；4.77(s，2H)；4.17-4.29(m，1H)；3.91(dt，J＝11.74，3.62Hz，2H)；3.81(s，3H)； 3.80(s，3H)；3.55(td，J＝11.25，1.96Hz，2H)；2.52(s，3H)；1.96(br.s.，2H)；1.33-1.48(m，2H)。

Step 2: 4- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2- (tetrahydro-2H-) -A solution of pyran-4-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (190mg, 0.339mmol) in TFA (5000. mu.L, 64.9mmol) and TfOH (100. mu.L, 1.126mmol) was heated for 3 h. The mixture was concentrated and then saturated NaHCO₃(10mL) was stirred for 30 min. The suspension was filtered and washed with water (2 × 5 mL). The resulting solid was washed briefly with DCM (5mL) and EtOAc (5mL) to give the product as a yellow solid (68 mg). LCMS (ES, cation): c₁₄H₁₇ClN₆Calculated value of O: 320.1 of the total weight of the mixture; measured value: 321.2(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ9.61(d，J＝7.24Hz，1H)；8.58(d，J＝2.15Hz，1H)；8.23(d，J＝2.15Hz，1H)；7.68(d，J＝17.41Hz，2H)；4.21(br.s.，1H)；3.88(d，J＝11.54Hz，2H)；3.47(t，J＝10.66Hz，2H)；2.38(s，3H)；1.92(d.，J＝11.932H)；1.64(q，J＝9.59Hz，2H)。

Example 189: 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4-chloro-N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine

2-Methoxyethylamine (Aldrich, 0.350g, 4.66mmol) was added to 2, 4-dichloro-6-methyl-1, 3, 5-triazine (0.80g, 4.88mmol) in bisAlkane (10 mL). Producing an addition. Husky's base (1.0mL, 5.73mmol) was added and the mixture was stirred for 5 min. The mixture was partitioned between DCM (15mL) and water. Passing the organic phase over Na ₂SO₄Dried and concentrated. The resulting yellow oil was purified by silica gel chromatography using EtOAc (20-80%) in hexanes to give the desired product as a yellow solid (300 mg). LCMS (ES, cation): c₇H₁₁ClN₄Calculated value of O: 202.1; measured value: 203.0(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ5.93(br.s.，1H)；3.60-3.70(m，2H)；3.49-3.58(m，2H)；3.38(s，3H)；2.42(d，3H)。

Step 2: 4- (5-chloro-2-fluoropyridin-3-yl) -N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine (300mg, 1.480mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (320mg, 1.825mmol), potassium acetate (298mg, 3.04mmol) and Am-phos PdCl at 100 ℃ under nitrogen₂(47mg, 0.066mmol) of bisThe mixture of alkanes (10mL) was heated. After 6h, the mixture was cooled to room temperature and partitioned between water (10mL) and EtOAc (20 mL). Subjecting the organic layer to Na₂SO₄Dried and concentrated. The oil was purified on silica using EtOAc (10-80%) in hexane to afford the desired product as a yellow solid (130 mg). LCMS (ES, cation): c₁₂H₁₃ClFN₅Calculated value of O: 297.1; measured value: 298.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.55(ddd，J＝16.24，7.92，2.64Hz，1H)；8.27(br.s.，1H)；5.91(br.s.，1H)；3.72(quin，J＝5.62Hz，2H)；3.59(t，J＝5.09Hz，2H)；3.40(2s，3H)；2.51(2s，3H)。

And step 3: 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, NJ, USA, 100mg, 0.704mmol) and 4- (5-chloro-2-fluoropyridin-3-yl) -N- (2-methoxyethyl) -6-methyl-1, 3, 5-triazin-2-amine (130mg, 0.437mmol) in THF (5mL) was cooled in an ice bath and LiHMDS (1.0M, 1500. mu.L, 1.500mmol) was added under nitrogen. After 5min, the cooling bath was removed. After 10min, the mixture was neutralized with HCl (5N, 0.3mL) and then in EtO Partition between Ac (20mL) and water (10 mL). The organic layer was washed with water (5 mL). The combined aqueous layers were extracted with EtOAc (2X 5 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated. The resulting solid was triturated with EtOAc (5mL) and filtered. The yellow solid was washed with diethyl ether (2X 3mL) to give the desired product as a yellow powder (115 mg). LCMS (ES, cation): c₁₈H₁₉ClFN₇O₂The calculated value of (a): 419.1, respectively; measured value: 420.2(M + H)⁺。¹H NMR (400MHz, d6-DMSO) rotamer mixtures delta 11.89, 11.67(s, 1H); 8.73(dd, J ═ 6.75, 2.64Hz, 1H); 8.14-8.58(m, 4H); 3.94(2s, 3H); 3.46-3.65(m, 4H); 3.23, 3.29(s, 3H); 2.46, 2.47(s, 3H).¹⁹F NMR(377MHz，d6-DMSO)δ-139.65(s)；139.26(s)。

Example 190: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea

Step 1: 5-Nitropyridin-2-ylcarbamic acid tert-butyl ester

A solution of 5-nitropyridin-2-amine (Aldrich) (3.05g, 21.9mmol), di-tert-butyl dicarbonate (Fluka) (5.76g, 26.4mmol) and N, N-dimethylpyridin-4-amine (Aldrich) (0.272g, 2.23mmol) in DCM (50mL) was stirred at room temperature for 1 h. EtOAc was added and the resulting precipitate was collected and washed with DCM. The filtrate was combined with the washings and concentrated, then EtOAc was added to the residue to induce more precipitate. The precipitates were combined to give tert-butyl 5-nitropyridin-2-ylcarbamate as a yellow solid (3.52g, 67% yield). ¹H NMR(300MHz，d6-DMSO)δ10.70(s，1H)；9.09(d，J＝2.19Hz，1H)；8.54(dd，J＝9.35，2.63Hz，1H)；8.02(d，J＝9.35Hz，1H)；1.50(s，9H)。

Step 2: 5-Aminopyridin-2-ylcarbamic acid tert-butyl ester

A mixture of tert-butyl 5-nitropyridin-2-ylcarbamate (3.76g, 15.7mmol) and Pd/C (Aldrich) (0.588g, 5.52mmol) in EtOH (100mL) was evacuated and refilled with hydrogen (6 times). The mixture was hydrogenated at room temperature under hydrogen balloon pressure for 2.5 h. The reaction mixture was passed through CeliteThe (celite) pad (eluent: EtOH) was filtered and concentrated to give tert-butyl 5-aminopyridin-2-ylcarbamate as a cream-colored solid (3.22g, 98% yield).¹H NMR (300MHz, d 6-DMSO). delta.9.06 (s, 1H); 7.62(d, J ═ 1.75Hz, 1H); 7.40(d, J ═ 8.62Hz, 1H); 6.94(dd, J ═ 8.70, 2.27Hz, 1H); 4.93(s, 2H); 1.44(s, 9H). M/z (ESI, cation) 210.2(M + H)⁺。

And step 3: 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-ylcarbamic acid tert-butyl ester

4- (2-Fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.150g, 0.337mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.0841g, 0.402mmol) were dissolved in THF (3 mL). The mixture was cooled to 0 ℃ and LiHMDS (Acros) (1.4mL, 1.4mmol) was added slowly. The dark red mixture was stirred at 0 ℃ for 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride (20mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25g, eluent: 0% -50% EtOAc in hexanes) to give tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-ylcarbamate (0.145g, 68% yield) as a yellow solid. ¹H NMR(300MHz，CDCl₃)δ11.83(s，1H)；8.76-8.87(m，1H)；8.39-8.48(m，1H)；8.25-8.34(m，1H)；7.91-8.03(m，1H)；7.76-7.87(m，1H)；7.10-7.24(m，5H)；6.86(t，J＝7.09Hz，4H)；6.70-6.81(m，1H)；4.83(br.s., 4H); 3.80(d, J ═ 5.70Hz, 6H); 2.58(s, 3H); 1.53(s, 9H). M/z (ESI, cation) 635.0(M + H)⁺。

And 4, step 4: n5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine

A solution of tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-ylcarbamate (0.145g, 0.228mmol) and TFA (Aldrich) (1.0mL, 13mmol) in DCM (3mL) was stirred at room temperature for 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40mL) and DCM (20 mL). Dissolving the aqueous phase in CHCl₃25% iPrOH + 1% NH in (1)%₄OH (2X 40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl)₃0% -10% iPrOH (w/10% NH)₄OH)) to afford N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine (0.116g, 95%) as an orange solid.¹H NMR(300MHz，CDCl₃) δ 11.51(s, 1H); 8.80(dd, J ═ 7.67, 1.53Hz, 1H); 8.18-8.33(m, 1H); 8.12(d, J ═ 1.75Hz, 1H); 7.78(dd, J ═ 8.70, 2.27Hz, 1H); 7.19(t, J ═ 8.84Hz, 4H); 6.85(t, J ═ 8.84Hz, 4H); 6.70(dd, J ═ 7.67, 4.75Hz, 1H); 6.50(d, J ═ 8.77Hz, 1H); 4.83(d, J ═ 6.58Hz, 4H); 4.26(br.s., 2H); 3.69-3.91(m, 6H); 2.56(s, 3H). M/z (ESI, cation) 535.1(M + H) ⁺。

And 5: 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea

A solution of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine (0.150g, 0.281mmol) and phenyl isocyanate (Fluka) (0.077mL, 0.70mmol) in THF (3mL) was stirred at room temperature for 5 h. The resulting solid was collected by filtration to obtain 1- (5- (3-)(4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea (0.0707 g). The filtrate and washings were concentrated and purified by silica gel chromatography (25g, eluent: 0% -30% EtOAc in hexane) to afford a second crop of product (0.0924 g). Total yield 0.1631g, 89%.¹H NMR(300MHz，CDCl₃) δ 11.83(s, 1H); 11.66(br.s., 1H); 8.80-8.89(m, 1H); 8.41(br.s., 1H); 8.27-8.36(m, 1H); 7.88-7.99(m, 1H); 7.62(d, J ═ 8.18Hz, 2H); 7.31-7.41(m, 3H); 7.15-7.24(m, 4H); 7.03-7.12(m, 1H); 6.75-6.93(m, 5H); 6.64-6.73(m, 1H); 4.85(br.s., 4H); 3.79(d, J ═ 10.96Hz, 6H); 2.61(s, 3H). M/z (ESI, cation) 654.0(M + H) ⁺。

Step 6: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea

A solution of 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea (0.0707g, 0.108mmol) and trifluoromethanesulfonic acid (TCI) (0.02mL, 0.225mmol) in 1mL TFA was stirred at room temperature for 3h, then heated to 50 deg.C and stirred for 3 h. Subsequently, the mixture was heated at 75 ℃ overnight. Saturated sodium bicarbonate was added slowly to quench the reaction and the resulting precipitate was collected by filtration. The crude product was passed through preparative HPLC using a Phenomenex, Gemni NX 5 micron 150X 30mm column (10% -90% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The resulting fractions were concentrated to dryness in vacuo. Saturated sodium bicarbonate was added to the residue and the resulting yellow precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-phenylurea (0.0210g, 47% yield) as a yellow solid.¹H NMR(400MHz，d6-DMSO)δ11.87(s，1H)；10.28(br.s.，1H)；9.30(s，1H)；8.71-8.84(m，2H)；8.34(dd，J＝4.60，1.86Hz，1H)；8.22(dd，J＝9.00，2.74Hz，1H)；7.87(br.s.，1H)；7.74(br.s.，1H)；7.47-7.58(m，3H)(ii) a 7.31(t, J ═ 7.92Hz, 2H); 7.01(t, J ═ 7.43Hz, 1H); 6.92(dd, J ═ 7.83, 4.69Hz, 1H); 2.44(s, 3H). M/z (ESI, cation) 414.0(M + H) ⁺。

Example 191: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea

Step 1: 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea

A solution of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine (example 190, step 4, 0.156g, 0.293mmol) and 3-fluorophenyl isocyanate (0.084mL, 0.73mmol) in THF (3mL) was stirred at room temperature for 5 h. The resulting precipitate was collected to give 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea (0.0707g) as a yellow solid. The filtrate and washings were concentrated and purified by silica gel chromatography (25g, eluent: 0% -30% EtOAc in hexane) to afford a second crop of product (0.1218 g). The total yield was 0.1925g (98%).¹H NMR(300MHz，CDCl₃) δ 11.77-11.96(m, 2H); 8.80-8.93(m, 1H); 8.43(br.s., 1H); 8.32(br.s., 1H); 7.93(br.s., 1H); 7.45-7.63(m, 2H); 7.27-7.35(m, 2H); 7.15-7.24(m, 4H); 6.66-6.95(m, 7H); 4.85(br.s., 4H); 3.79(d, J ═ 10.08Hz, 6H); 2.62(s, 3H). M/z (ESI, cation) 672.0(M + H) ⁺。

Step 2: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea

1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3,5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea (0.0824g, 0.123 mmol) and trifluoromethanesulfonic acid (TCI) (0.02mL, 0.225mmol) in TFA (1mL) were stirred for 3h, at 50 ℃ for 3h, then at 75 ℃ overnight. Saturated sodium bicarbonate was added slowly to quench the reaction and the resulting precipitate was collected by filtration. The crude product was passed through preparative HPLC using a Phenomenex, Gemni NX 5 micron 150X 30mm column (10% -90% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The resulting fractions were concentrated to dryness in vacuo. Saturated sodium bicarbonate was added to the residue and the resulting yellow precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3- (3-fluorophenyl) urea as a yellow solid (0.0305g, 58% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.89 (s, 1H); 10.49(br.s., 1H); 9.38(s, 1H); 8.71-8.83(m, 2H); 8.29-8.39(m, 1H); 8.23(dd, J ═ 9.00, 2.35Hz, 1H); 7.87(br.s., 1H); 7.74(br.s., 1H); 7.47-7.65(m, 2H); 7.34(q, J ═ 7.89Hz, 1H); 7.20(d, J ═ 8.02Hz, 1H); 6.92(dd, J ═ 7.63, 4.69Hz, 1H); 6.76-6.87(m, 1H); 2.44(s, 3H). M/z (ESI, cation) 432.0(M + H) ⁺。

Example 192: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea

Step 1: 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea

A stirred solution of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) pyridine-2, 5-diamine (example 190, step 4, 0.124g, 0.233mmol) in THF (2mL) was treated with 2-isocyanatopropane (Aldrich) (0.233 mmol)046mL, 0.465mmol) and the yellow solution is stirred at room temperature overnight. The mixture was concentrated and the crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl)₃0% -7.5% iPrOH (w/10% NH)₄OH)) to give 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea as a yellow solid (0.1044g, 72% yield).¹H NMR(300MHz，CDCl₃) δ 11.74(s, 1H); 8.98-9.14(m, 1H); 8.83(d, J ═ 7.75Hz, 1H); 8.35(d, J ═ 1.75Hz, 1H); 8.24-8.33(m, 1H); 7.84(dd, J ═ 8.77, 1.90Hz, 1H); 7.35(s, 1H); 7.20(t, J ═ 8.33Hz, 4H); 6.86(t, J ═ 7.38Hz, 4H); 6.77(dd, J ═ 7.75, 4.82Hz, 1H); 6.65(d, J ═ 8.77Hz, 1H); 4.84(d, J ═ 4.97Hz, 4H); 4.01-4.18(m, 1H); 3.80(d, J ═ 7.31Hz, 6H); 2.60(s, 3H); 1.28(d, J ═ 6.58Hz, 6H). M/z (ESI, cation) 620.0(M + H) ⁺。

Step 2: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea

A stirred solution of 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea (0.104g, 0.168mmol) in TFA (2mL) was treated with trifluoromethanesulfonic acid (TCI) (0.02mL, 0.2mmol) and the reaction mixture was stirred at 70 ℃ for 2h, followed by 80 ℃ for 2 h. TFA (2mL) and trifluoromethanesulfonic acid (0.05mL) were added. Heating was continued for an additional 2h at 75 ℃. The mixture was cooled to room temperature and some TFA was removed in vacuo. Slowly add saturated NaHCO₃Until no more bubbling was observed. Dissolving the aqueous phase in CHCl₃25% iPrOH + 1% NH in (1)%₄OH (3X 10mL) extraction. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl)₃0% -10% iPrOH (w/10% NH)₄OH)) to give 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2-yl) -3-isopropylurea (0.0312g, 49% yield) as a yellow powder.¹H NMR (300MHz, d 6-DMSO). delta.11.77 (s, 1H); 8.92(s, 1H); 8.77(d, J ═ 7.75Hz, 1H); 8.65(br.s., 1H); 8.31(br.s., 1H); 8.10(br.s., 1H); 7.85(br.s., 2H); 7.71(br.s., 1H); 7.38(d, J ═ 8.92Hz, 1H); 6.80-6.99(m, 1H); 3.77-3.91(m, 1H); 2.43(s, 3H); 1.15(d, J ═ 6.28Hz, 6H). M/z (ESI, cation) 380.1(M + H) ⁺。

Example 193: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide

Step 1: 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-ylcarbamic acid tert-butyl ester

A solution of 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-4-yl-1, 3, 5-triazin-2-amine (0.723g, 1.51mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (example 190, step 2, 0.317g, 1.52mmol) in THF (5mL) was treated dropwise with LiHMDS (4.52mL, 4.52mmol) at 0 deg.C. The dark red mixture was stirred for 30min at 0 ℃. Water (0.2mL) was added to quench the reaction. The reaction mixture was partitioned between saturated aqueous ammonium chloride (40mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50g, eluent: 0% -35% EtOAc in hexanes) to give tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-ylcarbamate as a yellow foam (0.697g, 69% yield). ¹H NMR(300MHz，CDCl₃)δ11.77(s，1H)；8.74(d，J＝2.34Hz，1H)；8.39(br.s.，1H)；8.22(s，1H)；7.79-7.94(m，2H)；7.28(br.s.，1H)；7.19(t，J＝9.28Hz，4H)；6.86(dd，J＝8.18，3.95Hz，4H)；4.83(d，J＝11.55Hz，4H)(ii) a 3.80(d, J ═ 4.97Hz, 6H); 2.58(s, 3H); 1.53(s, 9H). M/z (ESI, cation) 669.2(M + H)⁺。

Step 2: n5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-yl) pyridine-2, 5-diamine

A solution of tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-ylcarbamate (0.827g, 1.24mmol) and TFA (5.0mL, 64.9mmol) in DCM (10mL) was stirred at room temperature for 1.5 h. Toluene (3mL) was added and the mixture was concentrated in vacuo. A saturated aqueous solution of sodium bicarbonate (50mL) was carefully added. Dissolving the aqueous phase in CHCl₃25% iPrOH + 1% NH in (1)%₄OH (2X 50mL) extraction. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-yl) pyridine-2, 5-diamine as a bright orange solid (0.664g, 94% yield).¹H NMR(300MHz，CDCl₃) δ 11.46(s, 1H); 8.72(d, J ═ 2.48Hz, 1H); 8.17(d, J ═ 2.34Hz, 1H); 8.06-8.13(m, 1H); 7.64-7.75(m, 1H); 7.18(dd, J ═ 12.57, 8.48Hz, 4H); 6.86(t, J ═ 7.89Hz, 4H); 6.49(d, J ═ 8.77Hz, 1H); 4.83(d, J ═ 15.05Hz, 4H); 4.31(br.s., 2H); 3.80(d, J ═ 5.85Hz, 6H); 2.56(s, 3H). M/z (ESI, cation) 569.2(M + H) ⁺。

And step 3: n- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide

A solution of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-yl) pyridine-2, 5-diamine (0.0551g, 0.097mmol) and pyridine (0.05mL, 0.618mmol) in DMF (2mL) was treated dropwise with acetic anhydride (Aldrich) (10.0. mu.L, 0.107mmol) at 0 ℃. The orange solution was stirred at room temperature overnight. The mixture was concentrated in vacuo to reduce the solvent volume to about 1 mL. Water (2mL) and brine (20mL) were added and the aqueous phase was dissolved in CHCl₃25 in (1)％iPrOH+1％NH₄OH (2X 20mL) extraction. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide as a yellow powder (0.060g, 100% yield).¹H NMR(300MHz，CDCl₃) δ 11.88(s, 1H); 8.75(d, J ═ 2.19Hz, 1H); 8.47(s, 1H); 8.24(d, J ═ 2.34Hz, 1H); 8.06-8.16(m, 1H); 7.86-7.95(m, 1H); 7.83(br.s., 1H); 7.19(t, J ═ 8.48Hz, 4H); 6.87(d, J ═ 6.58Hz, 4H); 4.84(d, J ═ 10.96Hz, 4H); 3.80(d, J ═ 4.09Hz, 6H); 2.59(s, 3H); 2.20(s, 3H). M/z (ESI, cation) 611.2(M + H) ⁺。

And 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide

A solution of N- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide (0.060g, 0.098mmol) and trifluoromethanesulfonic acid (TCI) (40. mu.L, 0.450mmol) in TFA (2mL) was stirred at room temperature for 2.5 h. Subsequently, the mixture was stirred at 75 ℃ for 2 h. Most of the TFA was removed in vacuo and the residue was then taken up in a small amount of DCM. Solid NaHCO₃Add in portions until no more bubbling was observed. Water was added and the resulting solid was collected by filtration. The crude product was passed through preparative HPLC using a Phenomenex, Gemni 5 micron C18100X 30mm column (0% -10% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The fractions containing the product formed a precipitate which was collected by filtration and dried in a vacuum oven to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) acetamide as a yellow solid (0.0173g, 36% yield).¹H NMR (300MHz, d 6-DMSO). delta.11.87 (s, 1H); 10.43(s, 1H); 8.67-8.78(m, 2H); 8.37(br.s., 1H); 8.15-8.24(m, 1H); 7.93-8.07(m, 2H); 7.84(b r.s., 1H); 2.45(s, 3H); 2.09(s, 3H). M/z (ESI, cation) 371.0(M + H) ⁺。

Example 194: 5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-ylcarbamic acid methyl ester

N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-yl) pyridine-2, 5-diamine (example 194, step 2, 0.152g, 0.266mmol) and Et₃A solution of N (0.111mL, 0.799mmol) in DCM (3mL) was treated with methyl chloroformate (Aldrich) (0.025mL, 0.319mmol) and the mixture was stirred at room temperature for 2 days, during which time solvent was lost due to evaporation. The residue was taken up in a mixed solvent (1: 1 DCM/THF, 5mL) and Et was added₃N (0.5mL) and methyl chloroformate (0.1 mL). The mixture was stirred at room temperature for 2 h. The resulting solid was collected and transferred to an erlenmeyer flask using MeOH and DMSO. Water was added and the mixture was sonicated. The resulting orange solid was collected and this mixture was heated in the presence of triflic acid (TCI) (0.2mL) in TFA (2mL) for 30min at room temperature followed by heating at 60 ℃ overnight. Solid sodium carbonate was added until the bubbling subsided. Sodium bicarbonate was added slowly until no more bubbling was observed. The resulting solid was collected by filtration. The crude product was passed through preparative HPLC using a Phenomenex, Gemni 5 micron C18150X 30mm column (1% -90% CH) ₃CNw/0.1％TFA/H₂O w/0.1% TFA, within 15 min). The fractions containing the product were collected and freeze dried to give an orange fluffy solid, which was absorbed into water and the resulting yellow precipitate was collected, washed with water and dried to give methyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-ylcarbamate as a yellow solid (0.0074g, 7% yield).¹H NMR(400MHz，d6-DMSO)δ11.84(s，1H)；10.10(s，1H)；8.74(d，J＝2.74Hz，1H)；8.64(d，J＝2.54Hz，1H)；8.37(d，J＝2.74Hz，1H)；8.19(dd，J＝9.00，2.74Hz，1H)；7.98(br.s., 1H); 7.82-7.90(m, 1H); 7.80(d, J ═ 8.80Hz, 1H); 3.68(s, 3H); 2.45(s, 3H). M/z (ESI, cation) 386.9(M + H)⁺。

Example 195: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea

Step 1: 1- (2-methoxyethoxy) -4-nitrobenzene

A stirred solution of 4-nitrophenol (Fluka) (0.511g, 3.67mmol) in DMF (10mL) was treated with portionwise addition of 60% sodium hydride (Aldrich) (0.170g, 4.25mmol) at 0 ℃. The yellow mixture was stirred at this temperature for 10min, followed by dropwise addition of 2-bromomethyl ether (Aldrich) (0.380mL, 4.04mmol) at 0 ℃. The mixture was stirred at this temperature for 5min, warmed to room temperature and stirred for 3.5h, then stirred at 70 ℃ overnight. The reaction mixture was poured into ice-water (100 mL). The aqueous phase was extracted with EtOAc (2X 70 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 1- (2-methoxyethoxy) -4-nitrobenzene as an off-white solid (0.753g, 105% yield). ¹H NMR(400MHz，CDCl₃) δ 8.16-8.25(m, 2H); 6.95-7.03(m, 2H); 4.17-4.26(m, 2H); 3.73-3.84(m, 2H); 3.46(s, 3H). M/z (ESI, cation) 198.1(M + H)⁺。

Step 2: 4- (2-methoxyethoxy) aniline

A mixture of 1- (2-methoxyethoxy) -4-nitrobenzene (0.724g, 3.67mmol) and 10% Pd/C (Aldrich) (0.201g, 1.89mmol) in EtOH (10mL) was evacuated and refilled with hydrogen (4 times). The mixture was hydrogenated at room temperature under the capsule pressure for 1.5 h. Through Celite(diatomaceous earth)) Pad (eluent: EtOH) the reaction mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (25g, eluent: 0% -60% EtOAc in hexane) to give 4- (2-methoxyethoxy) aniline as a clear oil (0.548g, 89% yield).¹H NMR(400MHz，CDCl₃) δ 6.73-6.82(m, 2H); 6.58-6.68(m, 2H); 4.01-4.08(m, 2H); 3.67-3.76(m, 2H); 3.29-3.52(m, 5H). M/z (ESI, cation) 168.1(M + H)⁺。

And step 3: 4- (2-methoxyethoxy) phenylcarbamic acid 4-nitrophenyl ester

A solution of 4- (2-methoxyethoxy) aniline (0.397g, 2.37mmol) and pyridine (1mL, 12.4mmol) in DCM (3mL) was treated with 4-nitrophenyl chloroformate (Aldrich) (0.505g, 2.51mmol) added in portions (exotherm!). The pale yellow solution was stirred at room temperature for 5 h. The reaction mixture was partitioned between 0.5N HCl (20mL) and DCM (30 mL). The organic phase was washed with 0.5N HCl (30mL), saturated aqueous sodium bicarbonate (30mL), water (30mL), and saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50g, eluent: 10% -50% EtOAc in hexane) to give 4-nitrophenyl 4- (2-methoxyethoxy) phenylcarbamate (0.57g, 72% yield) as an off-white solid. ¹H NMR(400MHz，CDCl₃) δ 8.25-8.32(m, 2H); 7.32-7.43(m, 4H); 6.87-6.97(m, 3H); 4.09-4.15(m, 2H); 3.72-3.79(m, 2H); 3.46(s, 3H). M/z (ESI, cation) 333.0(M + H)⁺。

And 4, step 4: 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea

A mixture of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-yl) pyridine-2, 5-diamine (example 4, step 2, 0.158g, 0.277mmol) and 4-nitrophenyl 4- (2-methoxyethoxy) phenylcarbamate (0.118g, 0.354mmol) in DCM (3mL) was stirred at room temperature for 3 days.Et was added₃N (0.20mL) was added followed by 4-nitrophenyl 4- (2-methoxyethoxy) phenylcarbamate (0.142g, 0.428 mmol). The reaction mixture was stirred at room temperature for 2 h. The yellow solid was collected and washed with DCM to give 0.176g of crude 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea, which was used in the next step without further purification.

And 5: 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea

A solution of 1- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea (0.176g, 0.231mmol) and trifluoromethanesulfonic acid (0.020mL, 0.231mmol) in TFA (2mL) was stirred at room temperature for 30min, then warmed to 60 ℃ and stirred overnight. After cooling to room temperature, solid sodium carbonate was added in portions until the bubbling subsided. Will dissolve in CHCl₃25% iPrOH (+ 1% NH) in (C)₄OH) was added to the residue and the organic phase was washed with sodium bicarbonate. The material was not completely soluble in the organic layer, and therefore the organic layer containing the solids was directly dried in vacuo (no desiccant added). The crude product was passed through preparative HPLC using a Phenomenex, Gemni 5 micron C18150X 30mm column (1% -90% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 15 min). Fractions containing product were collected and concentrated in vacuo. Sodium bicarbonate was added and the resulting solid was collected to give 1- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) pyridin-2-yl) -3- (4- (2-methoxyethoxy) phenyl) urea as a yellow solid (0.0834g, 69% yield).¹H NMR(400MHz，d6-DMSO)δ11.82(br.s.，1H)；10.10(br.s.，1H)；9.30(br.s.，1H)；8.62-8.86(m，2H)；8.36(d，J＝2.54Hz，1H)；8.13(br.s.，1H)；7.96(br.s.，1H)；7.84(br.s.，1H)；7.51(br.s.，1H)；7.33-7.46(m，2H)；6.90(d，J＝8.41Hz，2H)；4.04(b r.s.，2H)；3.64(d，J＝3.72Hz，2H)；3.30(d，J ═ 5.87Hz, 3H); 2.44(d, J ═ 5.48Hz, 3H). M/z (ESI, cation) 521.9(M + H) ⁺。

Example 196: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide

Step 1: 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-ylcarbamic acid tert-butyl ester

LiHMDS (Aldrich) (2.44mL, 2.44mmol) was added dropwise to a stirred solution of 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.507g, 0.815mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204g, 0.976mmol) in THF (2mL) at 0 ℃. The dark red mixture was stirred at 0 ℃ for 2 h. At 0 deg.C, more LiHMDS (1.6mL, 1.6mmol) was added dropwise and stirring continued for an additional 30 min. By adding 0.3mL of saturated NH₄The reaction was quenched with Cl. The reaction mixture was partitioned between water (40mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2X 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (100g, eluent: dissolved in CHCl) ₃0% -10% iPrOH (w/10% NH)₄OH) to give tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-ylcarbamate (0.306g, 46% yield).¹H NMR(400MHz，CDCl₃)δ11.76(s，1H)；8.71(d，J＝2.54Hz，1H)；8.42(d，J＝2.35Hz，1H)；8.23(d，J＝2.35Hz，1H)；7.94(dd，J＝9.00，2.54Hz，1H)；7.83(d，J＝9.00Hz，1H)；7.15-7.25(m，5H)；6.86(dd，J＝11.15，8.61Hz，4H)；4.83(d，J＝10.17Hz，4H)；3.76-3.85(m，6H)；3.50(s，2H)；3.18(br.s.，4H)；2.71(s，3H)；2.59(s，3H)；2.55(t，J＝4.50Hz，4H)；1.53(s，9H)。

Step 2: n5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) pyridine-2, 5-diamine in two 20mL scintillation vials tert-butyl 5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-ylcarbamate (0.306g, 0.377mmol) was dissolved in DCM (5 mL total). TFA (2.5 mL total) was added and the solution was stirred at room temperature for 3 h. The reaction mixtures were combined and poured into 20mL of a saturated aqueous solution of sodium bicarbonate. Dissolving the aqueous phase in CHCl₃25% iPrOH + 1% NH in (1)%₄OH (2X 20mL) extraction. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl)₃0% -20% iPrOH (w/10% NH)₄OH)) to yield N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) pyridine-2, 5-diamine as a yellow solid (0.221g, 82% yield). ¹H NMR(400MHz，CDCl₃) δ 11.44(br.s., 1H); 8.69(br.s., 1H); 8.15-8.21(m, 1H); 8.12(br.s., 1H); 7.69-7.79(m, 1H); 7.21(d, J ═ 8.61Hz, 4H); 6.85(dd, J ═ 15.75, 8.51Hz, 4H); 6.49(d, J ═ 8.80Hz, 1H); 4.83(d, J ═ 15.85Hz, 4H); 4.27(br.s., 2H); 3.75-3.85(m, 6H); 3.48(br.s., 2H); 3.18(br.s., 4H); 2.68-2.76(m, 3H); 2.49-2.61(m, 7H). M/z (ESI, cation) 711.0(M + H)⁺。

And step 3: n- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide

Acetic anhydride (Aldrich) (0.13 mL) was added at 0 deg.C1.4mmol) was added slowly to a stirred solution of N5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) pyridine-2, 5-diamine (0.0864g, 0.122mmol) and pyridine (0.60mL, 7.4mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1.5 h. Water was added and the resulting solid was collected by filtration, washed with water and air-dried to give N- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide as a yellow solid (0.0857g, 94% yield). ¹H NMR(400MHz，CDCl₃) δ 11.86(s, 1H); 8.72(d, J ═ 2.15Hz, 1H); 8.51(d, J ═ 2.54Hz, 1H); 8.24(d, J ═ 2.35Hz, 1H); 8.09(s, 1H); 7.96(d, J ═ 2.15Hz, 1H); 7.91(s, 1H); 7.20(dd, J ═ 8.22, 6.26Hz, 4H); 6.86(t, J ═ 8.61Hz, 4H); 4.84(d, J ═ 8.80Hz, 4H); 3.80(d, J ═ 7.43Hz, 6H); 3.51(s, 2H); 3.18(br.s., 4H); 2.71(s, 3H); 2.60(s, 3H); 2.55(t, J ═ 4.21Hz, 4H); 2.20(s, 3H). M/z (ESI, cation) 753.0(M + H)⁺。

And 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide

N- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide (0.0806g, 0.107mmol) and trifluoromethanesulfonic acid (0.02mL, 0.2mmol) were dissolved in TFA (2 mL). The pale yellow solution was stirred at room temperature for 30 min. Subsequently, the mixture was stirred at 65 ℃ overnight. After cooling to room temperature, solid sodium carbonate was added followed by aqueous sodium bicarbonate. The resulting pale green solid was collected and the crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18100 × 30mm column (1% -90% CH) ₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The product-containing fractions were collected and concentrated to dryness in vacuo. The yellow residue was taken up in a saturated aqueous solution of sodium hydrogencarbonateAnd (4) carrying out ultrasonic treatment. The resulting yellow solid was collected and washed with water and dried in a vacuum oven overnight to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) pyridin-2-yl) acetamide (0.0361g, 66% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.90 (s, 1H); 10.35(s, 1H); 8.74(d, J ═ 2.54Hz, 1H); 8.71(d, J ═ 2.54Hz, 1H); 8.21-8.28(m, 2H); 8.02(d, J ═ 9.00Hz, 1H); 7.89(br.s., 1H); 7.74(br.s., 1H); 3.49(s, 2H); 3.10(d, J ═ 4.50Hz, 4H); 2.86(s, 3H); 2.44(s, 3H); 2.07(s, 3H). The 4 protons on piperazine are masked under the water peak and thus cannot be integrated. M/z (ESI, cation) 513.0(M + H)⁺。

Example 197: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2-fluoro-6-methylpyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

8mL of bis (Aldrich) (89mg, 0.126mmol) of 2-fluoro-6-methylpyridine-3-boronic acid (Asynchem Laboratories, Inc.) (430mg, 2.77mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (970mg, 2.52), potassium acetate (742mg, 7.56mmol), and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich) (89mg, 0.126mmol) were added at 110 deg.C A mixture of alkane and 2mL of water was heated by microwave for 30 min. It was diluted with EtOAc and washed with 1N NaOH. The organic layer was dried and concentrated. The residue was purified by chromatography, pre-packed with a silica gel column (12g) via Redi-Sep, eluting with a gradient of 25-50% EtOAc in hexane to give 4- (2-fluoro-6-methylpyridin-3-yl) -N, N-Bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (939mg, 2.043mmol, 81% yield).¹H NMR (400MHz, d 6-DMSO). delta.8.53 (1H, m); 7.37(1H, d, J ═ 6.5 Hz); 7.24(4H, dd, J ═ 8.6, 1.2 Hz); 6.89(4H, t, J ═ Hz); 4.75(4H, d, J ═ 6.5 Hz); 3.74(3H, s); 3.72(s, 3H); 2.51(3H, s); 2.45(3H, s). M/z (ESI, cation) 460(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6-methylpyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4-fluoro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (286mg, 0.776mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc.) (199mg, 1.397mmol) in THF (6.0mL) was purged with argon, cooled to 0 deg.C and treated slowly with LiHMDS (1.4mL of a 1M solution in THF, 1.4 mmol). The dark purple solution was stirred for 1h at 0 ℃ and then saturated NH ₄The Cl solution was quenched and extracted twice with EtOAc. The combined organic extracts were dried over MgSO₄Dried, filtered and concentrated. The residue was purified by chromatography, pre-filled with a silica gel column (12g) via a Redi-Sep, eluting with a gradient of 25-50% EtOAc in hexane, to give the title compound as a yellow crystalline solid (120mg, 26%).¹H NMR (400MHz, d 6-DMSO). delta.11.89 (1H, s); 8.68(1H, d, J ═ 7.8 Hz); 8.18(1H, d, J ═ 2.3 Hz); 8.13(1H, m); 7.23(4H, m); 6.89(4H, m); 6.81(1H, d, J ═ 2.3 Hz); 4.80(4H, d, J ═ 7.9 Hz); 3.93(3H, s); 3.74(3H, s); 3.70(3H, s); 2.56(3H, s); 2.43(3H, s). M/z (ESI, cation) 582(M + H)⁺。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (5-fluoropyridin-3-ylamino) -6-methylpyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (118mg, 0.214mmol) in 2mL TFA was treated with 2 drops of trifluoromethanesulfonic acid. At 80 ℃ the brown solution is brought into oilHeating in bath for 8 h. The solution was concentrated and the residue was stirred in 5mL EtOAc and 2mL 0.5N NaOH. The precipitated solid was collected by filtration, washed with 2X 2mL of water, followed by 2mL of EtOAc and 2X 2mL of DCM. The yellow crystalline solid was collected and dried in a vacuum oven at 40 ℃ for 18h to give 4- (2- (5-fluoropyridin-3-ylamino) -6-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (60mg, 0.193mmol, 90% yield). ¹H NMR (400MHz, d 6-DMSO). delta.12.33 (1H, s); 8.66(1H, s); 8.73(1H, d, J ═ 8.2 Hz); 8.60(1H, d, J ═ 12.9 Hz); 8.16(1H, s); 7.90(1H, br.); 7.75(1H, br.); 6.91(1H, d, J ═ 8.0 Hz); 2.48(3H, s); 2.44(3H, s). M/z (ESI, cation) 312(M + H)⁺。

Example 198: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- ((5-bromo-6-fluoropyridin-2-yl) methyl) morpholine

A solution of 3-bromo-2-fluoro-6-methylpyridine (1.44g, 7.58mmol) (Waterstone Technology) in carbon tetrachloride (15mL) was treated with N-bromosuccinimide (1.42g, 7.96mmol) and dibenzoyl peroxide (184mg, 0.758mmol) and heated in an oil bath for 2h at 80 deg.C, at which time LCMS detected a mixture of starting material, monobrominated product and dibrominated product. The reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate was concentrated and the resulting brown oil was purified on a Redi-Sep pre-packed silica gel column (40g) eluting with a gradient of 1-20% in hexane to give a thick oil containing a mixture of starting material, monobrominated product and dibrominated product. The residue was dissolved in 5mL of DMF at 0 deg.C, treated with morpholine (0.715mL, 8.21mmol) and potassium carbonate (1.1g, 7.70mmol), and stirred at 0 deg.C for 45 min. Ice water (10mL) was added and stirred at room temperature for 15 min. The off-white solid was filtered and washed with 2X 5m L of water and collected. The solid was dried in a vacuum oven at 40 ℃ for 48h to give 268mg of 4- ((5-bromo-6-fluoropyridin-2-yl) methyl) morpholine. The filtrate was transferred to a separatory funnel and extracted with 2X 50mL of EtOAc. The EtOAc solution was washed with brine, dried and concentrated. The residue was purified on a Redi-Sep pre-filled silica gel column (40g) eluting with a gradient of 50-75% EtOAc in hexane to give 432mg of 4- ((5-bromo-6-fluoropyridin-2-yl) methyl) morpholine.¹H NMR (400MHz, d 6-DMSO). delta.8.26 (1H, m); 7.36(1H, dd, J ═ 7.8, 1.4 Hz); 3.58(4H, t, J ═ 4.3 Hz); 3.52(2H, s); 2.41(4H, t, J ═ 4.3 Hz). M/z (ESI, cation) 275/277(M + H)⁺。

Step 2: 4- (2-fluoro-6- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

2mL of bis (4- ((5-bromo-6-fluoropyridin-2-yl) methyl) morpholine (277mg, 1.007mmol), 1' -bis (diphenylphosphino) ferrocene-dichloropalladium (49.3mg, 0.060mmol), bis (valeryl) diboron (307mg, 1.208mmol) and potassium acetate (198mg, 2.014mmol) were combined at 125 deg.CThe alkane mixture was heated by microwave for 20 min. Water (0.7mL), KOAc (100mg), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (504mg, 1.309mmol) and Am-Phos (35mg) were added and the mixture was microwaved at 102 ℃ for 35 min. It was diluted with 5mL EtOAc and washed with 1mL of 0.5N NaOH. The EtOAc layer was concentrated and purified on a Redi-Sep pre-filled silica gel column (12g) eluting with a gradient of 50-75% EtOAc in hexanes to give 4- (2-fluoro-6- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a brown amorphous solid (115mg, 21% yield). ¹H NMR (400MHz, d6-DMSO) δ 8.60(1H, dd, J ═ 9.8, 1.8 Hz); 7.55(1H, d, J ═ 7.4 Hz); 7.24(4H, d, J ═ 8.2 Hz); 6.89(4H, t, J ═ 8.1 Hz); 4.76(4H, d, J ═ 7.4 Hz); 3.74(3H, s); 3.72(3H, s); 3.60(6H, m); 2.44(7H, m). M/z (ESI, cation) 545(M + H)⁺。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner as described in example 197 (starting from step 2) using 4- (2-fluoro-6- (morpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine.¹H NMR (400MHz, d 6-DMSO). delta.12.00 (1H, s); 8.77(1H, d, J ═ 8.0 Hz); 8.52(1H, d, J ═ 11.2 Hz); 8.51(1H, s); 7.87(1H, s); 7.73(1H, s); 7.01(1H, d, J ═ 8.0 Hz); 3.94(3H, s); 3.63(4H, m); 3.59(2H, s); 2.48(4H, m); 2.42(3H, s). M/z (ESI, cation) 427(M + H)⁺。

Example 199: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- ((2, 2, 2-trifluoroethoxy) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 3-bromo-2-fluoro-6- ((2, 2, 2-trifluoroethoxy) methyl) pyridine

The title compound was prepared in a similar manner as described in example 198 (step 1) using 3-bromo-2-fluoro-6-methylpyridine (1.44g, 7.58mmol) (Waterstone Technology) and 2, 2, 2-trifluoroethanol.¹H NMR (400MHz, d6-DMSO) δ 8.34(1H, t, J ═ 8.5 Hz); 7.34(1H, d, J ═ 7.9 Hz); 4.69(2H, s); 4.22(2H, q, J ═ 9.5 Hz). M/z (ESI, cation) 288/290(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- ((2, 2, 2-trifluoroethoxy) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

3-bromo-2-fluoro-6- ((2, 2, 2-trifluoroethyl) was used in a similar manner to that described in example 198 (starting from step 2)Oxy) methyl) pyridine.¹H NMR (400MHz, d 6-DMSO). delta.12.00 (1H, s); 8.83(1H, d, J ═ 8.0 Hz); 8.47(1H, d, J ═ 2.1 Hz); 8.41(1H, dd, J ═ 12.8, 2.2 Hz); 7.89(1H, br.); 7.75(1H, br.); 6.97(1H, d, J ═ 8.0 Hz); 4.74(2H, s); 4.24(2H, q, J ═ 9.4 Hz); 3.93(3H, s); 2.43(3H, s). M/z (ESI, cation) 440(M + H)⁺。

Example 200: 4- (2- (5-Fluoropyridin-3-ylamino) -6-methylpyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in a similar manner to that described in example 197, starting from 2-fluoro-6-methylpyridine-3-boronic acid (Asynchem Laboratories, Inc.) and 3-amino-5-fluoropyridine (Matrix Scientific). ¹H NMR (400MHz, d 6-DMSO). delta.12.33 (1H, s); 8.66(1H, s); 8.73(1H, d, J ═ 8.2 Hz); 8.60(1H, d, J ═ 12.9 Hz); 8.16(1H, s); 7.90(1H, b r.); 7.75(1H, br.); 6.91(1H, d, J ═ 8.0 Hz); 2.48(3H, s); 2.44(3H, s). M/z (ESI, cation) 312(M + H)⁺。

Example 201: 4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- ((6-Fluoropyridin-3-Yl) methyl) Thiomorpholine

A solution of 5- (bromomethyl) -2-fluoropyridine (3.61g, 19.00mmol) in dry DMF (22mL) was treated with thiomorpholine (2.254g, 21.85mmol) (TCI America) and potassium carbonate (3.28g, 23.75mmol) dissolved in 3mL of DMF at 0 ℃. Slowly warm the suspension to room temperatureStir at room temperature for 2 h. The reaction was quenched with 30mL of ice water and stirred at room temperature for 30min, and the solid was collected by filtration and washed with water followed by ether to give 4- ((6-fluoropyridin-3-yl) methyl) thiomorpholine (3.33g, 15.69mmol, 83% yield) as an off-white crystalline solid.¹H NMR (400MHz, d 6-DMSO). delta.8.12 (s, 1H); 7.89(td, J ═ 8.20, 2.2Hz, 1H); 7.14(dd, J ═ 8.10, 2.80Hz, 1H); 3.53(s, 2H); 2.63-2.59 (br.8H). M/z (ESI, cation) 213(M + H) ⁺。

Step 2: 2-fluoro-5- (thiomorpholinomethyl) pyridin-3-ylboronic acid

A solution of diisopropylamine (0.767mL, 5.43mmol) in 2mL THF was treated with n-butyllithium (3.4mL of a 1.6M solution in hexanes, 5.43mmol) at-40 deg.C and stirred at this temperature for 30 min. The solution was cooled to-78 ℃ and treated dropwise with a solution of 4- ((6-fluoropyridin-3-yl) methyl) thiomorpholine (922mg, 4.34mmol) in THF (2+2mL) over 10min via cannula. The brown mixture was stirred at-78 ℃ for 90min and then treated dropwise via syringe with a solution of triisopropyl borate (1.49mL, 6.51mmol) in THF (1 mL). The mixture was stirred for 30min at-78 ℃. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture was quenched with 1.0N NaOH (5mL) and stirred for an additional 30 min. The mixture was transferred to a separatory funnel and extracted with 5mL of diethyl ether. The ether layer was discarded, and the aqueous layer was carefully acidified with 2.5N aqueous HCl until acidic (pH 4 to about 5), and the resulting cloudy mixture was diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (2X 15mL) and the combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated to give 2-fluoro-5- (thiomorpholinomethyl) pyridin-3-ylboronic acid as an off-white crystalline solid (790mg, 3.08mmol, 71.0% yield). ¹H NMR (400MHz, d4-MeOH) δ 8.11(1H, d, J ═ 2.5 Hz); 8.00(1H, dd, J ═ 8.0, 2.5 Hz); 3.75(2H, s.); 2.91(4H, m); 2.73(4H, br.s.). M/z (ESI, cation) 257(M + H)⁺。

And step 3: 4- (2-fluoro-5- (thiomorpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (312mg, 0.811mmol), 2-fluoro-5- (thiomorpholinomethyl) pyridin-3-ylboronic acid (249mg, 0.973mmol), Am-Phos (40mg, 0.057mmol) and potassium acetate (239mg, 2.432mmol) in EtOH (3.5mL) and water (1.5mL) was heated with a microwave at 100 ℃ for 30 min. The mixture was partitioned between EtOAc (20mL) and 1N NaOH (3 mL). The separated EtOAc layer was washed with brine, concentrated and purified on a Redi-Sep pre-filled silica gel column (40g) eluting with a gradient of 30-70% EtOAc in hexanes to give 4- (2-fluoro-5- (thiomorpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow viscous oil (306mg, 67.3% yield).¹H NMR (400MHz) δ 8.47(dd, J ═ 9.3, 1.9Hz, 1H); 8.28(s, 1H); 7.24(d, J ═ 8.4Hz, 4H); 6.90(t, J ═ 8.5Hz, 4H); 4.76(d, J ═ 4.9Hz, 4H); 3.74(s, 3H); 3.73(s, 3H); 3.60(s, 2H); 2.66-2.58(m, 8H); 2.47(s, 3H). M/z (ESI, cation) 561(M + H) ⁺。

And 4, step 4: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2-fluoro-5- (thiomorpholinomethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (390mg, 0.696mmol) and 6-methoxypyridin-3-amine (130mg, 1.043mmol) in 3mL THF at 0 deg.C was treated with LiHMDS (2.08mL of a 1.0M solution in THF, 2.08 mmol).

After stirring at 0 ℃ for 10min, the mixture is saturated with NH₄The Cl solution was quenched and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The brown residue was stirred with 30mL of EtOAc. The solid was collected by filtration and washed with 5mL of EtOAc. The yellow crystalline solid was dried in a vacuum oven at 45 ℃ for 18h to give the title compound (403mg, 87% yield).¹H NMR(400MHz, d 6-DMSO). delta.11.50 (s, 1H); 8.65(d, J ═ 2.3Hz, 1H); 8.30(d, J ═ 2.6Hz, 1H); 8.17(s, 1H); 7.88(dd, J ═ 8.3, 2.7Hz, 1H); 7.25(m, 4H); 6.91(m, 4H); 6.75(d, J ═ 8.8Hz, 1H); 4.85(s, 2H); 4.80(s, 2H); 3.82(s, 3H); 3.74(s, 3H); 3.70(s, 3H); 3.46(s, 2H); 3.31(br., 4H); 2.60(m, 4H); 2.56(s, 3H). M/z (ESI, cation) 665(M + H) ⁺。

And 5: 4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (86mg, 0.129mmol) in 2mL TFA was treated with 2 drops of trifluoromethanesulfonic acid. The brown solution was heated in an oil bath for 5h at 80 ℃. The volatiles were removed and the dark residue was basified with 1N NaOH and extracted twice with EtOAc followed by once with DCM. The combined organic extracts were concentrated and pre-packed on a silica gel column (12g) at Redi-Sep and purified by elution with a gradient of 2-6% MeOH in DCM to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (30mg, 55% yield) as an orange crystalline solid.¹H NMR (400MHz, d 6-DMSO). delta.11.75 (1H, s); 8.68(1H, d, J ═ 2.4 Hz); 8.54(1H, d, J ═ 2.7 Hz); 8.18(1H, d, J ═ 2.5 Hz); 8.16(1H, d J ═ 2.9 Hz); 7.87(1H, br.s); 7.73(1H, br.s); 6.82(1H, d, J ═ 9.0 Hz); 3.84(3H, s); 3.46(2H, s); 2.67-2.60(8H, m); 2.44(3H, s). M/z (ESI, cation) 425(M + H) ⁺。

Example 202: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1-sulphoxide morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1-sulphoxomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (thiomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (100mg, 0.150mmol) in 0.5mL DCM and 0.25mL TFA was treated dropwise with a PTFA solution (prepared by adding 0.3mL hydrogen peroxide (30% wt.) (17mg, 0.15mmol) to 0.47mL TFA) at 0 ℃. After stirring at 0-5 ℃ for 30min, the mixture was diluted with DCM and washed with 1N NaOH followed by brine. The DCM layer was dried and concentrated. The residue was purified on a pre-packed silica gel column (12g) on a Redi-Sep, eluting with a gradient of 2-10% MeOH in DCM to give the title compound as a brown amorphous solid (66mg, 64% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.50 (s, 1H); 8.67(d, J ═ 2.1Hz, 1H); 8.30(d, J ═ 2.7Hz, 1H); 8.21(d, J ═ 2.7Hz, 1H); 7.87(dd, J ═ 8.8, 2.8Hz, 1H); 7.25(m, 4H); 6.90(m, 4H); 6.75(d, J ═ 8.8Hz, 1H); 4.84(s, 2H); 4.80(s, 2H); 3.82(s, 3H); 3.74(s, 3H); 3.70(s, 3H); 3.53(s, 2H); 2.86(m, 4H); 2.60(m, 4H); 2.56(s, 3H). M/z (ESI, cation) 681(M + H) ⁺。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1-sulphoxide morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1-sulphoxomorpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (66mg, 0.097mmol) in 2mL TFA was treated with 2 drops of trifluoromethanesulfonic acid. The brown solution was heated in an oil bath for 5h at 80 ℃. The volatiles were removed under reduced pressure. The dark residue was treated with 1N NaOH and extracted with DCM (2X 10mL) followed by EtOAc (10 mL). The combined organic extracts were dried and concentrated. The residue was purified on a Redi-Sep pre-filled silica gel column (12g) eluting with a gradient of 2-10% MeOH in DCM to give the title compound as a yellow crystalline solidSubstance (20mg, yield 47%).¹HNMR (400MHz, d 6-DMSO). delta.11.76 (1H, s); 8.71(1H, d, J ═ 2.3 Hz); 8.54(1H, d, J ═ 2.5 Hz); 8.22(1H, d, J ═ 2.3 Hz); 8.18(1H, m); 7.88(1H, br.s); 7.73(1H, br.s); 6.82(1H, d, J ═ 8.8 Hz); 3.84(3H, s); 3.53(2H, s); 2.87(4H, m); 2.74(2H, m); 2.67(2H, m); 2.44(3H, s). M/z (ESI, cation) 441(M + H) ⁺。

Example 203: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -3-methyl-3H-imidazo [4, 5-b ] pyridin-6-amine

In a similar manner to that described in example 197 (starting from step 2), 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (388mg, 0.624mmol) and 3-methyl-3H-imidazo [4, 5-b) were used]Pyridin-6-amine (Adesis) was used as the starting material to prepare the title compound.¹H NMR (400MHz, d 6-DMSO). delta.12.00 (s, 1H); 8.73(d, J ═ 2.3Hz, 1H); 8.67(m, 2H); 8.36(s, 1H); 8.26(d, J ═ 2.5Hz, 1H); 7.93(br, 1H); 7.74(br, 1H); 3.84(s, 3H); 3.50(s, 2H); 3.11(m, 4H); 2.87(s, 3H); 2.48-2.49(m, 4H); 2.49(m, 3H). M/z (ESI, cation) 510(M + H)⁺。

Example 204: ((3S) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinyl) methanol

The procedure was analogous to that of example 97, except that instead of morpholine, (S) -3-hydroxymethylpyrrolidine (Aldrich) was used to synthesize the titleThe title compound.¹H NMR (400MHz, d 6-DMSO). delta.13.56 (br.s., 1H); 12.14(br.s., 1H); 9.25(br.s., 1H); 8.61(d, J ═ 0.59Hz, 1H); 8.49(br.s., 1H); 8.13(br.s., 1H); 7.79(br.s., 1H); 6.80(dd, J ═ 8.51, 1.08Hz, 1H); 4.75(br.s., 1H); 3.83(s, 3H); 3.41-3.53(m, 6H); 3.11(t, J ═ 7.82 Hz, 1H); 2.84(d, J ═ 0.59Hz, 3H); 2.08(br.s., 1H); 1.77(dt, J ═ 13.35, 6.72Hz, 1H). M/z (ESI, cation) 433.48(M + H) ⁺。

Example 205: (3S) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinol

The title compound was synthesized following a procedure similar to that of example 97, substituting morpholine with (R) - (+) -3-pyrrolidinol (Aldrich).¹H NMR (400MHz, d 6-DMSO). delta.13.56 (br.s., 1H); 12.11(br.s., 1H); 9.25(s, 1H); 8.61(s, 1H); 8.49(br.s., 1H); 8.15(d, J ═ 9.19Hz, 1H); 7.80(br.s., 1H); 6.80(d, J ═ 0.39Hz, 1H); 4.99(d, J ═ 0.39Hz, 1H); 4.46(br.s., 1H); 3.83(s, 3H); 3.30-3.54(m, 4H); 3.16(d, J ═ 9.98Hz, 1H); 2.84-2.85(br.s., 3H); 2.06-2.16(m, 1H). M/z (ESI, cation) 419.2(M + H)⁺。

Example 206: (3R) -1- (6- ((6-methoxy-3-pyridinyl) amino) -5- (2-methyl-9H-purin-6-yl) -3-pyridinyl) -3-pyrrolidinol

The title compound was synthesized according to a procedure similar to example 97, substituting morpholine by (S) -3-hydroxypyrrolidine (Aldrich).¹H NMR(400MHz，d6-DMSO)δ13.55(s，1H)；12.10(s，1H)；9.25(d, J ═ 2.74Hz, 1H); 8.61(s, 1H); 8.49(d, J ═ 1.17Hz, 1H); 8.15(dd, J ═ 8.51, 2.64Hz, 1H); 7.81(br.s., 1H); 6.79(d, J ═ 8.80Hz, 1H); 4.99(d, J ═ 4.11Hz, 1H); 4.45(d, J ═ 1.56Hz, 1H); 3.83(s, 3H); 3.50(dd, J ═ 9.88, 5.38Hz, 1H); 3.29-3.45(m, 2H); 3.17(d, J ═ 1.17Hz, 1H); 2.85(s, 3H); 2.09-2.16(m, 1H); 1.88-1.97(m, 1H). M/z (ESI, cation) 419.2(M + H) ⁺。

Example 207: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (2-methoxypyrimidin-5-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) piperazine-1-carboxylate (0.500g, 0.777mmol) and 2-methoxypyrimidin-5-amine (0.117g, 0.932mmol) (ACES PHARMA) in tetrahydrofuran (10mL, 123mmol) was stirred at 0 deg.C and treated dropwise with lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran; 2.330mL, 2.330mmol) via syringe. The solution was stirred at 0 ℃ for 1 h. The solution was quenched with water (10mL) and diluted with water (15mL) and EtOAc (100 mL). The organic layer was separated and passed over Na₂SO₄Dried, filtered and concentrated in vacuo to give tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (2-methoxypyrimidin-5-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate (0.420mg, 0.561mmol, 72% yield). M/z (ESI, cation) 749.4(M + H)⁺。

Example 208: n, N-bis (4-methoxybenzyl) -4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

TFA (4.00mL, 51.9mmol) was added slowly to a stirred solution of tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (2-methoxypyrimidin-5-ylamino) pyridin-3-yl) methyl) piperazine-1-carboxylate (413mg, 0.551mmol) in dichloromethane (5.00mL, 78mmol) cooled in an ice bath and the resulting mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo to remove as much TFA as possible. The viscous residue was taken up in dichloromethane (5.00mL) and triethylamine (0.384mL, 2.76mmol) and methanesulfonyl chloride (0.129mL, 1.654mmol) were added slowly thereto at 0 ℃. The mixture was stirred at 0 ℃ for 1h and concentrated. The crude product was partitioned between 1N NaOH (aq) and dichloromethane (20 mL each), and the separated aqueous layer was extracted with dichloromethane (2X 20 mL). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give the crude product, which was purified by flash column chromatography (ISCO Combiflash system, pure DCM to 3% MeOH w/NH in DCM)₃) Purification to give N, N-bis (4-methoxybenzyl) -4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (277mg, 0.381mmol, 69.1% yield) as a brown foam. M/z (ESI, cation) 727.2(M + H) ⁺。

Example 209: 4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (301mg, 0.414mmol) in trifluoroacetic acid(638. mu.L, 8.28mmol) of the mixture was treated with a few drops of trifluoromethanesulfonic acid and the mixture was heated at 80 ℃ overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% (2M NH in MeOH)₃) In DCM (5mL) and the crude product was adsorbed onto a silica gel packed column and chromatographed via a red-Sep pre-packed silica gel column (pure DCM → 3% MeOH in DCM). The isolated yellow solid was dissolved in DMSO and subjected to reverse phase preparative HPLC purification (in H)₂10% MeCN to 100% MeCN w/0.1% (v/v) TFA in O). The product fraction was taken up with saturated NaHCO₃Basified (aq), extracted with dichloromethane (3 × 20mL), and the combined organic layers were taken over Na₂SO₄Dried, filtered and concentrated to give 4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (65mg, 0.134mmol, 32.3% yield) as a bright yellow solid. ¹H NMR (400MHz, d 6-DMSO). delta.11.78 (s, 1H); 9.03(s, 2H); 8.73(d, J ═ 1.56Hz, 1H); 8.23(d, J ═ 1.76Hz, 1H); 7.91(br.s., 1H); 7.75(br.s., 1H); 3.91(s, 3H); 3.50(s, 2H); 3.11(br.s., 4H); 2.86(s, 3H); 2.46-2.49(m, 4H); 2.44(s, 3H). M/z (ESI, cation) 486.8(M + H)⁺。

Example 210: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethyl-1-piperazinesulfonamide

The title compound was synthesized following a procedure analogous to example 85, step 2, substituting dimethylsulfamoyl chloride (0.259mL, 2.408mmol) (Aldrich) for methanesulfonyl chloride. M/z (ESI, cation) 755.3(M + H)⁺。

Example 211: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methyl) -N, N-dimethyl-1-piperazinesulfonamide

A solution of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-sulfonamide (0.210g, 0.278mmol) in trifluoroacetic acid (5mL, 67.3mmol) and trifluoromethanesulfonic acid (0.2mL, 0.278mmol) was stirred at 80 ℃ for 2 h. The dark solution was cooled to room temperature and concentrated to a slurry. The slurry is treated with NaHCO ₃The aqueous solution was neutralized to pH 8. The precipitate was dissolved in DCM/MeOH and adsorbed onto a silica gel packed column, and the silica gel column (40g) was pre-filled via Redi-Sep with the solution in CH₂Cl₂5% to 10% 2M NH₃Chromatographic separation with MeOH gradient elution to give 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylpiperazine-1-sulfonamide (0.110g, 0.214mmol, 77% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.75 (s, 1H); 8.70(d, J ═ 2.15Hz, 1H); 8.55(d, J ═ 0.39Hz, 1H); 8.19(d, J ═ 2.54Hz, 2H); 8.17(dd, J ═ 8.90, 2.84Hz, 1H); 7.86(d, J ═ 0.98Hz, 1H); 7.71(d, J ═ 1.76Hz, 1H); 6.82(d, J ═ 8.80Hz, 1H); 3.84(s, 3H); 3.47(s, 2H); 3.31(s, 2H); 3.16(d, J ═ 4.89Hz, 3H); 2.75(s, 6H); 2.47(s, 2H); 2.44(s, 3H). M/z (ESI, cation) 515.2(M + H)⁺。

Example 212: (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- ((6-methoxy-3-pyridinyl) amino) -3-pyridinyl) methanol

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl acetate was stirred at 0 deg.C-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (1.0g, 1.731mmol) in dichloromethane (20mL, 306mmol) and methanol (20mL, 494mmol) and treated batchwise with sodium borohydride powder (Aldrich) (0.211g, 5.57 mmol). The resulting suspension was warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH ₄Treated with Cl (10mL), diluted with water (40mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with water (10mL) and extracted with dichloromethane (3X 50 mL). The combined organic extracts are passed over Na₂SO₄Dried, filtered and concentrated in vacuo to give (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol (0.850g, 1.466mmol, 85% yield). M/z (ESI, cation) 580.2(M + H)⁺。

Example 213: methanesulfonic acid (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl ester

A suspension of (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methanol (1.0g, 1.725mmol) in dichloromethane (25mL, 1.725mmol) was stirred at 0 deg.C and treated once with triethylamine (1.092mL, 7.85mmol) and methanesulfonyl chloride (0.497mL, 6.42 mmol). The resulting solution was stirred under nitrogen for 30 min. The reaction mixture was diluted with dichloromethane (10mL) and treated with water (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2X 50mL) and Na₂SO₄Dried, filtered and concentrated in vacuo to give methanesulfonic acid (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl ester (0.935g, 1.422mmol, 82% yield). M/z (ESI, cation) 658.2(M + H) ⁺。

Example 214: 1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidin-4-ol

A suspension of methanesulfonic acid (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl ester (0.510g, 0.775mmol), 4-hydroxypiperidine (0.254g, 2.51mmol) and triethylamine (0.491mL, 3.53mmol) in dichloromethane (25mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (20mL) and extracted with dichloromethane (3X 25 mL). The combined organic extracts are passed over Na₂SO₄Dried, filtered and concentrated. The crude product was adsorbed onto a silica gel packed column and pre-filled with silica gel column (40g) via Redi-Sep, dissolved in CH₂Cl₂5% to 20% 2M NH₃A gradient of MeOH to give 1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidin-4-ol (0.385g, 0.581mmol, 74.9% yield). M/z (ESI, cation) 663.3(M + H)⁺。

Example 215: 1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidin-4-ol

The title compound was synthesized from 1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) piperidin-4-ol (example 213) according to a similar procedure to example 209.¹H NMR(400MHz，d6-DMSO)δ11.75(s，1H)；8.68(d，J＝0.78Hz, 1H); 8.54(d, J ═ 2.74Hz, 1H); 8.18(d, J ═ 2.74Hz, 1H); 8.16(t, J ═ 2.35Hz, 1H); 7.87(d, J ═ 1.37Hz, 1H); 7.71(br.s., 1H); 6.80-6.83(d, J ═ 9.00Hz, 1H); 4.54(d, J ═ 4.11Hz, 1H); 3.84(s, 3H); 3.38(br.s., 3H); 2.67(dd, J ═ 4.60, 2.64Hz, 2H); 2.44(s, 3H); 1.99(m, 2H); 1.69(d, J ═ 3.33Hz, 2H); 1.38(d, J ═ 10.76Hz, 2H). M/z (ESI, cation) 423.2(M + H)⁺。

Example 216: (R) - (1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) pyrrolidin-3-yl) methanol

A mixture of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.310g, 0.537mmol) and (R) -pyrrolidin-3-yl-methanol (0.163mL, 1.610mmol) in dichloromethane (0.035mL, 0.537mmol) and methanol (0.022mL, 0.537mmol) was treated with sodium triacetoxyborohydride (0.341g, 1.610 mmol). The solution was stirred at room temperature overnight. The crude product was adsorbed onto a silica gel packed column and pre-filled with silica gel column (40g) via Redi-Sep, dissolved in CH ₂Cl₂5% to 10% 2M NH₃MeOH gradient elution to give (R) - (1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) pyrrolidin-3-yl) methanol (0.188g, 0.284mmol, 52.9% yield). M/z (ESI, cation) 663.2(M + H)⁺。

Example 217: (R) - (1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) pyrrolidin-3-yl) methanol

The title compound was synthesized from (R) - (1- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) pyrrolidin-3-yl) methanol (example 216) following a similar procedure to example 209.¹H NMR (400MHz, d 6-DMSO). delta.11.83 (s, 1H); 10.01-10.12(dd, J ═ 5.28, 2.35Hz, 1H); 8.91(dd, J ═ 5.28, 2.35Hz, 1H); 8.54(dd, J ═ 2.54, 0.39Hz, 1H); 8.42(dd, J ═ 3.72, 2.35Hz, 1H); 8.15(dd, J ═ 8.90, 2.84Hz, 1H); 7.93(d, J ═ 1.17Hz, 1H); 7.82(d, J ═ 0.78Hz, 1H); 6.85(d, J ═ 9.00Hz, 1H); 4.38(dd, J ═ 6.85, 0.39Hz, 2H); 3.85(s, 3H); 3.31-3.51(m, 4H); 3.07-3.29(m, 2H); 2.55-2.86(m, 1H); 2.44(s, 3H); 1.92-2.14(m, 1H); 1.61-1.82(m, 1H). M/z (ESI, cation) 423.2(M + H) ⁺。

Example 218: (S) -N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Will be provided withThe molecular sieves were added to a mixture of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.300g, 0.519mmol) and 3(S) -3-methylmorpholine (0.158mL, 1.558mmol) in toluene (50mL, 470mmol) and under N₂The mixture was stirred under reflux for 3 h. Passing the mixture through Celite(Celite) filtered and concentrated in vacuo to give a yellow colorAn oil. The oil was dissolved in methanol (50mL, 1234mmol) at 0 deg.C, and the stirred solution was treated with sodium cyanoborohydride (0.082mL, 1.558 mmol). Glacial acetic acid (0.500mL, 8.66mmol) was added slowly. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with 20% aqueous NaOH (5mL) and water (2mL), extracted with EtOAc and passed through K₂CO₃Dried and concentrated in vacuo. The crude product was adsorbed onto a silica gel packed column and chromatographed via a Redi-Sep pre-packed silica gel column (40g) eluting with a gradient of 20% to 50% EtOAc/hexanes to give (S) -N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.095g, 0.143mmol, 27.6% yield). M/z (ESI, cation) 663.3(M + H) ⁺。

Example 219: (S) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized from (S) -N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine following a procedure analogous to example 209.¹H NMR(400MHz，CDCl₃) δ 11.71(br.s., 1H); 8.85(br.s., 1H); 8.35(dd, J ═ 2.35, 0.39Hz, 1H); 8.21(d, J ═ 0.59Hz, 1H); 8.09(d, J ═ 8.80Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 5.70(br.s., 2H); 3.94(s, 3H); 3.64-3.84(m, 3H); 3.49(s, 2H); 2.62(s, 1H); 2.44(s, 3H); 1.24-1.26(m, 3H); 1.20-1.22(s, 3H). M/z (ESI, cation) 423.2(M + H)⁺。

Example 220: 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (228mg, 0.395mmol) and sodium triacetoxyborohydride (125mg, 0.592mmol) were added to a solution of azetidine hydrochloride (Aldrich, St. Louis, MO) (48.0mg, 0.513mmol) in methanol (2mL), DCM (2mL) and diisopropylethylamine (103. mu.L, 0.592 mmol). The reaction mixture was stirred at ambient temperature for 2 h. More sodium triacetoxyborohydride was added and the mixture allowed to stand at ambient temperature for 30 min. The reaction mixture was concentrated and diluted with 150mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), separated, diluted with a small amount of methanol to make a clear solution, dried over sodium sulfate, and concentrated to give 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (150mg, 61.4% yield). M/z (ESI, cation) 619.2(M + H) ⁺。

Step 2: 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (150mg, 0.242mmol) in TFA (2424. mu.L) was treated with trifluoromethanesulfonic acid (63.5. mu.L, 0.727mmol) and stirred at 80 ℃ for 1 h. The reaction mixture was concentrated and diluted with 100mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 75mL of sodium bicarbonate (saturated aqueous solution), separated, diluted with a small amount of methanol to make a clear solution, which was purified by filtrationDried over sodium sulfate and concentrated to give the crude product. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 8% 2M aqueous ammonia/DCM dissolved in MeOH to give 4- (5- (azetidin-1-ylmethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (11mg, 11.99% yield).¹H NMR(400MHz，CDCl₃) δ 11.75(s, 1H); 8.90(d, J ═ 2.35Hz, 1H); 8.37(d, J ═ 2.74Hz, 1H); 8.17(d, J ═ 2.35Hz, 1H); 8.08(dd, J ═ 8.90, 2.64Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 3.94(s, 3H); 3.76(s, 2H); 3.53(t, J ═ 7.34Hz, 4H); 2.53(s, 3H); 2.28(quin, J ═ 7.38Hz, 2H). M/z (ESI, cation) 379.1(M + H) ⁺。

Example 221: 4- (2- (6-methoxypyridin-3-ylamino) -5- (pyrrolidin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized following a procedure similar to example 220 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde and pyrrolidine (Aldrich, st. louis, MO).¹H NMR(400MHz，CDCl₃) δ 11.64(s, 1H); 8.71(d, J ═ 2.35Hz, 1H); 8.36(d, J ═ 2.54Hz, 1H); 8.20(d, J ═ 2.35Hz, 1H); 8.13(dd, J ═ 8.80, 2.74Hz, 1H); 6.76(d, J ═ 8.80Hz, 1H); 6.33(br.s., 2H); 3.94(s, 3H); 3.58(s, 2H); 2.57(br.s., 4H); 2.54(s, 3H); 1.80-1.90(M, 4H). M/z (ESI, cation) 392.9(M + H)⁺。

Example 222: 4- (2- (6-methoxypyridin-3-ylamino) -5- (piperidin-1-ylmethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized following a procedure similar to example 220 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (264mg, 0.457mmol) and piperidine (Aldrich, st. louis, MO) (67.7 μ L, 0.686 mmol).¹H NMR(400MHz，CDCl₃) δ 11.64(s, 1H); 8.72(d, J ═ 2.35Hz, 1H); 8.35(d, J ═ 2.54Hz, 1H); 8.21(d, J ═ 2.35Hz, 1H); 8.14(dd, J ═ 8.90, 2.84Hz, 1H); 6.77(d, J ═ 9.00Hz, 1H); 5.56(br.s., 2H); 3.94(s, 3H); 3.45(s, 2H); 2.56(s, 3H); 2.41(br.s., 3H); 1.60(dt, J ═ 10.95, 5.48Hz, 5H); 1.39-1.46(m, 2H). M/z (ESI, cation) 407.0(M + H) ⁺。

Example 223: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((3- (methylsulfonyl) azetidin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized in analogy to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.200g, 0.346mmol) and 3- (methylsulfonyl) azetidine (PharmaBlock, Carrboro, NC) (0.070g, 0.519 mmol).¹H NMR (400MHz, d 6-DMSO). delta.11.81 (s, 1H); 8.88(br.s., 1H); 8.54(d, J ═ 2.74Hz, 1H); 8.38(d, J ═ 1.76Hz, 1H); 8.13(dd, J ═ 8.90, 2.64Hz, 1H); 7.77-7.94(m, 2H); 6.85(d, J ═ 8.80Hz, 1H); 4.09-4.58(m, 7H); 3.85(s, 3H); 3.12(s, 3H); 2.44(s, 3H). M/z (ESI, cation) 456.8(M + H)⁺。

Example 224: 4- (2- (6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperidin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized in analogy to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.200g, 0.346mmol) and 4- (methylsulfonyl) piperidine (PharmaBlock, Carrboro, NC) (0.085g, 0.519 mmol). ¹H NMR(400MHz，CDCl₃) δ 11.67(s, 1H); 8.71(d, J ═ 2.15Hz, 1H); 8.36(d, J ═ 2.54Hz, 1H); 8.18(d, J ═ 2.35Hz, 1H); 8.11(dd, J ═ 9.00, 2.74Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 5.76(s, 2H); 3.94(s, 3H); 3.49(s, 2H); 3.10(d, J ═ 11.35Hz, 2H); 2.80-2.86(m, 4H); 2.55(s, 3H); 2.00-2.18(m, 4H); 1.84-2.00(m, 3H). M/z (ESI, cation) 484.9(M + H)⁺。

Example 225: 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methylamino) ethanol

The title compound was synthesized in analogy to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.200g, 0.346mmol) and ethanolamine (Aldrich, st. louis, MO) (0.031mL, 0.519 mmol).¹H NMR (400MHz, d6-DMSO) delta 11.79(s, 1H); 8.89(d, J ═ 2.35Hz, 1H); 8.55(d, J ═ 2.54Hz, 1H); 8.34(d, J ═ 2.35Hz, 1H); 8.13(dd, J ═ 8.90, 2.64Hz, 1H); 7.74-7.93(m, 1H); 6.84(d, J ═ 9.00Hz, 1H); 5.08(br.s., 1H); 4.08(s, 2H); 3.82-3.88(m, 3H); 3.63(q, J ═ 4.96Hz, 2H); 2.95(t, J ═ 5.09Hz, 2H); 2.44(s, 3H). M/z (ESI, cation) 383.1(M + H) ⁺。

Example 226: (R) -2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methylamino) propan-1-ol

The title compound was synthesized following a procedure similar to example 220 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.230g, 0.398mmol) and (R) -2-aminopropanol (Aldrich, st. louis, MO) (0.047mL, 0.597 mmol).¹H NMR (400MHz, d 6-DMSO). delta.11.82 (s, 1H); 8.93(d, J ═ 2.35Hz, 1H); 8.60-8.80(m, 2H); 8.56(d, J ═ 2.54Hz, 1H); 8.38(d, J ═ 2.54Hz, 1H); 8.13(dd, J ═ 8.90, 2.84Hz, 1H); 7.76-7.95(m, 2H); 6.85(d, J ═ 8.80Hz, 1H); 4.17(t, J ═ 5.67Hz, 2H); 3.85(s, 3H); 3.50-3.56(m, 2H); 3.22-3.32(m, 1H); 2.44(s, 3H); 1.26(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 397.1(M + H)⁺。

Example 227: 4- (5- ((2-methoxyethylamino) methyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized in analogy to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.24g, 0.415mmol) and 2-methoxyethylamine (Aldrich, St. Louis, MO) (0.054mL, 0.623 mmol). ¹H NMR(400MHz，CDCl₃)δ11.63(s，1H)；8.78(d，J＝2.54Hz，1H)；8.35(d，J＝2.54Hz，1H)；8.24(d，J＝2.54Hz，1H)；8.12(ddJ ═ 8.80, 2.74Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 5.63(s, 2H); 3.94(s, 3H); 3.78(s, 2H); 3.52-3.57(m, 2H); 3.36(s, 3H); 2.80-2.86(m, 2H); 2.55(s, 3H). M/z (ESI, cation) 397.0(M + H)⁺。

Example 228: (rac) -4- (2- (6-methoxypyridin-3-ylamino) -5- ((3- (methylsulfonyl) pyrrolidin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized in analogy to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.23g, 0.398mmol) and 3- (methylsulfonyl) pyrrolidine (PharmaBlock, Carrboro, NC) (0.089g, 0.597 mmol).¹H NMR(400MHz，CDCl₃) δ 11.63(s, 1H); 8.73(d, J ═ 2.35Hz, 1H); 8.36(d, J ═ 2.54Hz, 1H); 8.21(d, J ═ 2.15Hz, 1H); 8.10(dd, J ═ 8.80, 2.74Hz, 1H); 6.78(d, J ═ 8.80Hz, 1H); 5.55(br.s., 2H); 3.94(s, 3H); 3.56-3.68(m, 3H); 2.99-3.05(m, 1H); 2.88-2.95(m, 1H); 2.87(s, 3H); 2.76-2.84(m, 1H); 2.61-2.70(m, 1H); 2.56(s, 3H); 2.25-2.35(m, 2H). M/z (ESI, cation) 470.9(M + H)⁺。

Example 229: 1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) azetidin-3-ol

Following a procedure analogous to example 220, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (R0.22g, 0.381mmol) and 3-hydroxyazetidine hydrochloride (Oakwood Products, Inc., West Columbia, S.C.) (0.063g, 0.571 mmol).¹H NMR(400MHz，CDCl₃) δ 11.46(s, 1H); 8.53(br.s., 1H); 8.36(d, J ═ 2.54Hz, 1H); 8.14(d, J ═ 2.15Hz, 1H); 8.09(dd, J ═ 8.90, 2.64Hz, 1H); 6.77(d, J ═ 8.80Hz, 1H); 4.46-4.55(m, 1H); 3.94(s, 3H); 3.64(s, 2H); 3.59(t, J ═ 7.73Hz, 2H); 3.30-3.40(m, 2H); 2.56(s, 3H). M/z (ESI, cation) 395.0(M + H)⁺。

Example 230: 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -2, 5, 7-triazaspiro [3.4] octane-6, 8-dione

Step 1: 2-dibenzyl-2, 5, 7-triazaspiro [3.4] octane-6, 8-dione

Potassium cyanide (0.151g, 2.32mmol), ammonium carbonate (0.445g, 4.64mmol) and 1-dibenzylazetidin-3-one (WO2007109334) (0.500g, 2.11mmol) were dissolved in 10mL of 2: 1 EtOH/H₂Combined in O and heated in a sealed tube at 60 ℃ for 3 days. The reaction mixture was cooled and concentrated in vacuo to remove EtOH. Additional water was added and the solid was collected by filtration, washed with water and a very small volume of MeOH. This gave 441mg of a white solid. The material was suspended in 10mL MeOH and sonicated for 10 min. The solid was collected and washed with MeOH to give 2-dibenzyl-2, 5, 7-triazaspiro [3.4] as a white solid ]Octane-6, 8-dione (0.283g, 43.7% yield). M/z (ESI, cation) 308.1(M + H)⁺。

Step 2: 2, 5, 7-triazaspiro [3.4] octane-6, 8-dione acetate salt

A mixture of 2-dibenzyl-2, 5, 7-triazaspiro [3.4] octane-6, 8-dione (0.258g, 0.839mmol) and 10% palladium on carbon (0.179g, 0.168mmol) in 4mL MeOH was treated with acetic acid (0.0961mL, 1.68mmol) and the slurry was stirred under a balloon containing hydrogen overnight. The reaction was filtered, washed with MeOH and concentrated in vacuo to give an oil. Concentration from benzene gave a solid which was suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 2, 5, 7-triazaspiro [3.4] octane-6, 8-dione acetate as a white solid (0.117g, 69.3% yield).

And step 3: 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -2, 5, 7-triazaspiro [3.4] octane-6, 8-dione

Similar procedure as in example 220 was followed, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (109mg, 0.189mmol) and 2, 5, 7-triazaspiro [3.4] m]Octane-6, 8-dione acetate (56.9mg, 0.283 mmol). ¹H NMR (400MHz, d 6-DMSO). delta.11.75 (s, 1H); 10.71(br.s., 1H); 8.72(br.s., 1H); 8.60(s, 1H); 8.54(d, J ═ 2.54Hz, 1H); 8.20(br.s., 1H); 8.16(dd, J ═ 9.00, 2.74Hz, 1H); 7.90(br.s., 1H); 7.75(br.s., 1H); 6.82(d, J ═ 8.80Hz, 1H); 3.84(s, 3H); 2.44(s, 3H). M/z (ESI, cation) 463.1(M + H)⁺。

Example 231: 4- (5- ((3-Aminoazetidin-1-yl) methyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was synthesized according to a procedure similar to example 220 using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (0.56g, 0.969mmol) and tert-butyl azetidin-3-ylcarbamate (Astatech, Bristol, PA) (0.250g, 1.454 mmol).¹H NMR(400MHz，d4-MeOH)δ 8.85(d, 1H); 8.46(d, J ═ 2.54Hz, 1H); 8.18(d, J ═ 2.35Hz, 1H); 8.01(dd, J ═ 8.80, 2.74Hz, 1H); 6.81(d, J ═ 8.80Hz, 1H); 3.91(s, 3H); 3.83-3.88(m, 1H); 3.82(s, 2H); 3.75(t, J ═ 7.92Hz, 2H); 3.36-3.40(m, 2H); 2.47(s, 3H). M/z (ESI, cation) 394.0(M + H)⁺。

Example 232: n- (1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) azetidin-3-yl) methanesulfonamide

A solution of 4- (5- ((3-aminoazetidin-1-yl) methyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (106mg, 0.269mmol) and triethylamine (56.2. mu.L, 0.404mmol) in DCM (2.7mL) was treated with MsCl (20.85. mu.L, 0.269mmol) and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate and concentrated. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 6% 2M aqueous ammonia/DCM dissolved in MeOH to give N- (1- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) azetidin-3-yl) methanesulfonamide as a yellow solid (10mg, 7% yield). M/z (ESI, cation) 472.1(M + H)⁺。

Example 233: 4- (5- ((5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -yl) methyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Similar procedure as in example 220 was followed, using 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (178mg, 0.308mmol) and 5, 6, 7, 8-tetrahydro- [1, 2, 4-d ]Triazolo [1, 5-a]Pyrazine (GeneTech, Indianapolis, IN) (57.4mg, 0.462mmol) the title compound was synthesized.¹H NMR(400MHz，CDCl₃) δ 11.70(s, 1H); 8.78(d, J ═ 2.54Hz, 1H); 8.36(d, J ═ 2.74Hz, 1H); 8.25(d, J ═ 2.35Hz, 1H); 8.10(dd, J ═ 8.80, 2.74Hz, 1H); 7.87(s, 1H); 6.78(d, J ═ 8.61Hz, 1H); 5.59(s, 2H); 4.20(t, J ═ 5.38Hz, 2H); 3.94(s, 3H); 3.84(s, 2H); 3.73(s, 2H); 3.00(t, J ═ 5.48Hz, 2H); 2.56(s, 3H). M/z (ESI, cation) 445.9(M + H)⁺。

Example 234: 5- (1, 3-Dioxolan-2-yl) -2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-Dioxoborolan-2-yl) pyridine

Step 1: 5- (1, 3-Dioxolan-2-yl) -2-fluoropyridines

6-Fluoronicotinaldehyde (21.96g, 176mmol) was suspended in toluene (340mL) and ethylene glycol (10.4mL, 186mmol) and p-toluenesulfonic acid (Acros, 15% in acetic acid, 1.10mL) was added. The flask was fitted with a Dean-Stark head and reflux condenser, and placed in a pre-heated oil bath (120 ℃ C.) and the reaction stirred. After 45 minutes, the reaction was cooled to room temperature. The reaction was diluted with saturated sodium bicarbonate (50mL), water (150mL) and EtOAc (150 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over sodium sulfate, filtered, concentrated and purified on a silica gel filter (600 mL sintered filter with about 3 inches of silica; DCM to 100: 1 to 50: 1 DCM/MeOH to 40: 1 DCM/MeOH) to give 19.055g of 5- (1, 3-dioxolan-2-yl) -2-fluoropyridine. M/z (ESI, cation) 170(M + H) ⁺。

Step 2: 5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid

In a 1L round bottom flask, 5- (1, 3-dioxolan-2-yl) -2-fluoropyridine (18.803g, 111mmol) was dissolved in THF (300mL) and the flask was cooled in dry ice/acetone under nitrogen. Subsequently, lithium diisopropylamide (2.0M in heptane/tetrahydrofuran/ethylbenzene; Acros) (89mL, 178mmol) was added via syringe over 20 min. After 75min, triisopropyl borate (40.8mL, 178mmol) was added via syringe over 5min, and then the reaction was allowed to slowly warm to room temperature while stirring under nitrogen. After 4.5h, the reaction mixture was treated with 1N NaOH (300 mL). The layers were separated and the organic phase was discarded. The aqueous phase was treated with concentrated HCl and 5N aqueous HCl to reduce the pH to about 5. Subsequently, the aqueous phase was extracted with 10: 1 DCM/MeOH. The aqueous phase was treated with 5N HCl during extraction to maintain pH 5-6. Brine was also added to the aqueous phase to aid extraction. The extracts were combined, concentrated and dried under high vacuum to give 14.56g of product. M/z (ESI, cation) 214(M + H)⁺。

And step 3: 5- (1, 3-Dioxolan-2-yl) -2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-Dioxoborolan-2-yl) pyridine

5- (1, 3-Dioxolan-2-yl) -2-fluoropyridin-3-ylboronic acid (14.56g, 68.4mmol) was suspended in PhMe (300mL) and anhydrous magnesium sulfate (41.223g, 342mmol) and pinacol (8.27g, 70.0mmol) were added. The reaction was stirred at room temperature over the weekend under nitrogen. The suspension was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (2 × 200mL), and the organic phase was dried over sodium sulfate, filtered, concentrated and dried to give 19.19g of 5- (1, 3-dioxolan-2-yl) -2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine as a pale yellow powder.¹H NMR(CDCl₃，400MHz)δ8.39(d，J＝2.54Hz，1H)；8.28(dd，J＝8.02Hz，2.54Hz，1H)；5.84(s，1H)；4.17-4.04(m，4H)；1.37(s，12H)。

Example 235: 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide

Step 1: 2- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide

A solution of 4-bromo-N, N-dimethylbenzenesulfonamide (Aldrich; 152mg, 0.575mmol) in THF (1.0mL) was cooled to-78 deg.C and treated dropwise with N-butyllithium (1.60M solution in hexanes) (359. mu.L, 0.575 mmol). The resulting off-white solution was allowed to slowly warm to 0 ℃ over 30min to give a dark brown solution which was then added dropwise to a suspension of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (110.7mg, 0.192mmol) in THF (2.0mL) cooled to-78 ℃. The mixture was stirred for 2h, allowed to warm slowly to 0 ℃, and the resulting yellow suspension was quenched (water) and separated from NaHCO ₃The saturated aqueous solution was extracted into DCM. The extract was dried (MgSO)₄) Concentrated and purified by flash chromatography (0 to 10 to 20 to 30 to 40% EtOAc in DCM) to give recovered 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (54.6mg, 49%, eluted with 20% EtOAc/DCM) followed by 2- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, n-dimethylbenzenesulfonamide (30.0mg, 0.036mmol, 18.60% yield) (eluted with 30% EtOAc/DCM) was followed by 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide (38.3mg, 0.050mmol, 26.2% yield) (eluted with 40% EtOAc/DCM).

Step 2: 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide

A solution of 2- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide (30.0mg, 0.036mmol) in DCM (0.5mL) was treated with TFA (0.5mL) followed by triethylsilane (0.3 mL). The mixture was stirred at 72 ℃ for 16 h. An additional 1mL TFA was added, the mixture was placed in a sealed tube, and heated at 100 ℃ for 4h to give a darker orange solution. The mixture was concentrated with 2N NH ₃Neutralized with MeOH, concentrated and purified by preparative HPLC to give 2- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -4-bromo-N, N-dimethylbenzenesulfonamide (20mg, 0.033mmol, 93% yield) as a yellow solid. M/z (ESI, cation) 601/603(M + H)⁺。

Example 236: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide

Step 1: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide

A suspension of Mg chips (49Mg) in THF (0.5mL) was treated with 1, 2-dibromoethane (25. mu.L) and allowed to stand for 5 min. Bubbling was observed. The suspension was stirred and a solution of 4-bromo-N, N-dimethylbenzenesulfonamide (500mg, 1.893mmol) in THF (total volume 3.4mL) was added. The suspension was stirred for 1h, after which time most of the Mg had dissolved, giving an approximately 0.48M solution of (4- (N, N-dimethylsulfamoyl) phenyl) magnesium bromide in THF.

(4- (N, N-Dimethylsulfamoyl) phenyl) magnesium bromide (0.48M in THF) (2545. mu.L, 1.222mmol) was added to 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (176.4mg, 0.305mmol) to give a dark orange solution. The solution was stirred for 16h and then quenched with MeOH (1.0 mL). The product was extracted from water into DCM and dried (MgSO) ₄) And purified by flash chromatography (0 to 10% to 20% to 30% EtOAc/DCM) to give 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide (171.5mg, 0.225mmol, 73.6% yield) as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.11.51 (s, 1H); 8.74(s, 1H); 8.30(dd, J ═ 4.11, 2.54Hz, 2H); 7.85(d, J ═ 2.35Hz, 1H); 7.55-7.72(m, 4H); 7.26(d, J ═ 8.22Hz, 2H); 7.19(d, J ═ 8.41Hz, 2H); 6.90(d, J ═ 8.41Hz, 2H); 6.83(d, J ═ 8.61Hz, 2H); 6.74(d, J ═ 9.00Hz, 1H); 6.19(d, J ═ 3.91Hz, 1H); 5.86(d, J ═ 4.11Hz, 1H); 4.68-4.91(m, 4H); 3.82(s, 3H); 3.74(s, 3H); 3.70(s, 3H); 2.56(s, 6H); 2.54(s, 3H). M/z (ESI, cation) 763.1(M + H)⁺。

Step 2: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide

A solution of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide (38.3mg, 0.050mmol) in TFA (1.0mL) was heated in a sealed tube at 100 ℃ for 5 h. The dark solution was concentrated and purified by preparative HPLC to give 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide trifluoroacetate (25mg, 0.039mmol, 78% yield). The sample is extracted from The alkane was recrystallized and dried to give a yellow solid.¹H NMR(400MHz，d6-DMSO)δ11.79(s，1H)；10.37(br.s.，1H)；9.20(d，J＝2.35Hz，1H)；8.60(d，J＝2.54Hz，1H)；8.49(d，J＝2.54Hz，1H)；8.12(dd，J＝8.80，2.74Hz，1H)；7.85-8.00(m，3H)；7.78(br.s.，1H)；7.56(td，J＝7.58，1.27Hz，1H)；7.35-7.46(m，1H)；6.83(d，J＝8.80Hz，1H)；6.61(d，J＝9.39Hz，1H)；3.84(s，3H)；2.84(d，J＝4.50Hz，3H)；2.76(d，J＝4.69Hz，3H)；2.46(s，3H)。¹⁹F NMR (376MHz, d6-DMSO) delta-74.57 (br.s., 3F). M/z (ESI, cation) 523(M + H)⁺。

Example 237: 4- (amino- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylbenzenesulfonamide

Step 1: (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (4- (N, N-dimethylsulfamoyl) phenyl) methanesulfonic acid methyl ester

A solution of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (hydroxy) methyl) -N, N-dimethylbenzenesulfonamide (12.9mg, 0.017mmol) in DCM (0.2mL) was treated with pyridine (20. mu.L, 0.25mmol) followed by methanesulfonyl chloride (20. mu.L, 0.258 mmol). The mixture was allowed to stand overnight. Some crystals formed. The crystals were colorless and insoluble in DCM, but soluble in water. The mixture was diluted with DCM (10mL) and NaHCO₃Washed with saturated aqueous solution (5 mL). The DCM layer was dried and concentrated to give a yellow solid, which was soluble in DCM, but insoluble in EtOAc and slightly soluble in dioxane In an alkane. The crude product was used directly in the next step.

Step 2: 4- (amino- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylbenzenesulfonamide

A solution of methyl (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (4- (N, N-dimethylsulfamoyl) phenyl) methanesulfonate (14.22mg, 0.017mmol) in DCM (0.1mL) was dissolved in bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -methane sulfonate0.5M NH in alkane (2mL)₃And (6) processing. The mixture was allowed to stand overnight, after which time partial conversion to amine was observed by LCMS. Subsequently, the mixture was sealed and heated at 80 ℃ for 2h, after which time the starting material was consumed. The mixture was concentrated and used directly in the next step.

And step 3: 4- (amino- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylbenzenesulfonamide

A solution of 4- (amino (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylbenzenesulfonamide (12.88mg, 0.017mmol) in TFA (1mL) was heated in a sealed tube at 100 deg.C for 4h, after which time the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give 4- (amino (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N, N-dimethylbenzenesulfonamide trifluoroacetate (3.2 mg). M/z (ESI, cation) 522(M + H) ⁺。

Example 238: 3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) quinolin-2-amine

Step 1: 4- (2-chloroquinolin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-iodo-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.36g, 0.75mmol, example 115), 2-chloroquinolin-3-ylboronic acid (0.31g, 1.50mmol, Aldrich, St. Louis, MO), sodium carbonate (0.16g, 1.50mmol), tetrakis (triphenylphosphine) palladium (0) (43mg, 0.04mmol, Strem, Newburyport, MA), DME (4mL), and water (1mL) were charged to a 10mL reaction vial. The vial was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90 ℃ for 5h and then allowed to cool to room temperature. The organic phase was removed and the solvent was removed in vacuo. The crude material was adsorbed onto a silica gel packed column and pre-filled with silica gel column (12g) by chromatography via Redi-Sep to dissolve in CH₂Cl₂0% to 1% 2M NH₃MeOH gradient elution for purification. The title compound (90% pure) was obtained as a yellow solid and used without further purification. M/z (ESI, cation) 511.8(M + H)⁺。

Step 2: 3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) quinolin-2-amine

A mixture of 5-amino-2-methoxypyridine (0.08mL, 0.61mmol, Aldrich, St. Louis, MO) and 4- (2-chloroquinolin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (210mg, 0.410mmol) in THF (3mL) was cooled to 0 deg.C and LiHMDS (1M in THF, 1.23mL, 1.23mmol) was added. The reaction mixture was stirred at 0 ℃ for 1h with NH₄Saturated aqueous Cl (5mL) was diluted and extracted with EtOAc (20 mL). The organic extracts were washed with water and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo, and the residue was adsorbed onto a silica gel packed column. Column (12g) pre-filled with silica gel by chromatography via Redi-Sep, dissolved in CH₂Cl₂2% to 3% 2M NH₃Purification with a gradient of MeOH afforded the title compound (65% pure) as an orange solid, which was used without further purification. M/z (ESI, cation) 599.8(M + H)⁺。

And step 3: 3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) quinolin-2-amine

A solution of 3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) quinolin-2-amine (0.16g, 0.26mmol) in TFA (3mL) was treated with a few drops of triflic acid. The reaction mixture was stirred at 90 ℃ for 18h, allowed to cool to room temperature, and the solvent was removed in vacuo. Preparative HPLC on reversed phase using Phenomenex Gemini column, 10 micron, C18, 150X 30mm in CH₃0.1% TFA/H in CN₂O, gradient 10% to 90%, purified within 18min to give 3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) quinolin-2-amine as a yellow solid (31mg, 0.09mmol, 33% yield).¹H NMR (400MHz, d 6-DMSO). delta.11.99 (br.s., 1H); 9.33(s, 1H); 8.88(br.s., 1H); 8.42(d, J ═ 7.43Hz, 1H); 7.77-8.09(m, 3H); 7.67(br.s., 2H); 7.33(br.s., 1H); 6.87(d, J ═ 8.80Hz, 1H); 3.87(s, 3H); 2.49(s, 3H). M/z (ESI, cation) 359.9(M + H)⁺。

Example 239: 4- (2- (6-methoxypyridin-3-ylamino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2-aminophenyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

2- (4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.31g, 1.42mmol, Oakwood Products, West Columbia, SC), tetrakis (triphenylphosphine) palladium (0) (63mg, 0.06mmol, Newburyport, MA), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.42g, 1.10mmol), sodium carbonate (0.29g, 2.73mmol), DME (5mL) and water (1.5mL) were charged to a 20mL reaction vial. The vial was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90 ℃ for 2h and then allowed to cool to room temperature. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (20 mL). The organic extracts were washed with water and Na ₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was adsorbed onto silica gel and pre-filled with silica gel column (40g) by chromatography via Redi-Sep, dissolved in CH₂Cl₂To 1% MeOH to give the title compound as a light yellow oil. M/z (ESI, cation) 441.9(M + H)⁺。

Step 2: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4- (2-aminophenyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.54g, 1.22mmol), copper acetate (0.33g, 1.83mmol, Aldrich, St. Louis, MO), 6-methoxypyridin-3-ylboronic acid (0.56g, 3.67mmol, Boron Molecular, Research Triangle Park, NC) and diisopropylethylamine (0.85mL, 4.89mmol) in DCM (15mL) was stirred at room temperature for 16h via CeliteThe (celite) pad was filtered and the solvent was removed in vacuo. The crude material was adsorbed onto silica gel and pre-filled with silica gel column (40g) by chromatography via Redi-Sep, dissolved in CH₂Cl₂0% to 2% 2M NH₃Purification was performed by MeOH gradient elution to give the title compound as a dark yellow oil. M/z (ESI, cation) 548.8(M + H) ⁺。

And step 3: 4- (2- (6-methoxypyridin-3-ylamino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine (0.38g, 0.70mmol) in TFA (3mL) was treated with several drops of triflic acid and heated at 80 ℃ for 3 h. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18,150X 30mm, 0.1% TFA/H in MeCN₂Purify by gradient O to give 4- (2- (6-methoxypyridin-3-ylamino) phenyl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (47mg, 0.15mmol, 22% yield).¹H NMR (400MHz, d 6-DMSO). delta.10.92 (s, 1H); 8.44(dd, J ═ 8.12, 1.66Hz, 1H); 8.12(d, J ═ 2.74Hz, 1H); 7.68(dd, J ═ 8.80, 2.74Hz, 2H); 7.53(br.s., 1H); 7.28(ddd, J ═ 8.46, 6.99, 1.57Hz, 1H); 6.88(dd, J ═ 12.81, 8.51Hz, 2H); 6.69-6.82(m, 1H); 3.86(s, 3H); 2.38(s, 3H). M/z (ESI, cation) 309.0(M + H)⁺。

Example 240: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Step 1: n- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 128; 60.0mg, 0.097mmol) and benzo [ d ] via syringe at 0 deg.C]Thiazole-A mixture of 5-amine (29.0mg, 0.193mmol) (Maybridge, Trevillet, UK) in THF (1.0mL) was treated dropwise with LiHMDS (1.0M in THF, Aldrich, St. Louis, MO) (483 μ L, 0.483 mmol). The reaction was stirred for 15min at 0 ℃ followed by NH₄Quenched with saturated aqueous Cl (3 mL). The aqueous layer was extracted with EtOAc (3X 20mL) and the combined organic layers were dried (MgSO₄) Filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH, to give N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d — (methyl) pyridin-2-yl) benzo [ d ] as an orange solid]Thiazol-5-amine (51.0mg, 0.068mmol, 70.3% yield). ¹H NMR(400MHz，CDCl₃) δ 9.16(1H, br.s.); 8.99(1H, s); 8.40-8.54(2H, m); 7.84(1H, d, J ═ 8.8 Hz); 7.58(1H, d, J ═ 8.6 Hz); 7.12-7.25(4H, m); 6.77-6.92(4H, m); 4.93(2H, s); 4.89(2H, s); 4.15(2H, s); 3.79(12H, d, J ═ 18.0 Hz); 3.35-3.51(2H, m); 2.87-2.97(2H, m); 2.85(3H, s); 2.69(3H, s). M/z (ESI, cation) 752(M + H)⁺。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Dissolving N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] in trifluoroacetic acid (Aldrich, St. Louis, Mo) (1.50mL, 20.19mmol)]Thiazol-5-amine (45.0mg, 0.060mmol) was charged to a microwave vial (5 mL). The mixture was microwaved for 45min at 120 ℃ and the solvent was subsequently removed in vacuo. The residue was subjected to reverse phase preparative HPLC using a Phenomenex Gemini column, 5 micron, C18,150X 30mm (elution with 10% to 55% MeCN/water with 0.1% TFA in 30 minutes with a total flow rate of 45mL/min), after removal of the solvent and neutralization to give a solid Yellow solid N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d]Thiazol-5-amine (16.0mg, 0.031mmol, 52.3% yield).¹H NMR (400MHz, d 6-DMSO). delta.12.23 (1H, s); 9.35(1H, s); 8.90(1H, d, J ═ 1.8 Hz); 8.76(1H, d, J ═ 2.0 Hz); 8.34(1H, d, J ═ 2.0 Hz); 8.06(1H, d, J ═ 8.8 Hz); 7.91(1H, br.s.); 7.72-7.86(2H, m); 3.53(2H, s); 3.12(4H, d, J ═ 4.1 Hz); 2.87(3H, s); 2.48(7H, br.s.). M/z (ESI, cation) 512(M + H)⁺。

Example 241: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) benzo [ d ] thiazol-6-amine

In a similar manner to that described in example 240, benzo [ d ] was used in step 1]Thiazol-6-amine to prepare the title compound, and isolating it as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.12.30 (1H, s); 9.21(1H, s); 8.87(1H, d, J ═ 1.4 Hz); 8.76(1H, d, J ═ 2.0 Hz); 8.33(1H, d, J ═ 2.2 Hz); 8.01(1H, d, J ═ 8.8 Hz); 7.90(2H, dd, J ═ 9.3, 1.7 Hz); 7.79(1H, br.s.); 3.52(2H, s); 3.12(4H, br.s.); 2.87(3H, s); 2.48(7H, br.s.). M/z (ESI, cation) 512(M + H) ⁺。

Example 242: 4- (2- (5-Fluoropyridin-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a similar manner to that described in example 240, 3-amino-5-fluoropyridine (SynChem,elk Grove Village, IL) to prepare the title compound, and isolate it as a yellow solid.¹H NMR (400MHz, d 6-DMSO). delta.12.33 (1H, s); 8.82(1H, s); 8.77(1H, s); 8.56(1H, d, J ═ 12.1 Hz); 8.35(1H, s); 8.17(1H, d, J ═ 2.0 Hz); 7.97(1H, br.s.); 7.81(1H, br.s.); 3.54(2H, s); 3.12(4H, br.s.); 2.87(3H, s); 2.46(7H, br.s.). M/z (ESI, cation) 474(M + H)⁺。

Example 243: 4- (2- (1H-pyrazol-4-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 1- (4-methoxybenzyl) -4-nitro-1H-pyrazoles

A solution of 4-nitro-1H-pyrazole (500mg, 4.42 mmol; Bionet Research, Cornwall, UK) in DMF (5mL) was treated with potassium carbonate (400. mu.L, 6.63mmol) and 4-methoxybenzyl chloride (600. mu.L, 4.42 mmol). The reaction was stirred at room temperature for 2h, then diluted with DCM (200mL) and washed with water (4X 40 mL). The organic layer was then dried (MgSO) ₄) Filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification.

Step 2: 1- (4-methoxybenzyl) -1H-pyrazol-4-amine

1- (4-methoxybenzyl) -4-nitro-1H-pyrazole (1031mg, 4.42mmol) in a sealed tube (125mL) was combined with EtOH (25mL) and NH₄A saturated aqueous solution (15mL) of Cl was treated with iron (1234mg, 22.10mmol, Aldrich, St. Louis, Mo.). The mixture was stirred at 105 ℃ for 1h, then cooled to room temperature. The mixture was diluted with EtOAc (200mL) and passed through Celite(diatomaceous earth) pad filtration. The filtrate was separated and the organic layer was dried (MgSO₄) Filtered and concentrated in vacuo. The residue was filtered through a silica gel packed column (eluting with DCM: EtOAc: MeOH ═ 25: 1) to give 1- (4-methoxybenzyl) -1H-pyrazol-4-amine (560mg, 2.76mmol, 62.3% yield) as a brown solid. M/z (ESI, cation) 204(M + H)⁺。

And step 3: 4- (2- (1H-pyrazol-4-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 240 using 1- (4-methoxybenzyl) -1H-pyrazol-4-amine in step 1 and was isolated as yellow solid. ¹H NMR (400MHz, d6-DMSO) δ 12.46(1H, br.s.); 11.59(1H, s); 8.67(1H, d, J ═ 2.0 Hz); 8.24(1H, d, J ═ 2.2 Hz); 7.92-8.07(2H, m); 7.83(1H, br.s.); 7.69(1H, br.s.); 3.47(2H, s); 3.11(4H, br.s.); 2.86(3H, s); 2.46-2.48(4H, m); 2.43(3H, s). M/z (ESI, cation) 445(M + H)⁺。

Example 244: 4- (2- (1H-pyrazol-3-ylamino) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 240 using 1- (4-methoxybenzyl) -1H-pyrazol-3-amine in step 1 (prepared in analogy to the procedure described for example 243 using 3-nitro-1H-pyrazole in step 1 (Maybridge, Trevillett, UK)) and was isolated as a yellow solid.¹H NMR (400MHz, d6-DMSO) δ 12.21(1H, d, J ═ 1.0 Hz); 12.04(1H, s); 8.67(1H, s); 8.23(1H, s); 7.69(2H, br.s.); 7.62(1H, s); 6.76(1H, s); 3.47(2H, s); 3.10(4H, br.s.); 2.87(3H, s); 2.46-2.49(4H, m); 2.44(3H, s). M/z (ESI, cation) 445(M + H)⁺。

Example 245: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -6-fluoro-1H-indazol-4-amine

The title compound was prepared in analogy to the procedure described for example 240 using 6-fluoro-1- (4-methoxybenzyl) -1H-indazol-4-amine in step 1 (prepared in analogy to the procedure described for example 243 using 6-fluoro-4-nitro-1H-indazole (Aldrich, st.louis, MO) in step 1) and was isolated as a yellow solid.¹H NMR (400MHz, d6-DMSO) δ 13.19(1H, br.s.); 12.51(1H, s); 8.77(1H, s); 8.41(1H, s); 8.15-8.29(2H, m); 7.83(2H, br.s.); 6.90(1H, d, J ═ 8.8 Hz); 3.55(2H, s); 3.12(4H, br.s.); 2.87(3H, s); 2.59(4H, s). M/z (ESI, cation) 513(M + H)⁺。

Example 246: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 5-fluoro-6-methoxypyridin-3-amine (87mg, 0.613mmol) (Anichem) and 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 52; 182mg, 0.409mmol) in THF (3mL) was cooled to 0 ℃ in an ice bath and treated dropwise with 1M LiHMDS (1.226mL, 1.226 mmol). At this temperature, the solution was stirred for 1.5h and with NH ₄And (4) quenching by using a Cl saturated solution. The product was extracted with EtOAc (15mL) viaMgSO₄Dried, filtered and concentrated to give crude 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (269.7mg, 0.475mmol) as a bright yellow amorphous solid which was used in the next step without further purification. M/z (ESI, cation) 568.0(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.94(1H，s)；8.82(1H，dd，J＝7.8，2.0Hz)；8.29(1H，dd，J＝4.8，2.1Hz)；8.05(1H，dd，J＝12.3，2.2Hz)；7.97(1H，d，J＝2.3Hz)；7.20(4H，dd，J＝10.6，8.6Hz)；6.86(4H，t，J＝9.0Hz)；6.78(1H，dd，J＝7.8，4.7Hz)；4.84(2H，br.s.)；4.83(2H，br.s.)；4.01(3H，s)；3.81(3H，s)；3.79(3H，s)；2.58(3H，s)。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (232mg, 0.409mmol) was treated with TFA (8.0mL) (Aldrich) and heated with a reflux condenser at 75 ℃ for 17 h. TFA was removed in vacuo and the crude product was treated with 2M NH3 dissolved in MeOH to give a suspension which was filtered and washed with water to give the desired product in approximately 80% purity. Subsequently, it was resuspended in MeOH and filtered and washed with 1N NaOH (aq), MeOH and hexanes and dried to give an olive-colored amorphous solid. It was further purified on ISCO (12g column, 1-25% MeOH in DCM) to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (68.6mg, 0.210mmol, 51.3% yield) as a fibrous yellow amorphous solid. M/z (ESI, cation) 328.1(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)11.95(1H，s)；8.80(1H，dd，J＝7.8，2.0Hz)；8.42(1H，d，J＝2.3Hz)；8.33-8.40(2H，m)；7.91(1H，br.s.)；7.77(1H，br.s.)；6.94(1H，dd，J＝7.8，4.7Hz)；3.94(3H，s)；2.43(3H，s)。

Example 247: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (454mg, 2.59mmol) (Combi-Blocks Inc.), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (950mg, 2.468mmol), Amphos 2(87mg, 0.123mmol) and potassium acetate (744mg, 7.58mmol) (Aldrich) in EtOH (15mL) and water (1.5mL) was purged with argon and heated in a microwave reactor at 100 ℃ for 30 min. The reaction mixture was concentrated to remove EtOH and partitioned between water (20mL) and EtOAc (20 mL). The aqueous phase was further extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified on ISCO (40g column, eluent: 30-80% EtOAc in hexane) to give 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (913mg, 1.902mmol, 77% yield) as a pale yellow viscous solid. The material was used in the next step without further purification. M/z (ESI, cation) 480.1(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ8.53(1H，dd，J＝7.9，2.6 Hz)；8.25(1H，dd，J＝2.6，1.3Hz)；7.21(4H，d，J＝8.6Hz)；6.80-6.90(4H，m)；4.82(2H，s)；4.80(2H，s)；3.81(3H，s)；3.80(3H，s)；2.54(3H，s)。

6-methoxypyridin-3-amine (354mg, 2.85mmol) (Aldrich) and 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methylA solution of-1, 3, 5-triazin-2-amine (913mg, 1.902mmol) in THF (15mL) was cooled to 0 deg.C in an ice bath and treated dropwise with 1M LiHMDS (5.71mL, 5.71 mmol). After stirring at this temperature for 1h, the reaction mixture is taken up in NH at 0 ℃₄The Cl saturated solution was quenched and extracted with EtOAc (50mL) over MgSO₄Dried, filtered and concentrated. Purification on ISCO (40g column, 20-100% EtOAc in hexane) afforded 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (717.3mg, 1.228mmol, 64.6% yield) as a bright yellow crystalline solid. M/z (ESI, cation) 584.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.65(1H，s)；8.73(1H，d，J＝2.7Hz)；8.26(1H，d，J＝2.7Hz)；8.19(1H，d，J＝2.7Hz)；7.83(1H，dd，J＝8.8，2.7Hz)；7.19(4H，dd，J＝16.2，8.6Hz)；6.86(4H，dd，J＝10.4，8.8Hz)；6.70(1H，d，J＝8.8Hz)；4.86(2H，s)；4.81(2H，s)；3.93(3H，s)；3.81(3H，s)；3.79(3H，s)；2.57(3H，s)。

And step 3: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (41.5mg, 0.199mmol) (Aldrich), 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (97mg, 0.166mmol), Pd ₂dba₃A mixture of (6.08mg, 6.64. mu. mol) (Strem Chemicals) and 2- (dicyclohexylphosphino) -2 ', 4', 6 ', -triisopropyl-1, 1' -biphenyl (6.33mg, 0.013mmol) (Strem Chemicals) was purged with argon and treated with diAlkane (2mL) and 1M aqueous sodium carbonate (0.415mL, 0.415mmol) and microwaved at 140 ℃ for 30 min. The reaction mixture was treated with 1N NaOH and extracted with EtOAc (30mL), washed with brine and over MgSO₄Drying, filtering and concentratingTo give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (140mg, 0.222mmol), which was the next step without further purification. M/z (ESI, cation) 630.0(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.60(1H，s)；8.83(1H，d，J＝2.5Hz)；8.41(1H，d，J＝2.5Hz)；8.27(1H，d，J＝2.7Hz)；7.89(1H，dd，J＝8.8，2.7Hz)；7.68(1H，s)；7.52(1H，s)；7.21(4H，dd，J＝13.5，8.6Hz)；6.86(4H，dd，J＝13.1，8.6Hz)；6.71(1H，d，J＝9.0Hz)；4.88(2H，s)；4.82(2H，s)；3.93(3H，s)；3.93(3H，s)；3.81(3H，s)；3.78(3H，s)；2.59(3H，s)。

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (140mg, 0.222mmol) was treated with TFA (10mL) and heated with a reflux condenser at 80 ℃ for 18H. TFA was removed in vacuo and the residue was taken up in 2M NH in MeOH ₃Treated to pH 7 and dry-loaded with silica gel. Purification on ISCO (12g column, 1-20% MeOH in DCM) gave 4- (2- (6-methoxypyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (71.7mg, 0.184mmol, 83% yield) as an orange crystalline solid. M/z (ESI, cation) 390.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.69(1H，s)；8.87(1H，d，J＝2.5Hz)；8.55(2H，t，J＝3.1Hz)；8.18(1H，dd，J＝8.8，2.7Hz)；8.12(1H，s)；7.90(1H，s)；7.82(1H，s)；7.77(1H，s)；6.84(1H，d，J＝8.8Hz)；3.88(3H，s)；3.85(3H，s)；2.46(3H，s)。

Example 248: 4- (2- (5, 6-difluoropyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described in example 246 using 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 3, 4-difluoroaniline (Aldrich) and was isolated as orange amorphous solid (59%). . M/z (ESI, cation) 315.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.11(1H，s)；8.80(1H，dd，J＝7.8，2.0Hz)；8.39(1H，dd，J＝4.7，2.0Hz)；8.19(1H，ddd，J＝13.8，7.5，2.5Hz)；7.89(1H，br.s.)；7.78(1H，br.s)；7.55-7.62(1H，m)；7.32-7.41(1H，m)；6.97(1H，dd，J＝7.8，4.7Hz)；2.44(3H，s)。

Example 249: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1, 2, 3, 6-tetrahydropyridin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described in example 247 using 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate and was isolated as a bright yellow amorphous solid (13%). M/z (ESI, cation) 391.1(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.74(1H，br.s.)；8.81(1H，b r.s.)；8.54(1H，br.s.)；8.40(1H，br.s.)；8.17(1H，br.s.)；7.88(1H，br.s.)；7.73(1H，br.s.)；6.83(1H，br.s.)；6.17(1H，d，J＝1.0Hz)；3.84(3H，s)；2.93(2H，br.s.)；2.44(4H，br.s.)；1.56(4H，s)。

Example 250: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 247 using 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (Strem Chemicals) and was isolated as an orange amorphous solid (95%). M/z (ESI, cation) 376.1(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.98(1H，br.s.)；11.70(1H，s)；8.89(1H，br.s.)；8.59(2H，br.s.)；8.17(2H，br.s.)；7.87(2H，br.s.)；7.74(1H，br.s.)；6.84(1H，s)；3.85(3H，s)；2.46(3H，br.s.)。

Example 251: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -6 '-methyl-3, 3' -bipyridin-6-amine

The title compound was prepared in analogy to the procedure described in example 247 using 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 6-methylpyridin-3-ylboronic acid (40.5mg, 0.296mmol) (Frontier Scientific) and was isolated as yellow crystalline solid (56%). M/z (ESI, cation) 401.0(M + H)⁺.¹H NMR(400MHz，d6-DMSO)δ11.85(1H，s)；9.03(1H，d，J＝2.7Hz)；8.77(1H，d，J＝2.2Hz)；8.67(1H，d，J＝2.5Hz)；8.56(1H，d，J＝2.7Hz)；8.20(1H，dd，J＝8.8，2.7Hz)；7.99(1H，dd，J＝8.1，2.2Hz)；7.91(1H，br.s.)；7.77(1H，br.s.)；7.38(1H，d，J＝8.2Hz)；6.85(1H，d，J＝8.8Hz)；3.86(3H，s)；2.52(3H，s)；2.46(3H，s)。

Example 252: 4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (190mg, 0.325mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (15.51mg, 0.033mmol) (Strem Chemicals), tris (dibenzylideneacetone) dipalladium (0) (14.89mg, 0.016mmol) (Strem Chemicals) and 4- (tributylstannyl) pyridazine (156mg, 0.423mmol) (Synthonix) were weighed in vials, purged with argon and then treated with toluene (1.6 mL). The vial was sealed and heated in an oil bath at 110 ℃ for 21 h. The reaction mixture was treated with water and extracted with EtOAc (2X 30mL), washed with brine (20mL) and over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography using ISCO Combiflash company (12g column, 20-100% EtOAc in hexanes) to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (157.1mg, 0.250mmol, 77% yield) as a bright yellow crystalline solid. M/z (ESI, cation) 628.0(M + H) ⁺。 ¹H NMR(400MHz，CDCl₃)δ11.96(1H，s)；9.44(1H，d，J＝1.4Hz)；9.16(1H，d，J＝5.1Hz)；9.10(1H，d，J＝2.7Hz)；8.64(1H，d，J＝2.7Hz)；8.30(1H，d，J＝2.5Hz)；7.88(1H，dd，J＝8.7，2.6Hz)；7.58(1H，dd，J＝5.4，2.6Hz)；7.23(2H，d，J＝8.6Hz)；7.17(2H，d，J＝8.8Hz)；6.87(4H，dd，J＝12.7，8.6Hz)；6.75(1H，d，J＝8.8Hz)；4.91(2H，s)；4.83(2H，s)；3.95(3H，s)；3.81(3H，s)；3.78(3H，s)；2.62(3H，s)。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (140mg, 0.223mmol) was treated with TFA (10mL) and equipped with a reflux condenser and heated at 80 ℃ for 15 h. TFA was removed in vacuo and the residue was pipetted into ice-cooled NaHCO₃In a saturated solution, a yellow suspension was produced, which was collected by filtration on a sintered glass frit. The resulting yellow solid was washed with water and MeOH, dried loaded onto silica gel, and attempted to be purified on ISCO (12g column, 1-40% MeOH in DCM (also tested with 25% 2M NH3 in MeOH in DCM)) without liberating the desired product from silica gel. The silica gel was washed with DMSO (20mL) and filtered through 0.45 μm acrodiscs, and DMSO was removed over the weekend in Genevac to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (pyridazin-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (9.5mg, 0.025mmol, 10.99% yield) as a bright yellow amorphous solid. M/z (ESI, cation) 388.1(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.99(1H，s)；9.66(1H，s)；9.25(1H，s)；9.21(1H，d，J＝2.3Hz)；8.91(1H，d，J＝2.3Hz)；8.55(1H，d，J＝2.7Hz)；8.16-8.20(1H，m)；7.98-8.02(1H，m)；7.92(1H，s)；7.81(1H，s)；6.88(1H，d，J＝8.8Hz)；3.87(3H，s)；2.54(3H，s)。

Example 253: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5 '-fluoro-N- (6-methoxypyridin-3-yl) -3, 3' -bipyridin-6-amine

The title compound was prepared in analogy to the procedure described for example 247 using 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 5-fluoropyridin-3-ylboronic acid ((Combi-Blocks Inc.) and isolated as orange crystalline solid (22%). M/z (ESI, cation) 405.0(M + H)⁺。 ¹H NMR(400MHz，d6-DMSO)δ11.90(1H，s)；9.09(1H，d，J＝2.7Hz)；8.80(1H，s)；8.75(1H，d，J＝2.7Hz)；8.56(2H，t，J＝2.5Hz)；8.19(1H，dd，J＝8.9，2.8Hz)；8.10(1H，br.s.)；7.92(1H，br.s.)；7.77(1H，br.s.)；6.86(1H，d，J＝9.0Hz)；3.86(3H，s)，2.47(3H，s)。

Example 254: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine

Step 1: 6-fluoro-2, 3' -bipyridine

2-chloro-6-fluoro-pyridine (0.436mL, 3.31mmol) (Oakwood), 3-pyridineboronic acid (448mg, 3.65mmol) (Combi-Blocks Inc.), and tetrakis (triphenylphosphine) palladium (0) (77mg, 0.066mmol) (Strem Chemicals) were purged with argon and bis (triphenylphosphine) was addedAlkane (10mL) and 1M sodium carbonate solution (4.97mL, 4.97 mmol). The mixture was heated by microwave for 30min at 110 ℃. The cooled reaction mixture was treated with 1N NaOH and extracted with EtOAc (30mL), washed with brine and over MgSO₄Dried, filtered and concentrated. Purification on ISCO (12g column, 70-100% EtOAc in hexane) afforded 6-fluoro-2, 3' -bipyridine (581mg, 3.34mmol, 99% yield) as a pale yellow crystalline solid. M/z (ESI, cation) 175.1(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ9.20(1H，d，J＝1.6Hz)；8.67(1H，d，J＝3.9Hz)；8.34(1H，d，J＝8.0Hz)；7.90(1H，q，J＝8.0Hz)；7.67(1H，dd，J＝7.5，2.4Hz)；7.42(1H，dd，J＝7.9，4.8Hz)；6.94(1H，dd，J＝8.0，2.9Hz)。

Step 2: 6-fluoro-2, 3' -bipyridin-5-ylboronic acid

A stirred solution of diisopropylamine (0.531mL, 3.79mmol) (Aldrich) in THF (4mL) was treated with 1.6M n-butyllithium (2.368mL, 3.79mmol) (Aldrich) in hexane at-40 deg.C, and the pale yellow solution was stirred for 1h and then cooled to-78 deg.C. Through the cannula, a solution of 6-fluoro-2, 3' -bipyridine (550mg, 3.16mmol) in THF (5mL) was added slowly over 2 min. The resulting bright orange solution was stirred at-78 deg.C for 1.5h, and then a solution of triisopropyl borate (1.089mL, 4.74mmol) (Aldrich) in THF (4mL) was added slowly. The resulting mixture was stirred at-78 ℃ for 30min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the yellow heterogeneous mixture was quenched with 1N NaOH (aq) (10mL) and stirred for 30 min. The separated aqueous layer was removed and carefully acidified with 5N HCl until acidic (pH 5 to about 6) and the resulting cloudy mixture was extracted with EtOAc (20 mL). Most of the product remained in the aqueous phase, so water was removed overnight on a freeze-dryer to yield a salt-blended white fluffy product. M/z (ESI, cation) 219.1(M + H)⁺。¹H NMR(400MHz，MeOH)δ9.22(1H，s)；8.62(1H，d，J＝4.5Hz)；8.51(1H，d，J＝8.0Hz)；8.12(1H，t，J＝7.9Hz)；7.89(1H，dd，J＝7.3，2.8Hz)；7.59(1H，dd，J＝8.0，4.9Hz)。

And step 3: 4- (6-fluoro-2, 3' -bipyridin-5-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

6-fluoro-2, 3' -bipyridin-5-ylboronic acid (555mg, 2.55mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (700mg, 1.819mmol), Amphos 2(64.4mg, 0.091mmol) (Aldrich) and potassium acetate (548mg, 5.58mmol) (Aldrich) in bisA mixture of alkane (12mL) and water (3.0mL) was purged with argon and heated in a microwave reactor at 120 ℃ for 30 min. The reaction mixture was treated with 1N NaOH (15mL) and extracted with EtOAc (50mL), washed with brine and over MgSO₄Dried, filtered and concentrated. The crude product was purified on ISCO (40g column, 40-100% EtOAc in hexanes) to give 4- (6-fluoro-2, 3' -bipyridin-5-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (490.3, 0.938mmol, 51.6% yield) as a bright yellow crystalline solid. M/z (ESI, cation) 523.0(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ9.26(1H，d，J＝1.8Hz)；8.67-8.72(2H，m)；8.40(1H，dt，J＝8.0，2.0Hz)；7.77(1H，dd，J＝7.8，1.6Hz)；7.43(1H，dd，J＝8.0，5.3Hz)；7.20-7.25(4H，m)；6.83-6.90(4H，m)；4.83(4H，s)；3.82(3H，s)；3.80(3H，s)；2.56(3H，s)。

And 4, step 4: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine

A solution of 4- (6-fluoro-2, 3' -bipyridin-5-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (230mg, 0.440mmol) and 5-amino-2-methoxypyridine (0.082mL, 0.660mmol) (Aldrich) in THF (6.0mL) was cooled to 0 ℃ in an ice bath and treated with 1M LiHMDS (1.320mL, 1.320mmol) (Aldrich) to give a dark purple solution which was stirred at 0 ℃ for 30 min. By addition of NH ₄The reaction was quenched with a saturated solution of Cl and extracted with EtOAc (20mL), washed with brine and over MgSO₄Dried, filtered and concentrated. The crude material was used in the next step without further purification. M/z (ESI, cation) 627.0(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.89(1H，s)；9.25(1H，d，J＝1.6Hz)；8.91(1H，d，J＝8.2Hz)；8.64(1H，dd，J＝4.8，1.7Hz)；8.37(1H，d，J＝2.5Hz)；8.31(1H，dt，J＝8.0，2.0Hz)；8.01(1H，dd，J＝8.9，2.6Hz)；7.66(1H，d，J＝2.7Hz)；7.39(1H，dd，J＝7.8，4.7Hz)；7.18-7.25(4H，m)；7.03(1H，dd，J＝8.6，2.9Hz)；6.82-6.91(4H，m)；4.85(4H，s)；3.86(3H，s)；3.81(3H，s)；3.79(3H，s)；2.60(3H，s)。

And 5: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine

A solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine (276mg, 0.440mmol) in TFA (10mL) was heated to 75 ℃ for 15 h. About 80% of the TFA was removed in vacuo and the crude oily residue was pipetted into NaHCO₃Is cooled in the solution. The resulting suspension was collected by filtration and washed with water and MeOH. Subsequently, the solid was dry-loaded onto silica gel and purified on ISCO (12g column, 1-25% MeOH in DCM) to give a partially purified product. This product was suspended in MeOH and filtered, and the filter cake was dry-loaded with silica gel and purified on ISCO (12g column, 3-15% MeOH in DCM) to give 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine (17.2mg, 0.045mmol, 10.11% yield) as a brown amorphous solid. M/z (ESI, cation) 387.0(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.86(1H，s)；9.26(1H，d，J＝2.0Hz)；8.88(1H，d，J＝8.0Hz)；8.66(2H，d，J＝2.9Hz)；8.41(1H，dt，J＝8.1，1.8Hz)；8.21(1H，dd，J＝8.9，2.6Hz)；7.89(1H，br.s.)；7.74(1H，br.s.)；7.58(1H，d，J＝8.0Hz)；7.52-7.56(1H，m)；6.90(1H，d，J＝9.0Hz)；3.87(3H，s)；2.45(3H，s)。

Example 255: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -N- (5-fluoro-6-methoxypyridin-3-yl) -2, 3' -bipyridin-6-amine

In a similar manner to that described in example 254, 4- (6-fluoro-2, 3' -bipyridin-5-yl) -N, N-bis (4-methoxybenzyl) was usedYl) -6-methyl-1, 3, 5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem) the title compound was prepared and isolated as an orange amorphous solid (5.7%). M/z (ESI, cation) 405.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.03(1H，s)；9.27(1H，d，J＝2.0Hz)；8.91(1H，d，J＝8.2Hz)；8.67(1H，dd，J＝4.8，1.5Hz)；8.55(1H，d，J＝2.2Hz)；8.39-8.43(1H，m)；8.36(1H，dd，J＝12.7，2.3Hz)；7.93(1H，br.s.)；7.79(1H，br.s.)；7.62(1H，d，J＝8.2Hz)；7.57(1H，dd，J＝7.9，4.8Hz)；3.96(3H，s)；2.45(3H，s)。

Example 256: 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described in example 247 using 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (Frontier Scientific) and was isolated as yellow amorphous solid (35%). M/z (ESI, cation) 392.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.76(1H，s)；8.83(1H，d，J＝2.5Hz)；8.54(1H，d，J＝2.7Hz)；8.44(1H，d，J＝2.5Hz)；8.17(1H，dd，J＝8.8，2.7Hz)；7.87(1H，br.s.)；7.73(1H，br.s.)；6.83(1H，d，J＝8.8Hz)；6.22(1H，br.s.)；4.24(2H，d，J＝2.5Hz)；3.82-3.87(5H，m)；2.47(2H，m)；2.44(3H，s)。

Example 257: 4- (5-chloro-2- (5-fluoropyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described in example 246 using 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 5-fluoropyridin-3-amine (Matrix Scientific) and was isolated as an orange amorphous solid (10%). M/z (ESI, cation) 332.0(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.27(1H，s)；8.77-8.84(2H，m)；8.44-8.51(2H，m)；8.21(1H，d，J＝2.5Hz)；8.05(1H，br.s.)；7.91(1H，br.s.)；2.47(3H，s)。

Example 258: 4- (2- (5-Fluoropyridin-3-ylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described in example 247 using 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (Aldrich) and was isolated as dark brown amorphous solid (82%). M/z (ESI, cation) 378.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.27(1H，br.s.)；8.93(1H，br.s.)；8.84(1H，br.s.)；8.71(1H，br.s.)；8.58(1H，br.s.)；8.17(2H，br.s.)；8.00(1H，br.s.)；7.87(2H，br.s.)；3.90(3H，br.s.)；2.50(3H，s)。

Example 259: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 2-fluoro-6- (2-methoxyethoxy) pyridine

Sodium hydride (60 wt% dispersion in mineral oil, 2.51g, 62.8mmol) (Aldrich) was added to a stirred mixture of anhydrous 2-methoxyethanol (Aldrich, 2.87mL, 36.4mmol) and DMF (30mL) at 0 ℃. After stirring at 0 ℃ for 30min, the reaction mixture turned into a white solid. Subsequently, it was treated with 2, 6-difluoropyridine (3.00mL, 33.1mmol) (Aldrich) and allowed to warm to room temperature over 1.5 h. The reaction is treated with NaHCO₃The saturated aqueous solution was quenched and stirred for 1h, partitioned between EtOAc, and the layers were separated. The organic layer was washed with NaHCO ₃Washed with saturated aqueous solution, brine and dried (MgSO)₄) Filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (40g column, 0-5% EtOAc in hexanes) to give 2-fluoro-6- (2-methoxyethoxy) pyridine as a viscous clear colorless oil (3.0769g, 17.98mmol, 54% yield). M/z (ESI, cation) 172.1(M + H)⁺.¹H NMR(400MHz，CDCl₃)δ7.64(1H，q，J＝8.2Hz)；6.67(1H，dd，J＝8.0，1.0Hz)；6.46(1H，dd，J＝7.8，2.3Hz)；4.41-4.47(2H，m)；3.70-3.76(2H，m)；3.44(3H，s)。

Step 2: 2-fluoro-6- (2-methoxyethoxy) pyridin-3-ylboronic acid

2-fluoro-6- (2-methoxyethoxy) pyridine (1.13g, 6.60mmol) dissolved in THF (5mL) was cooled to-60 deg.C and treated with a 2.0M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (4.95mL, 9.90mmol) (Aldrich) and stirred at-60 deg.C for 1 h. Subsequently, the mixture was treated with triisopropyl borate (2.277mL, 9.90mmol) (Aldrich) and allowed to warm to room temperature over 30 min. Subsequently, it was quenched by addition of a saturated solution of ammonium chloride and stirred for 30 min. The reaction mixture was extracted with EtOAc (3X 25mL) over MgSO₄Dried, filtered and concentrated. Purification on ISCO (12g column, 5-100% EtOAc) afforded 2-fluoro-6- (2-methoxyethoxy) pyridin-3-ylboronic acid (226mg, 1.051mmol, 15.92% yield) and was a semi-crystalline solid A mixture of 6-fluoro-2- (2-methoxyethoxy) pyridin-3-ylboronic acids. M/z (ESI, cation) 216.1(M + H)⁺。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 254 using 4- (2-fluoro-6- (2-methoxyethoxy) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem) and was isolated as yellow amorphous powder (4.9%). M/z (ESI, cation) 402.0(M + H)⁺。¹H NMR(400MHz，d4-MeOH)δ12.15(1H，br.s.)；8.77(1H，d，J＝8.6Hz)；8.32(1H，br.s.)；8.15(1H，br.s.)；6.30(1H，s)；3.98(3H，s)；3.72(2H，br.s.)；3.37(4H，s)；2.44(4H，s)。

Example 260: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-amine

In an analogous manner to that described in example 246, 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and 1- (4-methoxybenzyl) -1H-benzo [ d ] b]Imidazol-5-amine with 1- (4-methoxybenzyl) -1H-benzo [ d]Mixture of imidazol-6-amines the title compound was prepared and isolated as a yellow amorphous solid (5.5%). M/z (ESI, cation) 495.2(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ12.29(1H，br.s.)；12.04(1H，br.s.)；8.72(1H，d，J＝2.5Hz)；8.39(1H，br.s.)；8.25(1H，d，J＝2.3Hz)；8.11(1H，s)；7.80-7.86(1H，m)；7.72(1H，br.s.)；7.51(1H，br.s.)；7.37(1H，br.s.)；3.50(2H，s)；3.11(4H，d，J＝4.5Hz)；2.87(3H，s)；2.50(4H，s)；2.47(3H，s)。

Example 261: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (piperazin-1-ylmethyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-amine

In the presence of N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) -1H-benzo [ d]The title compound was also formed during the synthesis of imidazol-5-amine (example 260) and isolated as a yellow amorphous solid (3.1%). M/z (ESI, cation) 417.2(M + H)⁺。¹H NMR(400MHz，d4-MeOH)8.84(1H，d，J＝2.3Hz)；8.23(1H，d，J＝1.6Hz)；8.17(1H，d，J＝2.3Hz)；8.08(1H，s)；7.55(1H，d，J＝8.8Hz)；7.36(1H，dd，J＝8.7，1.7Hz)；3.48(2H，s)；2.83(4H，t，J＝4.9Hz)；2.63(2H，s)；2.49(6H，s)。

Example 262: 4- (5- (difluoromethoxy) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5- (benzyloxy) -2-fluoropyridines

At room temperature, in N₂Next, a solution of 2-fluoro-5-hydroxypyridine (Combi-block) (1.00g, 8.84mmol) in DMF (12mL) was treated with a 60% dispersion of sodium hydride (Alfa-Aesar) (0.88g, 22.1mmol) in mineral oil. After stirring for 40min, benzyl chloride (Aldrich) (3.05mL, 26.5mmol) and tetrabutylammonium iodide (Aldrich) (0.33g, 0.88mmol) were added and the reaction mixture was stirred for an additional 2 h. Water (2mL) was added to quench the reaction and the reaction mixture was quenched in EtOAc and saturated NaHCO₃Between themAnd (4) preparing. The aqueous layer was extracted with EtOAc (2X 15 mL). The combined organic extracts were extracted with saturated NaHCO ₃Washed with brine and over MgSO₄Dried and concentrated. The residue was purified by column chromatography (120g, 10% to 20% acetone in hexane) to give the product as a colorless liquid (1.32 g). M/z (ESI, cation) 204.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ7.91(br.s.，1H)；7.32-7.51(m，6H)；6.86(dd，J＝8.84，3.29Hz，1H)；5.10(s，2H)。

Step 2: 5- (benzyloxy) -2-fluoropyridin-3-yl boronic acids

A solution of diisopropylamine (Aldrich) (0.33mL, 2.16mmol) in THF (5mL) was cooled to 0 deg.C and treated with n-butyllithium (Aldrich) (0.94mL, 2.36 mmol). The resulting mixture was stirred at 0 ℃ for 30min and then cooled to-78 ℃. 5- (benzyloxy) -2-fluoropyridine (Aldrich) (0.200g, 0.982mmol) in THF (3mL) was added dropwise and the solution was stirred at-78 deg.C for 40min before treatment with triisopropyl borate (Aldrich) (0.50mL, 2.16mmol) in THF (2 mL). After addition, the cooling bath was removed and the reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 5% NaOH (10 mL). The aqueous layer was separated and acidified to pH 5 using 5N HCl. The resulting mixture was extracted with EtOAc (2X 15 mL). The combined organic extracts were dried over MgSO₄Dried and concentrated to give the crude product as a yellow solid (0.210 g). M/z (ESI, cation) 248.0(M + H)⁺。¹H NMR(300MHz，d4-MeOH)δ6.60(br.s.，1H)；6.36(br.s.，1H)；6.00-6.24(m，5H)；3.87(s，2H)。

And step 3: 4- (5- (benzyloxy) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

In N₂Next, a mixture of 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.150g, 0.390mmol), 5- (benzyloxy) -2-fluoropyridin-3-ylboronic acid (0.107g, 0.432mmol), Amphos (Aldrich) (0.014g, 0.020mmol), potassium acetate (Strem) (0.119g, 1.22mmol), EtOH (3mL) and water (0.3mL) was sealed and at 100 deg.CThen, the mixture was heated by microwave for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 10% to 20% EtOAc in hexanes) to give the product as a white solid (0.090 g). M/z (ESI, cation) 552.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ8.17(d，J＝7.31Hz，1H)；8.01(br.s.，1H)；7.31-7.48(m，5H)；7.23(d，J＝7.89Hz，4H)；6.87(t，J＝7.60Hz，4H)；5.13(s，2H)；4.81(d，J＝6.28Hz，3H)；3.81(d，J＝8.33Hz，6H)；2.55(s，3H)。

And 4, step 4: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-ol

In N₂A solution of 4- (5- (benzyloxy) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.080g, 0.145mmol) in EtOAc (8mL) was treated with 10% palladium on carbon (Aldrich) (7.72mg, 0.073mmol) under gas. The reaction mixture is treated with N₂Purified and then at room temperature in H₂Stirring for 2 h. The reaction mixture was passed through Celite(diatomaceous earth). The filtrate was concentrated. The crude product was purified by column chromatography (12g, 20% to 30% acetone in hexanes) to afford the product as a white solid (0.050 g). M/z (ESI, cation) 462.0(M + H) ⁺.¹H NMR(300MHz，CDCl₃)δ8.03(dd，J＝7.60，3.07Hz，1H)；7.89(br.s.，1H)；7.23(d，J＝6.43Hz，4H)；6.87(t，J＝7.53Hz，4H)；5.78(br.s.，1H)；4.82(s，4H)；3.81(d，J＝4.82Hz，6H)；2.55(s，3H)。

And 5: 4- (5- (difluoromethoxy) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-ol (0.050g,0.108mmol) of DMF (3mL) was treated with sodium 2-chloro-2, 2-difluoroacetate (Aldrich) (0.033g, 0.217mmol) and cesium carbonate (Aldrich) (0.053g, 0.163 mmol). At 100 ℃ under N₂Next, the reaction mixture was heated for 2 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO₃Washed with water, brine, over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (12g, 10% to 20% EtOAc in hexanes) to give the product as a white solid (0.030 g). M/z (ESI, cation) 512.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ8.39(d，J＝7.45Hz，1H)；8.18(br.s.，1H)；7.23(d，J＝7.89Hz，4H)；6.87(t，J＝7.60Hz，4H)；6.23-6.83(m，1H)；4.82(d，J＝8.04Hz，4H)；3.81(d，J＝4.82Hz，6H)；2.55(s，3H)。

Step 6: 4- (5- (difluoromethoxy) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

In N₂Next, a solution of 4- (5- (difluoromethoxy) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.030g, 0.059mmol) and 5-amino-2-methoxypyridine (Aldrich) (8.06. mu.L, 0.065mmol) in THF (1mL) was cooled to 0 ℃ and treated with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (Aldrich) (0.039mL, 0.235 mmol). The dark red mixture was stirred at 0 ℃ for 1h, and then in EtOAc with saturated NH ₄Partition between Cl. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with water, brine, and MgSO₄Dried and concentrated. The crude product was purified by column chromatography (12g, 10% to 20% EtOAc in hexanes) to afford the product as a yellow solid (0.022 g). M/z (ESI, cation) 616.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ11.65(s，1H)；8.63(br.s.，1H)；8.26(s，1H)；8.17(br.s.，1H)；7.89(d，J＝8.77Hz，1H)；7.11-7.25(m，4H)；6.78-6.95(m，4H)；6.72(d，J＝8.77Hz，1H)；6.11-6.69(m，1H)；4.74-4.93(m，4H)；3.94(s，3H)；3.81(d，J＝8.48Hz，6H)；2.59(s，3H)。

And 7: 4- (5- (difluoromethoxy) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (5- (difluoromethoxy) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.022g, 0.036mmol) in trifluoroacetic acid (Aldrich)0.531mL, 7.15mmol) and trifluoromethanesulfonic acid (TCI) (3.16. mu.L, 0.036mmol) was heated at 80 ℃ for 20 min. The reaction mixture was concentrated and the first residue was taken up with saturated NaHCO₃Diluted (8mL) and then diluted with CHCl₃(3X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (12g, 10% to 20% acetone in hexanes) to afford the product as a yellow solid (0.010 g). M/z (ESI, cation) 376.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ11.65(s，1H)；8.67(br.s.，1H)；8.35(br.s.，1H)；8.20(br.s.，1H)；8.09(d，J＝9.94Hz，1H)；6.79(d，J＝8.92Hz，1H)；6.11-6.75(m，1H)；5.41(br.s.，2H)；3.95(s，3H)；2.58(s，3H)。

Example 263: 4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2 (1H) -one

Step 1: 2- (4-methoxybenzyloxy) pyridin-4-amine

A solution of 4-amino-2-chloropyridine (Aldrich) (1.000g, 7.78mmol) in 4-methoxybenzyl alcohol (Fluka) (9.66mL, 78mmol) was treated with sodium hydroxide (J.T. Baker) (0.584mL, 31.1mmol) and tetrabutylammonium iodide (Aldrich) (0.287g, 0.778 mmol). At 160 ℃ under N₂Next, the resulting mixture was heated for 2 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2X 15mL)And (6) taking. The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (120g, 20% to 30% acetone in hexanes) to afford the product as a white solid (1.32 g). M/z (ESI, cation) 231.1(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ7.85(d，J＝5.70Hz，1H)；7.38(d，J＝8.18Hz，2H)；6.91(d，J＝8.48Hz，2H)；6.22(d，J＝7.02Hz，1H)；5.99(s，1H)；5.27(s，2H)；4.04(br.s.，2H)；3.82(s，3H)。

Step 2: n, N-bis (4-methoxybenzyl) -4- (2- (2- (4-methoxybenzyloxy) pyridin-4-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In N₂Next, a solution of 2- (4-methoxybenzyloxy) pyridin-4-amine (0.500g, 2.171mmol) in THF (10mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide (Aldrich) in tetrahydrofuran (6.51mL, 6.51mmol) was added dropwise and the mixture stirred at 0 deg.C for 30 min. 4- (2-Fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.161g, 2.61mmol) was added to the reaction mixture. After addition, the resulting mixture was stirred at 0 ℃ for 10min and then removed from the ice bath and stirred at room temperature for 2 h. The reaction was quenched with water. The resulting mixture was washed with EtOAc and saturated NH ₄Partition between Cl. The organic layer was washed with water, brine, MgSO₄Dried and concentrated. The crude product was purified by column chromatography (120g, 20% to 30% EtOAc in hexanes) to give the product as a white solid (0.950 g). M/z (ESI, cation) 656.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ12.36(s，1H)；8.85(d，J＝7.75Hz，1H)；8.40(d，J＝4.38Hz，1H)；7.98(d，J＝5.41Hz，1H)；7.50(s，1H)；7.43(d，J＝8.33Hz，2H)；7.21(d，J＝8.18Hz，4H)；7.02(d，J＝4.38Hz，1H)；6.73-6.98(m，7H)；5.32(s，2H)；4.85(b r.s.，4H)；3.69-3.96(m，9H)；2.62(s，3H)。

And step 3: 4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) pyridin-2 (1H) -one

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (2- (4-methoxybenzyloxy) pyridin-4-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.120g, 0.183mmol) in trifluoroacetic acid (Aldrich) (1.631mL, 21.96mmol) and trifluoromethanesulfonic acid (TCI) (0.810mL, 9.15mmol) was heated at 80 deg.C for 1h in a sealed tube. The reaction mixture was washed with saturated NaHCO₃And (4) neutralizing. The precipitate was collected by filtration. The precipitate was purified by preparative HPLC to give the product as a white solid (0.010 g). M/z (ESI, cation) 296.1(M + H)⁺。¹H NMR(300MHz，d6-DMSO)δ12.14(s，1H)；10.94(br.s.，1H)；8.81(d，J＝6.87Hz，1H)；8.46(d，J＝4.09Hz，1H)；7.66-8.04(m，2H)；7.24(d，J＝7.31Hz，1H)；7.19(s，1H)；7.08(dd，J＝7.97，4.75Hz，1H)；6.53(d，J＝5.70Hz，1H)；2.44(s，3H)。

Example 264: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide

Step 1: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -4-fluorobenzenesulfonamide

N- (5-bromo-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (inogen, Inc.) (1.000g, 2.74mmol), palladium (II) acetate (Aldrich) (0.035g, 0.156mmol), (diphenylphosphino) xanthene (Acros) (0.176g, 0.304mmol), sodium tert-butoxide (Fluka) (0.620g, 6.45mmol), toluene (10mL) and benzophenone imine (Aldrich) (0.459mL, 2.74mmol) were heated at 100 deg.C in a sealed tube for 6 h. The reaction mixture was partitioned between EtOAc and Tris HCl (1M, pH 7). The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO ₄Dried and concentrated. The crude product was purified by column chromatography (120g, 10% to 20% acetone in hexanes) to afford the product as a yellow solid (0.520 g). m/z (ESI)Cation) 466.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ7.75(d，J＝7.45Hz，2H)；7.61(d，J＝2.05Hz，1H)；7.50-7.59(m，3H)；7.40-7.49(m，3H)；7.35(br.s.，3H)；7.03-7.17(m，4H)；6.73(br.s.，1H)。

Step 2: n- (5-amino-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide

A solution of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -4-fluorobenzenesulfonamide (0.520g, 1.116mmol) in THF (8mL) and 2N hydrochloric acid (J.T. Baker) (0.837mL, 1.674mmol) was stirred at room temperature in a sealed tube for 30 min. The reaction mixture was washed with EtOAc and saturated NaHCO₃Are distributed among the devices. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g, 20% to 40% acetone in hexanes) to afford the product as a yellow solid (0.270 g). M/z (ESI, cation) 302.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)7.80(dd，J＝8.77，4.97Hz，2H)；7.61(d，J＝2.63Hz，1H)；7.34(d，J＝2.48Hz，1H)；7.16(t，J＝8.48Hz，2H)；6.82(br.s.，1H)；3.84(br.s.，2H)。

And step 3: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide

In N₂Next, a solution of N- (5-amino-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (0.124g, 0.409mmol) in THF (5mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (Aldrich) (1.706mL, 1.706mmol) was added dropwise and the mixture was stirred at 0 deg.C for 30 min. 4- (2-Fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.070g, 0.341mmol) was added and the mixture was stirred at 0 ℃ for 10 min. The reaction mixture was subsequently stirred at room temperature for 20 h. The reaction mixture is saturated with NH ₄Cl was quenched, and the resulting mixture was quenched with saturated NaHCO₃With CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by preparative HPLC. Fractions containing product were pooled and concentrated. With saturated NaHCO₃The residue was basified (10 mL). The aqueous layer was washed with CHCl₃(3X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated to give the product as a yellow solid (0.050 g). M/z (ESI, cation) 486.8(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ12.38(s，1H)；8.74-9.01(m，2H)；8.44(d，J＝3.22Hz，1H)；8.39(d，J＝2.34Hz，1H)；7.95(dd，J＝8.62，5.12Hz，2H)；7.15(t，J＝8.48Hz，2H)；6.86-7.03(m，2H)；5.43(br.s.，2H)；2.60(s，3H)。

Example 265: n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-chloropyridine-3, 5-diamine

Step 1: n- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide

In N₂Next, a mixture of N- (5-amino-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (0.08g, 0.265mmol) in THF (5mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide (Aldrich) in tetrahydrofuran (0.795mL, 0.795mmol) was added dropwise and the mixture was stirred at 0 deg.C for 30min before 4- (2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.142g, 0.318mmol) was added. The resulting mixture was stirred at 0 ℃ for 10min, then removed from the ice bath and stirred for 3 h. The reaction mixture was quenched with water. The resulting mixture was washed with EtOAc and saturated NH ₄Partition between Cl. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with water, brine, and MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 20% to 30% acetone in hexanes) to give a yellow solidThe product of (1) (0.090 g). M/z (ESI, cation) 727.1(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ12.48(s，1H)；8.78-8.95(m，2H)；8.41(d，J＝3.51Hz，1H)；8.27(s，1H)；7.93(dd，J＝8.62，4.97Hz，2H)；7.22(d，J＝6.58Hz，4H)；7.14(t，J＝8.48Hz，2H)；6.77-6.97(m，6H)；4.85(d，J＝3.36Hz，4H)；3.81(d，J＝5.12Hz，6H)；2.61(s，3H)。

Step 2: n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -2-chloropyridine-3, 5-diamine

A solution of N- (5- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (0.087g, 0.120mmol) in trifluoroacetic acid (Aldrich) (0.622mL, 8.37mmol) and trifluoromethanesulfonic acid (TCI) (0.265mL, 2.99mmol) was heated in a sealed tube at 80 deg.C for 20 min. The reaction mixture was first washed with saturated NaHCO₃Neutralisation and subsequent use of CHCl₃(3X 15 mL). The combined organic layers were washed with water, brine, and MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 20% to 30% acetone in hexanes) to afford the product as a white solid (0.025 g). M/z (ESI, cation) 329.0(M + H)⁺。 ¹H NMR(300MHz，d6-DMSO)12.01(s，1H)；8.79(d，J＝7.16Hz，1H)；8.37(d，J＝4.39Hz，1H)；7.96(s，2H)；7.61-7.88(m，2H)；6.96(dd，J＝7.89，4.82Hz，1H)；5.48(s，2H)；2.45(s，3H)。

Example 266: n- (4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-fluorophenyl) acetamide

In N₂Next, a mixture of N- (4-amino-2-fluorophenyl) acetamide (0.084g, 0.501mmol) in THF (5mL) was cooled to 0 ℃. Adding bis (trimethylsilyl)Yl) amide lithium in 1.0M solution in tetrahydrofuran (Aldrich) (0.487mL, 2.504mmol) and the mixture was stirred at 0 deg.C for 30min before 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.100g, 0.417mmol) was added. The resulting mixture was stirred at 0 ℃ for 10min and then removed from the ice bath and stirred for 2 h. The reaction mixture is saturated with NH₄And (4) quenching by Cl. The resulting mixture was buffered at pH 7 (1M TRIS-HCl) with CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by preparative HPLC. The fractions containing the product were combined and the solvent removed in vacuo. With saturated NaHCO₃The residue was basified (10 mL). The aqueous layer was washed with CHCl₃(3X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated to give the product as a brown solid (40 mg). M/z (ESI, cation) 388.0(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.08(s，1H)；9.63(s，1H)；8.75(d，J＝2.74Hz，1H)；8.43(d，J＝2.74Hz，1H)；7.93-8.06(m，2H)；7.88(br.s.，1H)；7.71(t，J＝8.80Hz，1H)；7.45(dd，J＝8.80，1.76Hz，1H)；2.45(s，3H)；2.06(s，3H)。

Example 267: n- (4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) -2-fluorophenyl) acetamide

Step 1: n- (4- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) -2-fluorophenyl) acetamide

In N₂Next, a mixture of N- (4-amino-2-fluorophenyl) acetamide (0.110g, 0.654mmol) in THF (5mL) was cooled to 0 ℃. 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (Aldrich) was added (0.636mL, 3.27mmol), and the mixture is stirred at 0 ℃ for 30min before adding 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.447g, 0.720 mmol). The resulting mixture was stirred at 0 ℃ for 10min, and then the ice bath was removed and stirring was continued for 2 h. The reaction mixture is saturated with NH₄And (4) quenching by Cl. The resulting mixture was buffered at pH 7 (1M TRIS-HCl) with CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in hexanes and 12% EtOAc) to afford the product as a yellow solid (0.125 g). M/z (ESI, cation) 770.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ11.99(br.s.，1H)；8.73(s，1H)；8.28(s，1H)；8.02-8.16(m，1H)；7.91(s，1H)；7.22(d，J＝7.45Hz，5H)；6.96(d，J＝8.33Hz，1H)；6.88(d，J＝8.18Hz，4H)；4.86(br.s.，4H)；3.81(d，J＝2.92Hz，6H)；3.52(s，2H)；3.19(br.s.，4H)；2.72(s，3H)；2.61(s，3H)；2.48-2.59(m，4H)；2.21(s，3H)。

Step 2: n- (4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) -2-fluorophenyl) acetamide

A solution of N- (4- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) -2-fluorophenyl) acetamide (0.125g, 0.162mmol) in trifluoroacetic acid (Aldrich) (1.206mL, 16.24mmol) and trifluoromethanesulfonic acid (TCI) (0.431mL, 4.87mmol) was stirred in a sealed tube at room temperature for 1 h. The reaction mixture was first washed with saturated NaHCO₃Neutralisation and subsequent use of CHCl₃(3X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (120g, 3% MeOH in DCM) to give the product as a yellow solid (0.070 g). M/z (ESI, cation) 530(M + H)⁺。 ¹H NMR(300MHz，CDCl₃)δ12.03(s，1H)；8.73(s，1H)；8.31(s，1H)；8.19(t，J＝8.70Hz，1H)；8.07(d，J＝13.74Hz，1H)；7.15(d，J＝9.50Hz，1H)；5.44(br.s.，2H)；3.54(s，2H)；3.27(br.s.，4H)；2.79(s，3H)；2.60(s，7H)；2.22(s，3H)。

Example 268: n- (4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenyl) acetamide

Step 1: n- (4- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenyl) acetamide

In N₂Next, a solution of 4' -aminoacetanilide (0.097g, 0.643mmol) in THF (5mL) was cooled to 0 ℃. A 1.0M solution of lithium bis (trimethylsilyl) amide (Aldrich) in tetrahydrofuran (0.313mL, 1.608mmol) was added and the mixture was stirred at 0 ℃ for 30min before adding 4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.200g, 0.322 mmol). The resulting mixture was stirred at 0 ℃ for 10min, and then the ice bath was removed and stirring was continued for 2 h. The reaction mixture is saturated with NH ₄And (4) quenching by Cl. The resulting mixture was buffered at pH 7 (1M TRIS-HCl) with CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in hexanes and 12% EtOAc) to afford the product as a yellow solid (0.140 g). M/z (ESI, cation) 752.0(M + H)⁺。¹H NMR(300MHz，CDCl₃)δ11.82(s，1H)；8.72(s，1H)；8.24(s，1H)；7.54(d，J＝8.48Hz，2H)；7.40(d，J＝8.62Hz，2H)；7.22(d，J＝7.75Hz，4H)；7.07(br.s.，1H)；6.87(dd，J＝8.18，4.09Hz，4H)；4.85(d，J＝4.68Hz，4H)；3.81(d，J＝3.95Hz，6H)；3.51(s，2H)；3.19(br.s.，4H)；2.71(s，3H)；2.60(s，3H)；2.44-2.58(m，4H)；2.18(s，3H)。

Step 2: n- (4- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenyl) acetamide

A solution of N- (4- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-ylamino) phenyl) acetamide (0.140g, 0.186mmol) in trifluoroacetic acid (Aldrich) (1.383mL, 18.62mmol) and trifluoromethanesulfonic acid (TCI) (0.494mL, 5.59mmol) was stirred in a sealed tube at room temperature for 1 h. The reaction mixture was first washed with saturated NaHCO₃Neutralization followed by CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (120g, 4% MeOH in DCM) to give the product as a yellow solid (0.070 g). M/z (ESI, cation) 512.0(M + H) ⁺。¹H NMR(300MHz，CDCl₃)δ11.85(s，1H)；8.72(s，1H)；8.28(d，J＝0.73Hz，1H)；7.68(s，2H)；7.48(d，J＝8.48Hz，2H)；7.12(br.s.，1H)；5.43(br.s.，2H)；3.53(s，2H)；3.26(br.s.，4H)；2.78(s，3H)；2.59(s，7H)；2.19(s，3H)。

Example 269: (R, S) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol

A stirred solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (130mg, 0.225mmol) in DMF (2.00mL, 25.8mmol) was treated with CsF (34.2mg, 0.225mmol) followed by trimethyl (trifluoromethyl) silane (96mg,0.675mmol) for 10min and subsequently allowed to warm to room temperature for 2 h. Reacting the mixture with NH₄Cl (aq) and water (5mL each) and diluted with ethyl acetate (5 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The residue was taken up in TFA (3mL) and several drops of TfOH were added. The mixture was heated at 75 ℃ for 4h, and then cooled to room temperature and concentrated. The residue was redissolved in 5% MeOH (w/NH) in DCM₃) In the middle, with SiO₂Concentrated and purified by chromatography through a pre-packed silica gel column (pure DCM → 5% MeOH in DCM) with a Redi-Sep to give the product as a yellow solid (9.3mg, 10%). M/z (ESI, cation) 408(M + H) ⁺。 ¹H NMR(400MHz，d6-DMSO)δ11.87(s，1H)；8.92(d，J＝2.15Hz，1H)；8.53(d，J＝2.74Hz，1H)；8.35(d，J＝2.35Hz，1H)；8.15(dd，J＝8.80，2.74Hz，1H)；7.92(br.s.，1H)；7.76(br.s.，1H)；6.93(d，J＝5.48Hz，1H)；6.84(d，J＝8.80Hz，1H)；5.09-5.35(m，1H)；3.85(s，3H)；2.44(s，3H)。

Example 270: (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (S) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) potassium trifluoroborate

A mixture of potassium (bromomethyl) trifluoroborate (AldSich, 1.20g, 5.38mmol) and (S) -tert-butyl 3-methylpiperazine-1-carboxylate (Aldrich, 1.131g, 5.65mmol) in THF (7.00mL) was heated at 80 deg.C under nitrogen for 24 h. The mixture was cooled to ambient temperature and then concentrated in vacuo. The residue was redissolved in acetone (125mL) and treated with K₂CO₃(1 equivalent) treatment. The suspension was stirred for 30min and then passed through Celite(diatomaceous earth) short packed column filtration. The filter cake was washed with additional acetone and the combined organic filtrates were concentrated to give the crude product as a colorless foam (1.51g, 88%). The pure material was obtained as a beige powder by adding acetone-diethyl ether (2: 1) to the foam, and then slowly adding hexane while sonicating the mixture.¹⁹F-NMR (377MHz, d 6-acetone) delta-141.28.

Step 2: 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi Block, Inc., 2.507g, 14.30mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (5.24g, 13.62mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.482g, 0.681mmol) and potassium acetate (4.10g, 41.8mmol) in ethanol (100mL) and water (10mL) was degassed and at 100 ℃ in N (10mL)₂Stirring for 16 h. Subsequently, the reaction mixture was cooled to ambient temperature, concentrated in vacuo, and the residue was partitioned between water (50mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2X 20mL) and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue (silica gel, 15 to 50% EtOAc/hexanes) afforded 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.62g, 7.54mmol, 55.4% yield). M/z (ESI, cation) 480(M + H)⁺。

And step 3: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester

4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (8.99g, 18.73mmol), (S) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) potassium trifluoroborate (6.00g, 18.73mmol) was reacted at 80 deg.C, A mixture of diacetoxypalladium (0.210g, 0.937mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (0.893g, 1.873mmol) and cesium carbonate (18.31g, 56.2mmol) in THF (100mL) and water (10.0mL) was heated overnight. After cooling to ambient temperature, the resulting mixture was passed through CeliteThe column was short packed (celite), washed with EtOAc (3 × 30 mL). The combined organic filtrates were concentrated and purified by flash chromatography (silica gel, 5% to 50% ethyl acetate/hexanes) to give (S) -tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylate (10.39g, 15.80mmol, 84% yield) as a pale yellow foam. M/z (ESI, cation) 658(M + H)⁺。

And 4, step 4: (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A stirred solution of (S) -tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylate (10.386g, 15.79mmol) in DCM (25.0mL, 389mmol) was cooled in an ice bath and slowly treated with TFA (25.0mL, 324 mmol). The resulting mixture was stirred at room temperature for 1h and then concentrated. The viscous residue was taken up in DCM (100mL) and cooled to-45 ℃. TEA (22.0mL, 158mmol) was then added via the addition funnel followed by slow addition of methanesulfonyl chloride (6.15mL, 79mmol) dissolved in DCM (20 mL). The heterogeneous mixture was stirred for 30min at-30 ℃ and then with water and NH ₄Cl (aq) (50mL each). The organic layer was separated and the aqueous layer was extracted with DCM (2X 50 mL). Subsequently, the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (13.6g crude) as a pale yellow foam, which was used directly without further purificationIn the next step. M/z (ESI, cation) 636(M + H)⁺。

And 5: (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-fluoro-6-methoxypyridin-3-amine (3.34g, 23.53mmol) and (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (13.6g of crude from the previous step) in THF (150mL) was treated dropwise with LiHMDS (1.0M in THF, Aldrich; 64.2mL, 64.2mmol) at-10 deg.C and the mixture was stirred for 30 min. The reaction was washed with water and saturated NH₄Cl (aq) (100 mL each) and diluted with EtOAc (50 mL). The organic layer was separated and the precipitated solid was collected by filtration. Subsequently, the filtered organic layer was concentrated to a minimum volume and the precipitated tan solid was collected by filtration and washed with a minimum amount of EtOAc. All collected solids were then combined, slurried in isopropanol, collected by filtration, and dried in vacuo to give (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (9.678g, 81% over 2 steps) as a yellow solid. M/z (ESI, cation) 758(M + H) ⁺。

Step 6: (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (9.6775g, 12.77mmol) in TFA (65mL) was treated dropwise with trifluoromethanesulfonic acid (5.67mL, 63.8mmol) and the mixture was stirred at 70 ℃ for 1 h. The volatile material was removed in vacuo and the residual viscous oil was cooled to 0 deg.C(external ice bath). About 100g of ice was added and the mixture was carefully quenched with 1N NaOH (aq) until slightly basic. The mixture was stirred overnight, and the resulting yellow precipitate was collected by filtration and washed with isopropanol (100 mL). The collected yellow solid was purified by column chromatography (silica gel, 0% to 5% (2.0M aqueous ammonia in MeOH)/DCM, followed by re-purification on silica gel, DCM to 40% EtOAc/DCM to EtOAc) to afford a yellow solid. This solid was washed several times with hot toluene to give (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (3.808g, 58%). M/z (ESI, cation) 518(M + H) ⁺；¹H NMR(400MHz，d₆-DMSO)δ11.95(s，1H)，8.67-8.75(m，1H)，8.41(s，1H)，8.38(d，J＝12.91Hz，1H)，8.27(s，1H)，7.90(br s，1H)，7.76(br s，1H)，3.93(s，3H)，3.91(br s，1H)，3.12-3.30(m，3H)，2.90(d，J＝14.28Hz，1H)，2.85(s，3H)，2.65-2.78(m，2H)，2.55-2.64(m，1H)，2.44(s，3H)，2.13-2.28(m，1H)，1.16(d，J＝6.06Hz，3H)。

Example 271: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((S) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone

4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 313, step 2; 0.6020g, 1.000mmol), X-Phos-Pd (OAc) under nitrogen₂Grinding the mixture (1: 1, 0.070g, 0.100mmol) and cesium fluoride (0.129mL, 3.50mmol)1, 4-diAn alkane (5.00mL, 58.5mmol) stirred mixture was treated with tributyl (1-ethoxyvinyl) tin (0.507mL, 1.500 mmol). The mixture was sealed and heated at 110 ℃ for 16 h. Subsequently, the reaction mixture was cooled to room temperature and passed through Celite(diatomaceous earth) short packed columns. The filter cake was washed with EtOAc (3 × 20mL) and the combined filtrates were concentrated in vacuo. The residue was loaded onto a short plug of silica gel, the tin by-product was eluted with DCM, and the desired product was subsequently eluted with 5% MeOH/DCM to give a mixture of the desired product and a small amount of dechlorinated product. Chromatographic purification of this mixture (silica gel, 0% to 30% EtOAc/hexanes) afforded 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone as a pale yellow solid (0.482g, 0.791mmol, 79% yield). M/z (ESI, cation) 610(M + H) ⁺。

Step 2: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

A stirred solution of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (0.1350g, 0.221mmol) in THF (5.00mL) was treated with sodium boron hydride (0.042g, 1.107mmol) at 0 ℃ and the resulting mixture was stirred for 10min before it was allowed to warm to room temperature for 1 h. The resulting suspension was quenched with 1N aqueous NaOH, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). Subsequently, the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol, which was used without further purification.

And step 3: methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester

A solution of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (0.4361g, 0.713mmol) in DCM (10.00mL) was treated with Et at 0 deg.C ₃N (0.298mL, 2.139mmol) and methanesulfonyl chloride (0.139mL, 1.782 mmol).

The resulting mixture was stirred at 0 ℃ for 2h and then quenched with water (10 mL). The aqueous layer was extracted with DCM (2X 5mL) and the combined organic layers were successively washed with 1N HCl (aq), NaHCO₃Saturated aqueous solution and brine. Subsequently, the combined organic layers were passed over Na₂SO₄Dried and concentrated to give crude methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester as a yellow residue, which was used without further purification.

And 4, step 4: 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester and 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester -formic acid (S) -tert-butyl ester

The crude methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester (0.492g, 0.713mmol) in CH ₃A stirred solution of CN (10.00mL, 191mmol) was treated with 2, 2, 6, 6-tetramethylpiperidine (0.182mL, 1.070mmol) and 3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (Aldrich, st. louis, MO, 0.186g, 0.927mmol) and the mixture was heated at reflux overnight. Subsequently, the mixture was cooled to room temperature and the resulting suspension was diluted with water and DCM (20 mL each). Separating the organic layerAnd the aqueous layer was extracted with DCM (2X 20 mL). Subsequently, all organic layers were combined, washed with brine, and washed with Na₂SO₄Dried and concentrated. The residue was purified by flash column chromatography (silica gel, 0% to 15% ethyl acetate/DCM followed by elution with 5% MeOH/DCM) to give two separate diastereomers, 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (first eluting diastereomer; 101mg, 17.8%) and 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (second eluting diastereomer; 101mg, 17.8%). In that With PI3K γ, the absolute stereochemistry of the two diastereomers was determined by the eutectic structure of example 272 (derived from the second eluting diastereomer) in the complex. M/z (ESI, cation) 794(M + H)⁺。

And 5: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((S) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (0.101g, 0.127mmol) (the first eluting diastereomer from example 271, step 4) in DCM (3.00mL, 46.6mmol) was treated with TFA (3.00mL, 38.9mmol) and the resulting mixture was stirred at room temperature for 30min before being concentrated to give a brown oil. This oil was redissolved in DCM (3.00mL) and successively treated with Et at-15 deg.C₃N (0.089mL, 0.636mmol) and methanesulfonyl chloride (0.030mL, 0.382mmol) (added slowly) and the resulting mixture was stirred for 1 h. Subsequently, the reaction mixture was washed with NaHCO₃Saturated aqueous solution and water quench.The separated aqueous layer was extracted with DCM (2 ×), and the combined organic layers were taken over Na ₂SO₄Dried and concentrated. The crude product was treated with TFA (2.00mL) and heated at 80 ℃ overnight. The resulting mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude product was adsorbed onto silica gel and purified by chromatography (silica gel, 0% to 5% MeOH/DCM) to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((S) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (29mg, 0.055mmol, 42.9% yield) as a yellow solid. M/z (ESI, cation) 532(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.95(s，1H)；8.74(d，J＝2.54Hz，1H)；8.27-8.46(m，3H)；7.90(b r.s.，1H)；7.77(br.s.，1H)；3.99-4.09(m，1H)；3.93(s，3H)；3.20-3.30(m，1H)；2.94-3.11(m，2H)；2.84(s，3H)；2.75-2.84(m，2H)；2.45(s，3H)；2.40(dd，1H)；2.29-2.35(m，1H)；1.28(d，J＝6.65Hz，3H)；1.15(d，J＝6.26Hz，3H)。

Example 272: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared as a yellow solid in 59% yield from (S) -tert-butyl 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylate (the second eluting diastereomer from example 271, step 5) according to a procedure similar to example 271, step 5. In thatWith PI3K γ, the absolute stereochemistry at the chiral center was confirmed by the eutectic structure of example 272 in the complex. m/z (ESI, cation) )532(M+H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.93(s，1H)；8.72(d， J＝2.35Hz，1H)；8.35-8.45(m，2H)；8.32(d，J＝2.35Hz，1H)；7.89(br.s.，1H)；7.76(br.s.，1H)；3.96-4.08(m，1H)；3.93(s，3H)；3.07-3.15(m，2H)；3.05(dd，J＝10.86，2.84Hz，1H)；2.73-2.90(m，5H)；2.51-2.55(m，2H)；2.44(s，3H)；1.37(d，J＝6.85Hz，3H)；1.07(d，J＝6.06Hz，3H)。

Example 272 was also prepared by the following sequence of reaction conditions:

step 1: (3S) -4- ((1R) -1- (6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylic acid tert-butyl ester

A mixture of 5- (1-bromoethyl) -2-fluoropyridine (example 146, step 2; 8.95g, 43.9mmol) and (S) -tert-butyl 3-methylpiperazine-1-carboxylate (9.22g, 46.1mmol) (CNHTECologies Inc.) in acetonitrile (200mL) was mixed with K₂CO₃(7.27g, 52.6mmol) and KI (1.456g, 8.77 mmol). The mixture was placed in a preheated (70 ℃) oil bath and allowed to stir under an inert atmosphere overnight. The heating bath was then removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with chloroform (200mL) and water (300 mL). The organic layer was separated and the aqueous layer was extracted with chloroform (1X 100 mL). Subsequently, the combined organic layers were washed with saturated brine solution and then with Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (120g silica gel, 0% to 40% EtOAc/hexanes) to afford tert-butyl (3S) -4- ((1R) -1- (6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylate (5.02g, 15.52mmol, 35.4% yield) as a viscous yellow-orange oil (lower R)_fDiastereomers). M/z (ESI, cation) 324.1(M + H) ⁺。¹HNMR(400MHz，CDCl₃)δ8.09-8.14(m，1H)；7.75(td，J＝8.0，2.2Hz，1H)；6.90(dd，J＝8.5，2.8Hz，1H)；3.94(br.s.，1H，＝)；3.55(br.s.，1H)；3.37(br.s.，2H)；3.20(br.s.，1H)；2.71(ddd，J＝11.3，7.6，3.5Hz，1H)；2.43(dd，J＝9.6，5.5Hz，2H)；1.43(s，9H)；1.38(d，J＝6.8Hz，3H)；0.99(d，J＝6.3Hz，3H)。

Step 2: (5- ((1R) -1- ((2S) -4- (tert-butoxycarbonyl) -2-methyl-1-piperazinyl) ethyl) -2-fluoro-3-pyridinyl) boronic acid

N-butyllithium (2.5M in hexane; 7.23mL, 18.07mmol) was added dropwise to a solution of diisopropylamine (2.55mL, 18.07mmol) in 8mL THF at-40 deg.C. The mixture was stirred at-40 ℃ for 1 h. This solution was added by catheter to a 3-neck 250mL round bottom flask containing a solution of (3S) -4- ((1R) -1- (6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylic acid tert-butyl ester (4.87 g, 15.06mmol) in 60mL THF at-78 ℃. After 15min at-78 deg.C triisopropyl borate (Aldrich; 6.92mL, 30.1mmol) was added and the resulting mixture was stirred for 15min at-78 deg.C and then allowed to warm to ambient temperature. Subsequently, the reaction mixture was treated with 1M NaOH (80mL) and allowed to stir for 20 min. The aqueous layer was separated and the organic layer was discarded. The aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6 was reached. The resulting mixture was diluted with EtOAc (20mL) and the mixture was extracted with 8: 2 EtOAc/MeOH (200 mL). The combined organic extracts are passed over Na₂SO₄Dried, filtered and concentrated to give (5- ((1R) -1- ((2S) -4- (tert-butoxycarbonyl) -2-methyl-1-piperazinyl) ethyl) -2-fluoro-3-pyridinyl) boronic acid as an off-white solid (5.01g, 13.64mmol, 91% yield). M/z (ESI, cation) 368.1(M + H) ⁺。

And step 3: (3S) -4- ((1R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylic acid tert-butyl ester

(5- ((1R) -1- ((2S) -4- (tert-butoxycarbonyl) -2-methyl-1-piperazinyl) ethyl) -2-fluoro-3-pyridinyl) boronic acid (11.90g, 32.4mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 51; 13.72g, 35.6mmol), KOAc (10.18g, 104mmol), bisAlkane (180mL) and water (36.0mL) were charged to a 1L round bottom flask. Nitrogen was bubbled through the mixture for 10 min. AddingBis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (2.295g, 3.24mmol) was charged and a reflux condenser was attached to the flask. The mixture was heated overnight at 100 ℃ under nitrogen (17 h). After cooling to ambient temperature, water was added and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic extracts were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (330g silica gel, 5% to 75% EtOAc/hexanes) to give tert-butyl (3S) -4- ((1R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylate as a pale yellow foam (13.35g, 19.87mmol, 61.3% yield). M/z (ESI, cation) 672.2(M + H) ⁺。 ¹H NMR(400MHz，CDCl₃)δ8.39-8.46(m，1H)8.19-8.24(m，1H)7.19-7.25(m，4H)6.83-6.90(m，4H)4.82(d，J＝11.93Hz，4H)3.97-4.07(m，1H)3.81(s，3H)3.80(br s，1H)3.79(s，3H)3.31-3.44(m，2 H)3.08-3.18(m，1H)2.69-2.77(m，1H)2.55(s，3H)2.42-2.48(m，2H)1.39-1.46(m，12H)1.00(d，J＝6.26Hz，3H)。

And 4, step 4: 4- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

(3S) -tert-butyl 4- ((1R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylate (9.17g, 13.65mmol) in CH at 0 deg.C₂Cl₂(136mL) the solution was treated with TFA (52.6mL, 682mmol), which was added over 10 min. The ice bath was then removed and the reaction mixture was stirred at ambient temperature for 90 min. The solvent was removed in vacuo at 25 ℃ using a heating bath to provide a viscous oil which was cooled to 0 ℃ and 150mL of CH₂Cl₂And (6) diluting. Ice was added to the resulting solution followed by solid NaHCO with rapid stirring₃Until bubbling ceases. The resulting mixture was washed with water (100mL) and CH₂Cl₂(150mL) dilution. The organic layer was separated and washed with CH₂Cl₂(2X) extract the aqueous layer. Followed byAll organic layers were combined, dried over sodium sulfate, and passed through a 0.45 μm ZAPCAP filter (Whatman, Schleicher)&Schuell) filtration. Subsequently, the filtrate was concentrated to about 150mL and cooled to 0 ℃. Addition of NEt₃(7.61mL, 54.6mmol) followed by methanesulfonyl chloride (2.11mL, 27.3 mmol). After 1h at 0 ℃ NaHCO was added ₃The aqueous solution was saturated and the resulting mixture was washed with CH₂Cl₂(3x) extracting. The combined organic extracts are passed over Na₂SO₄Dried, filtered and concentrated. Adding CH to the crude material₂Cl₂The solution was loaded onto a silica gel column (330g) and purified by column chromatography (20% to 100% (10% MeOH/EtOAc)/hexanes) to give 4- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as an off-white foam (7.45g, 11.47mmol, 84% yield). M/z (ESI, cation) 650.2(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.41-8.47(m，1H)；8.21-8.25(m，1H)；7.20-7.25(m，4H)；6.83-6.89(m，4H)；4.81(d，J＝8.61Hz，4H)；4.02(q，J＝6.78Hz，1H)；3.81(s，3H)；3.79(s，3H)；3.28-3.35(m，1H)；3.12-3.20(m，1H)；3.05-3.10(m，1H)；2.92-2.99(m，1H)；2.87(ddd，J＝11.44，7.92，3.33Hz，1H)；2.70(s，3H)2.60-2.68(m，2H)2.55(s，3H)1.43(d，J＝6.85Hz，3H)1.08(d，J＝6.46Hz，3H)。

And 5: 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Lithium bis (trimethylsilyl) amide (1.0M solution in THF, Aldrich; 9.23mL, 9.23mmol) was added dropwise to a mixture of 4- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.000g, 3.08mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc., 0.656g, 4.62mmol) in THF (30.8mL) at 0 ℃ over 5min and at 0 ℃ lithium bis (trimethylsilyl) amide (1.0M solution in THF, Aldrich; 9.23mL, 9.23mmol) was added The resulting reddish brown solution was stirred for 1 h. Adding saturated NH₄Cl (aq, 50mL), and the reaction mixture was dissolved in EtOAc (100mL) with half-saturated NH₄Partition between Cl (aq, 50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 100 mL). The combined organic extracts were washed with brine, over Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (80g silica gel, 0% to 100% EtOAc/hexanes) to give 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.90g, 2.461mmol, 80% yield) as a yellow solid. M/z (ESI, cation) 771.8(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.89(s，1H)；8.69-8.73(m，1H)；8.20-8.24(m，1H)；8.08(dt，J＝12.37，1.05Hz，1H)；7.95-7.98(m，1H)；7.18-7.24(m，4H)；6.82-6.90(m，4H)；4.78-4.88(m，4H)；4.01(s，3H)；3.97-4.01(m，1H)；3.81(s，3H)；3.78(s，3H)；3.18-3.20(m，1H)；3.08-3.15(m，2H)；2.75-2.87(m，2H)；2.67(s，3H)；2.56-2.63(m，1H)；2.59(s，3H)；2.43-2.51(m，1H)；1.40(d，J＝6.85Hz，3H)；1.07(d，J＝6.26Hz，3H)。

Step 6: 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (4.76g, 6.17mmol) in TFA (30.8mL) was treated with trifluoromethanesulfonic acid (3.12mL, 35.1mmol) via a glass pipette. The reaction mixture was stirred at 70 ℃ for 2 h. Subsequently, the mixture was cooled to ambient temperature and concentrated. The brown residue was cooled in an ice bath, and ice was added followed by 1m naoh (aq, 60mL) to bring the pH of the resulting mixture to about 9. The resulting yellow-brown slurry was washed with CH ₂Cl₂(3X 75mL) and the combined organic extracts are extracted over Na₂SO₄Dried and concentrated. The crude product was adsorbed onto silica gel and purified by column chromatography (330g silica gel, 5% to 100% (10% MeOH in EtOAc)/hexanes) to give 2.87g of a dark yellow solid. This solid was suspended in 25mL of EtOAc and stirred at ambient temperature overnight. The yellow solid was filtered and washed with EtOAc, and then dried under high vacuum while heating to 50 ℃ to give 4- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine (2.15g, 4.19mmol, 68% yield) as a bright yellow solid. M/z (ESI, cation) 532.0(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.93(s，1H)8.72(dd，J＝2.05，0.49Hz，1H)8.36-8.43(m，2H)8.32(dd，J＝1.96，0.59Hz，1H)7.88(br.s，1H)7.74(br.s，1H)3.96-4.01(m，1H)3.94(s，3H)3.12(t，J＝5.09Hz，2H)3.04(d，J＝0.39Hz，1H)2.77-2.89(m，5H)2.45(s，3H)1.37(d，J＝6.85Hz，3H)1.07(d，J＝6.26Hz，3H)。

Example 273: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Step 1: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone

A solution of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (example 271; 332mg, 0.54mmol) in TFA (3mL) was treated with TfOH (0.1 mL). The solution was heated in an oil bath for 4h at 80 ℃, allowed to cool to room temperature and concentrated. The dark residue was treated with several ice cubes followed by saturated NaHCO ₃Process while treatingAnd (4) stirring rapidly. The precipitated yellow solid was collected by filtration and washed with water (5 mL). The yellow solid was purified by flash chromatography, eluting with 1-15% MeOH in DCM, to give 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone as a bright yellow crystalline solid (140mg, 69%). M/z (ESI, cation) 460(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ12.38(br.，1H)；9.26(d，J＝2.2Hz，1H)；8.96(d，J＝2.2Hz，1H)；8.42(s，1H)；8.35(dd，J＝12.3，1.6Hz，1H)；8.00(s，1H)；7.83(s，1H)；3.96(s，3H)；2.57(s，3H)；2.46(s，3H)。

Step 2: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

A suspension of 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (140mg, 0.38mmol) in THF (2mL) was treated with methylmagnesium bromide (1.9mL of 1.4M, 2.65mmol in toluene/THF 75/25) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 5min, then at room temperature for 30min, and then with saturated NH₄The Cl solution was quenched and extracted with EtOAc. The organic layer was concentrated and purified on a silica gel column eluting with 5-10% MeOH in DCM to give 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol as a yellow crystalline solid (50mg, 34%). M/z (ESI, cation) 386.0(M + H) ⁺。¹H NMR(400MHz，d6-DMSO)δ11.91(br.，1H)；8.95(d，J＝2.6Hz，1H)；8.43-8.37(m，3H)；7.89(s，1H)；7.73(s，1H)；5.15(s，1H)；3.93(s，3H)；2.45(s，3H)；1.47(s，6H)。

Example 274: 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid

Step 1: 1- (6-Fluoropyridin-3-yl) ethanol

A solution of 6-fluoronicotinaldehyde (1.12g, 8.95mmol, Frontier Scientific, Cat.: F1911, Lot.: RP09-2154) in THF (11.0mL) was treated dropwise with methylmagnesium bromide (1.4M solution in PhMe/THF (75: 25), 7.03mL, 9.85mmol, Aldrich) and allowed to stir at room temperature for 20 min. By adding NH₄The reaction mixture was quenched with a saturated solution of Cl (aq) and allowed to stir for 10 min. The reaction mixture was extracted with EtOAc (2X 60mL) over MgSO₄Dried, filtered and concentrated. Purification on ISCO (12g column, 25-70% EtOAc in hexanes) afforded the title compound as a pale yellow viscous oil (1.05g, 83% yield).¹H NMR(400MHz，CDCl₃) δ 8.20(d, J ═ 2.0Hz, 1H); 7.85(td, J ═ 8.1, 2.5Hz, 1H); 6.93(dd, J ═ 8.4, 2.9Hz, 1H); 4.98(qd, J ═ 6.5, 3.9Hz, 1H); 1.53(d, J ═ 6.5Hz, 3H). M/z (ESI, cation) 142.1(M + H)⁺。

Step 2: 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine

A solution of 1- (6-fluoropyridin-3-yl) ethanol (1.05g, 7.44mmol) in DCM (20.0mL) was cooled in an ice bath and treated with methanesulfonyl chloride (0.863mL, 11.16mmol, Aldrich) and Et at 0 deg.C ₃N (2.074mL, 14.88mmol, Aldrich, Cat No. 471283-100ML, Lot No. 29296KJ) was treated dropwise and stirred for 30 min. The resulting pale yellow suspension was quenched with water and extracted with DCM (2X 25mL), over MgSO₄Dried, filtered and concentrated to give the mesylated alcohol as a pale yellow viscous oil. The alcohol was treated with DCM (20.0mL), THF (3mL), morpholine (2.59mL, 29.8mmol, Aldrich) and Et₃Treated with N (4.0mL) and allowed to stir at room temperature for 24 h. The reaction mixture was treated with water and extracted with DCM (2X 50mL) over MgSO₄Dried, filtered and concentrated. Purification on ISCO (40g column, 5-100% EtOAc in hexanes) gave the title compound as a viscous yellow oil (1.14g, 73.0% yield).¹H NMR(400MHz，CDCl₃)δ8.12(d，J ═ 2.2Hz, 1H); 7.79(td, J ═ 8.1, 2.3Hz, 1H); 6.90(dd, J ═ 8.4, 2.9Hz, 1H); 3.63-3.74(m, 4H); 3.40(q, J ═ 6.7Hz, 1H); 2.49(d, J ═ 4.9Hz, 2H); 2.29-2.39(m, 2H); 1.35(d, J ═ 6.7Hz, 3H). M/z (ESI, cation) 211.1(M + H)⁺。

And step 3: 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid

A solution of LDA was prepared by adding n-butyllithium (1.6M in hexane, 9.60mL, 15.35mmol) to a solution of diisopropylamine (2.152mL, 15.35mmol) in THF (20mL) at-40 ℃. The LDA solution was cooled to-78 deg.C and a solution of 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine (2.69g, 12.79mmol) in THF (15mL) was added slowly over 20 min. The dark red mixture was stirred at-78 ℃ for 1.5 h. A solution of triisopropyl borate (4.41mL, 19.19mmol) in THF (10mL) was added slowly. The resulting mixture was stirred at-78 ℃ for 30min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the brown-yellow mixture was quenched with 1N NaOH (aq) (15 mL). The separated aqueous layer was removed, and the flask was washed with 1N NaOH (aq) (2X 20mL), and the organic layer was extracted with 1N NaOH (2X 10 mL). The aqueous layer was collected and carefully acidified with 5N HCl until acidic (pH 5 to about 6). The aqueous layer was frozen and the water was removed by freeze drying. The mixture was diluted with 1: 1 MeOH/DCM and placed in the sonicator for 5 min. The mixture was filtered through a fine sintered funnel. The filtrate was concentrated in vacuo to give 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid (3.120g, 12.28mmol, 96% yield) as a yellow solid. ¹H NMR (400MHz, d4-MeOH) δ 8.00(dd, J ═ 8.22, 2.54Hz, 1H); 7.88(d, J ═ 2.35Hz, 1H); 3.68(t, J ═ 4.69Hz, 4H); 3.40-3.54(m, 1H); 2.56(d, J ═ 10.76Hz, 2H); 2.35-2.50(m, 2H); 1.41(t, J ═ 6.65Hz, 3H). M/z (ESI, cation) 255.1(M + H)⁺。

Examples 275 and 276: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine and 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

Step 1: 6- (2-fluoro-5- (1- (4-morpholinyl) ethyl) -3-pyridyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

In an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.245g, 0.346mmol) and potassium acetate (1.275g, 12.99mmol) at 120 deg.C, were added (1.100g, 4.33mmol) of (2-fluoro-5- (1- (4-morpholinyl) ethyl) -3-pyridinyl) boronic acid (6-chloro-N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (example 117; 1.828g, 4.76mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine)A mixture of alkane (3.2mL) and water (0.533mL) was stirred and heated for 15 min. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, pre-packed through a Redi-Sep silica gel column (120g), eluting with a gradient of 0% to 100% EtOAc in hexane to give 6- (2-fluoro-5- (1- (4-morpholinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.570g, 1.022mmol, 23.61% yield) as a pale yellow oil. ¹H NMR(400MHz，CDCl₃) δ 8.38-8.45(m, 1H); 8.14-8.19(m, 1H); 7.17(d, J ═ 8.61Hz, 4H); 6.82-6.88(m, 5H); 4.75(br s, 4H); 3.79(s, 6H); 3.69(ddd, J ═ 5.62, 3.77, 1.76Hz, 4H); 3.48(q, J ═ 6.72Hz, 1H); 2.62(s, 3H); 2.46-2.56(m, 2H); 2.33-2.42(m, 2H); 1.39(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 558.2(M + H)⁺。

Step 2: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1- (4-morpholinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

Lithium bis (trimethylsilyl) amide (1.0M solution in hexane, 0.592mL, 0.592mmol) was added to a solution of 6- (2-fluoro-5- (1- (4-morpholinyl) ethyl) -3-pyridyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.110g 0.197mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.042g, 0.296mmol, Anichem, North Brunswick, NJ) in THF (1.5mL) at-10 ℃. After 1h, more lithium bis (trimethylsilyl) amide (1.0M solution in hexanes, 0.592mL, 0.592mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.042g, 0.296mmol) were added. After another 1h, saturated NH was added₄Cl (aqueous solution). The mixture was extracted with EtOAc (3 ×). The combined organic layers were passed over anhydrous Na ₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, pre-packed with silica gel column (12g) via Redi-Sep, eluting with a gradient of 0% to 100% EtOAc in hexanes to give 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1- (4-morpholinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.104g, 0.153mmol, 78% yield) as a brown oil.¹H NMR(400MHz，CDCl³) δ 11.92(s, 1H); 8.26(dd, J ═ 12.72, 2.35Hz, 1H); 8.11(d, J ═ 2.15Hz, 1H); 8.02(d, J ═ 2.35Hz, 1H); 7.56-7.61(m, 1H); 7.18(dd, J ═ 8.61, 0.98Hz, 4H); 6.82-6.91(m, 4H); 6.53(s, 1H); 4.80(br s, 4H); 4.01(s, 3H); 3.79(s, 6H); 3.62(t, J ═ 4.69Hz, 4H); 3.30(q, J ═ 6.65Hz, 1H); 2.66(s, 3H); 2.39-2.47(m, 2H); 2.30-2.37(m, 2H); 1.31(d, J ═ 6.85Hz, 3H). M/z (ESI, cation) 680.2(M + H)⁺。

And step 3: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1S) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine and 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

Reacting 6- (2- ((5-fluoro-6-methoxy-3-pyridyl) amino) -5- (1- (4-)Morpholinyl) ethyl) -3-pyridyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.272g, 0.400mmol) in TFA (3mL) was treated with a few drops of trifluoromethanesulfonic acid and heated at 80 ℃ for 3 h. After cooling to room temperature, the reaction mixture was concentrated. Adding ice cubes and adding saturated NaHCO₃(aqueous solution) until the pH is about 7. The aqueous layer is replaced by CH₂Cl₂n-BuOH (3X) extraction. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was adsorbed onto a silica gel packed column and pre-filled with silica gel column (12g) by chromatography, via Redi-Sep, to dissolve in CH₂Cl₂To give 120mg of 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- (1- (4-morpholinyl) ethyl) -3-pyridinyl) -2-methyl-4-as a mixture of yellow solid enantiomers.¹H NMR (400MHz, d 6-DMSO). delta.12.21 (s, 1H); 8.33(dd, J ═ 13.01, 2.25Hz, 1H); 8.12-8.21(m, 2H); 7.96(d, J ═ 2.15Hz, 1H); 7.04(s, 2H); 6.79(s, 1H); 3.92(s, 3H); 3.57(t, J ═ 4.79Hz, 4H); 3.43(q, J ═ 6.65Hz, 1H); 2.51(s, 3H); 2.38-2.47(m, 2H); 2.27-2.36(m, 2H); 1.34(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 440.1(M + H) ⁾⁺。

Chromatography by SFC using a chiral pak AD-H column (250X 21mm, 5mm), column temperature 40 ℃ with 80/20 liquid CO₂The enantiomers were separated by elution with a mobile phase of/EtOH (0.2% DEA) at a flow rate of 70mL/min and an outlet pressure of 100 bar. These conditions provided the individual enantiomers with > 99% ee (calculated as peak area at 215 nm), using the following SFC conditions: chiral pak AD-H column (150X 4.6mm, 5mm), column temperature 40 ℃, eluting with 80/20 liquid CO2/EtOH (0.2% DEA) mobile phase, at a flow rate of 4.0mL/min and an outlet pressure of 100 bar. The absolute stereochemistry of the two enantiomers was deduced by a method similar to that of example 146.

Example 277: 4- (5- (2-Aminoprop-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (prop-1-en-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a sealed tube, isopropenylboronic acid pinacol ester (0.119mL, 0.633mmol, Aldrich, St. Louis, Mo.), potassium carbonate (0.175g, 1.267mmol), (Amphos)₂PdCl₂(0.022g, 0.032mmol) and 4: 1 bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 155, 0.185g, 0.317mmol) of 4- (5-chloro-2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine The alkane/water (2.5mL) mixture was heated for 24 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (25g column) using 0-30% EtOAc/hexanes. The fractions containing the product were concentrated to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (prop-1-en-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.171g, 0.290mmol, 92% yield) as an orange solid. M/z (ESI, cation) 590(M + H)⁺。 ¹H NMR(400MHz，CDCl₃)δ11.71(br.s.，1H)；8.94(s，1H)；8.44(d，J＝2.5Hz，1H)；8.27(d，J＝2.3Hz，1H)；7.91(br.s.，1H)；7.22range(m，4H)；6.86range(m，4H)；6.73(d，J＝9.0Hz，1H)；5.33(s，1H)；5.01(s，1H)；4.89(s，2H)；4.82(s，2H)；3.94(s，3H)；3.82(s，3H)；3.79(s，3H)；2.59(s，3H)；2.13(s，3H)。

Step 2: 4- (5- (2-azidopropan-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

At-15 ℃ at 10Within min, sodium azide (0.075g, 1.160mmol) and N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (prop-1-en-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.171g, 0.290mmol) in CHCl₃(1mL) slurry was made up with trifluoroacetic acid (0.223mL, 2.90mmol) in CHCl via syringe₃(1mL) solution treatment. The cooled reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction was sealed and heated at 60 ℃. After 2h, the reaction was poured onto ice and basified with 10N NaOH. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4- (5- (2-azidopropan-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.184g, 0.291mmol, 100% yield). M/z (ESI, cation) 633(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ11.67(br.s.，1H)；8.90(d，J＝2.7Hz，1H)；8.38(d，J＝2.5Hz，1H)；8.26(d，J＝2.5Hz，1H)；7.91(dd，J＝8.8，2.7Hz，1H)；7.18-7.26(m，4H)；6.81-6.94(m，4H)；6.73(d，J＝8.8Hz，1H)；4.90(s，2H)；4.81(s，2H)；3.94(s，3H)；3.82(s，3H)；3.78(s，3H)；2.59(s，3H)；1.64(s，6H)。

And step 3: 4- (5- (2-Aminoprop-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5- (2-azidopropan-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.184g, 0.291mmol) and 10% palladium on carbon (0.186g, 0.174mmol) were combined in a flask and flushed with nitrogen. THF (5mL) was added and the reaction was stirred under an atmosphere of H2 for 1.5H. The reaction was passed through Celite(celite) filtration, washing with DCM, and concentrating the filtrate in vacuo to give 4- (5- (2-aminopropyl-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -NN-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.176g, 0.290mmol, 100% yield). M/z (ESI, cation) 607(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.55(s，1H)；8.92(d，J＝2.7Hz，1H)；8.48(d，J＝2.5Hz，1H)；8.23(d，J＝2.5Hz，2H)；7.91(dd，J＝8.8，2.7Hz，1H)；7.15-7.25(m，4H)；6.78-6.95(m，4H)；6.69(d，J＝8.8Hz，1H)；4.89(s，2H)；4.81(s，2H)；3.92(s，3H)；3.81(s，3H)；3.77(s，3H)；2.58(s，3H)；1.53(s，6H)。

And 4, step 4: 4- (5- (2-Aminoprop-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (5- (2-aminopropan-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.025g, 0.041mmol) in TFA (1mL) was treated with trifluoromethanesulfonic acid (0.029mL, 0.330mmol), sealed and heated at 80 ℃ for 2 h. The reaction was cooled and treated with ice and 10N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO and purified by preparative HPLC (5-50% MeCN/H with 0.1% TFA) ₂O) purifying. Fractions containing the product were concentrated in vacuo to give 4- (5- (2-aminopropyl-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate as an orange solid (9mg, 0.019mmol, 45.5% yield). M/z (ESI, cation) 367(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.76(s，1H)；8.93(d，J＝2.7Hz，1H)；8.54(d，J＝2.5Hz，1H)；8.50(d，J＝2.7Hz，1H)；8.37(br.s.，3H)；8.13(dd，J＝8.8，2.7Hz，1H)；7.90(br.s.，1H)；7.80(br.s.，1H)；6.84(d，J＝9.0Hz，1H)；3.85(s，3H)；2.45(s，3H)；1.68(s，6H)。

Example 278: 4- (5- (2-Aminoprop-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared in analogy to the procedure described for example 277 using 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 313) in step 1 to give 4- (5- (2-aminopropyl-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (52%, 3 steps). M/z (ESI, cation) 385(M + H)⁺。 ¹H NMR(400MHz，d6-DMSO)δ11.90(s，1H)；8.98(d，J＝2.5Hz，1H)； 8.53(d，J＝2.5Hz，1H)；8.40(s，2H)；8.37(d，J＝2.2Hz，1H)；7.88(br.s.，1H)；7.73(br.s.，1H)；3.93(s，3H)；2.44(s，3H)；1.42(s，6H)。

Example 279: 4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a sealed vial 4- (5- (2-aminopropan-2-yl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 277, 0.176g, 0.290mmol) and 2, 2' - (methylsulfonyluretidioyl) bis (ethane-2, 1-diyl) dimesylate (Tetrahedron 1985, 41, 1959-1964; 0.118g, 0.348mmol) were combined in DIPEA (2mL) and heated at 130 ℃ overnight. Reacting the reactantsIn saturated NaHCO₃And DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25g column) using 0-100% EtOAc/hexanes to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.034g, 0.045mmol, 15.55% yield). M/z (ESI, cation) 754(M + H)⁺。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.034g, 0.045mmol) in trifluoroacetic acid (1mL) was treated with trifluoromethanesulfonic acid (0.032mL, 0.361 mmol). The light yellow reaction was sealed and heated at 80 ℃. After 30min, the reaction was cooled with ice and basified with 10N NaOH, then partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO and purified by preparative HPLC (5-70% MeCN/H with 0.1% TFA) ₂O) purifying. The fractions containing the product were concentrated and subsequently treated with NaHCO₃Saturated aqueous solution and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.006g, 0.012mmol, 25.9% yield) as a yellow solid. M/z (ESI, cation) 514(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.70(s，1H)；8.83(d，J＝2.5Hz，1H)；8.53(d，J＝2.7Hz，1H)；8.45(d，J＝2.5Hz，1H)；8.19(dd，J＝8.9，2.8Hz，1H)；7.61-7.93(m，2H)；6.81(d，J＝9.0Hz，1H)；3.84(s，3H)；3.01-3.16(m，4H)；2.86(s，3H)；2.48-2.63(m，4H)；2.44(s，3H)；1.36(s，6H)。

Example 280: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2- (4- (methylsulfonyl) piperazin-1-yl) propan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared as a yellow solid in analogy to the procedure described for example 279 using 4- (5- (2-aminopropan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 279) in step 1 (29% yield, 2 steps). M/z (ESI, cation) 532(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.91(s，1H)；8.86(d，J＝2.5Hz，1H)；8.51(d，J＝2.5Hz，1H)；8.37-8.45(m，2H)；7.88(br.s.，1H)；7.74(br.s.，1H)；3.93(s，3H)；3.09(m，4H)；2.86(s，3H)；2.51-2.58(m，4H)；2.44(s，3H)；1.37(s，6H)。

Example 281: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinylpropan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-morpholinopropionitrile

A solution of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (example 271, 0.564g, 0.925mmol) and morpholine (0.201mL, 2.313mmol) in DCM (4.5mL) was treated with titanium tetraisopropoxide (0.678mL, 2.3 mL)13 mmol). The reaction was sealed and stirred rapidly overnight. Aluminum diethylcyanide (1.0M in toluene; 2.313mL, 2.313mmol) was added and the reaction was resealed and stirred overnight. EtOAc was added followed by saturated NaHCO₃(carefully added). Exothermic and bubbling was observed, so the reaction was poured onto ice and washed with EtOAc and NaHCO₃And (4) treating with saturated aqueous solution. The aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-morpholinopropionitrile (0.650g, 0.921mmol, 100% yield) as a yellow solid. M/z (ESI, cation) 706(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.99(br.s.，1H)；9.00(d，J＝2.5Hz，1H)；8.50(d，J＝2.5Hz，1H)；8.03(dd，J＝12.1，2.2Hz，1H)；7.97(d，J＝2.2Hz，1H)；7.17-7.26(m，4H)；6.82-6.93(m，4H)；4.73-5.01(m，4H)；4.03(s，3H)；3.82(s，3H)；3.79(s，3H)；3.61-3.71(m，4H)；2.64-2.76(m，2H)；2.60(s，3H)；2.44-2.54(m，2H)；1.75(s，3H)。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinopropan-2-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-morpholinopropionitrile (0.500g, 0.708mmol) in THF (2mL) was treated with methylmagnesium bromide (3.0M in ether; 1.181mL, 3.54mmol) at 0 deg.C. After 10min the cooling bath was removed and the reactants were allowed to warm to ambient temperature. After a total of 2h, the reaction was cooled to 0 ℃ and ice and NH were attached with EtOAc (1mL)₄And (4) quenching by a saturated Cl aqueous solution. Reacting the mixture in saturated NH₄Partition between Cl and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 10-80% EtOAc/hexanes. Will contain the productThe fractions were concentrated to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinopropan-2-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.363g, 0.522mmol, 73.7% yield) as a yellow solid. M/z (ESI, cation) 695(M + H)⁺。 ¹H NMR(400MHz，CDCl₃)δ11.86(s，1H)；8.96(d，J＝2.5Hz，1H)；8.47(d，J＝2.5Hz，1H)；8.13(dd，J＝12.5，2.2Hz，1H)；7.91-8.01(m，1H)；7.17-7.26(m，4H)；6.75-6.96(m，4H)；4.89(s，2H)；4.84(s，2H)；4.02(s，3H)；3.82(s，3H)；3.79(s，3H)；3.55-3.65(m，4H)；2.59(s，3H)；2.42-2.51(m，4H)；1.35(s，6H)。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinylpropan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinylpropan-2-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.363g, 0.522mmol) dissolved in TFA (3mL) was treated with trifluoromethanesulfonic acid (0.232mL, 2.61 mmol). The reaction was sealed and heated at 80 ℃ for 30min, cooled and poured onto ice. The mixture was basified with 10N NaOH, and the reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO and purified by preparative HPLC (10-55% MeCN/H with 0.1% TFA)₂O) purifying. The product-containing fraction was treated with NaHCO₃Saturated aqueous solution and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-morpholinopropan-2-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.069g, 0.152mmol, 29.1% yield). M/z (ESI, cation) 455(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.91(s，1H)；8.90(d，J＝2.5Hz，1H)；8.48(d，J＝2.5Hz，1H)；8.33-8.44(m，2H)；7.88(br.s.，1H)；7.73(b r.s.，1H)；3.93(s，3H)；3.57(br.s.，4H)；2.44(s，3H)；2.36-2.43(m，4H)；1.35(s，6H)。

Example 282: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (4- (methylsulfonyl) piperazin-1-yl) methanone

A mixture of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (example 144, 1.00g, 1.731mmol), active manganese (IV) oxide (< 5 microns; 4.52g, 51.9mmol), sodium cyanide (0.053mL, 1.731mmol) and 1- (methylsulfonyl) piperazine (0.711g, 4.33mmol) in THF (15mL) was stirred rapidly under nitrogen for 72 h. The reaction was passed through Celite(celite) filtration, washing with 10% MeOH/DCM followed by EtOAc. The filtrate was concentrated and adsorbed onto 5g of silica gel and passed through an 80g column using 20-100% EtOAc/hexanes to give (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (4- (methylsulfonyl) piperazin-1-yl) methanone (0.352g, 0.476mmol, 27.5% yield) as a yellow foam. M/z (ESI, cation) 740(M + H)⁺。 ¹H NMR(400MHz，CDCl₃)δ12.02(s，1H)；8.91(d，J＝2.3Hz，1H)；8.42(d，J＝2.5Hz，1H)；8.29(d，J＝2.5Hz，1H)；7.90(dd，J＝8.8，2.7Hz，1H)；7.11-7.24(m，4H)；6.80-6.94(m，4H)；6.75(d，J＝9.0Hz，1H)；4.85(s，2H)；4.82(s，2H)；3.95(s，3H)；3.82(s，3H)；3.80(s，3H)；3.71-3.78(m，4H)；3.17-3.25(m，4H)；2.70(s，3H)；2.60(s，3H)。

Step 2: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) (4- (methylsulfonyl) piperazin-1-yl) methanone (0.163g, 0.220mmol) and titanium (IV) isopropoxide (0.194mL, 0.661mmol) in THF (2mL) was treated dropwise with ethylmagnesium bromide (1.0M solution in t-butyl methyl ether; 1.322mL, 1.322mmol) at 0 deg.C under nitrogen. The reaction was warmed to ambient temperature and an additional 3 equivalents of EtMgBr were added. After 1h, the reaction was quenched with ice and DCM and passed through Celite(celite) was filtered and washed with a sufficient amount of DCM. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange solid. The solid was absorbed in TFA (1.5mL) and 20 drops of TfOH were added from a Pasteur pipette. The resulting mixture was sealed and heated at 80 ℃ for 1 h. The reaction was cooled in an ice bath and treated with ice and 10N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO and purified by preparative HPLC (5-50% MeCN/H with 0.1% TFA) ₂O) purifying. The fractions containing the product were concentrated to give 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) cyclopropyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate (0.0063g, 10.07 μmol, 4.57% yield) as an orange solid. M/z (ESI, cation) 512(M + H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.80(s，1H)；8.68(d，J＝2.3Hz，1H)；8.52(d，J＝2.5Hz，1H)；8.27(d，J＝2.2Hz，1H)；8.16(dd，J＝8.8，2.7Hz，1H)；7.90(br.s.，1H)；7.74(br.s.，1H)；6.83(d，J＝8.8Hz，1H)；3.85(s，3H)；3.01-3.23(m，4H)；2.84(s，3H)；2.60-2.79(m，4H)；2.44(s，3H)；1.00-1.13(m，2H)；0.84-0.97(m，2H)。

Example 283: 6- (3- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine

Step 1: 3-bromo-5-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) pyrazin-2-amine

A mixture of 3-bromo-5-chloropyrazin-2-amine (780mg, 3.74mmol, Ark Phar.Inc., Libertyville, IL), 5-fluoro-6-methoxypyridin-3-ylboronic acid (1919mg, 11.23mmol, Anichem), N-diisopropylethylamine (1.953mL, 11.23mmol, Aldrich, St.Louis, MO) and copper (II) acetate (1.12g, 5.61mmol, Aldrich, St.Louis, MO) in dichloromethane (30mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 40 mL). The combined organic extracts were washed with saturated NaCl (20mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow solid. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 3-bromo-5-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) pyrazin-2-amine (218mg, 0.654mmol, 17.47% yield). ¹H NMR(300MHz，CDCl₃) δ 4.03(s, 3H)7.00(s, 1H)7.82(dd, J ═ 11.25, 1.75Hz, 1H)8.04(d, J ═ 9.06Hz, 2H). M/z (ESI, cation) 331.9(M + H)⁺。

Step 2: 5-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine

Will dissolve in II3-bromo-5-chloro-N- (5) in alkane (3mL)-fluoro-6-methoxypyridin-3-yl) pyrazin-2-amine (216mg, 0.648mmol), 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine (334mg, 0.777mmol), copper (I) iodide (25mg, 0.130mmol, Aldrich, st. louis, MO), cesium fluoride (197mg, 1.295mmol, Alfa Aesar) and tetrakis (triphenylphosphine) palladium (74.8mg, 0.065mmol, Strem) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (5mL) and CH₂Cl₂(2X 30 mL). The combined organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% EtOAc/CH₂Cl₂Purification by elution to give 5-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (176mg, 0.448mmol, 69.2% yield). ¹H NMR(300MHz，CDCl₃) δ 2.63(s, 3H)2.79(s, 3H)4.04(s, 3H)8.01-8.29(m, 4H)12.45(s, 1H). M/z (ESI, cation) 393.0(M + H)⁺。

And step 3: 1- (5- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone

Di-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (151mg, 0.384mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (36.6mg, 0.077mmol, Aldrich, St. Louis, MO), palladium diacetate (8.63mg, 0.038mmol, Aldrich, St. Louis, MO), copper (I) iodide (15mg, 0.077mmol, Aldrich, St. Louis, MO), cesium fluoride (117mg, 0.769mmol, Alfa Aesar) and tributyl (1-ethoxyvinyl) tin (0.195mL, 0.577mmol, Aldrich, St. Louis, MO) were reacted at 100 deg.CThe mixture of alkanes (3mL) was stirred for 18 h. The mixture was cooled to room temperature. Mixing the reactionThe material was diluted with water (10mL) and CH₂Cl₂(2X 30 mL). The combined organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 10% EtOAc/CH ₂Cl₂Purify by elution to give 1- (5- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone (102mg, 0.255mmol, 66.3% yield).¹H NMR(300MHz，CDCl₃) δ 2.66(s, 3H)2.71(s, 3H)2.81(s, 3H)4.05(s, 3H)8.04-8.33(m, 3H)8.92(s, 1H)12.99(s, 1H). M/z (ESI, cation) 401.0(M + H)⁺。

And 4, step 4: 1- (5- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) pyrazin-2-yl) ethanone

1- (5- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone (52mg, 0.130mmol) and 3-chloroperoxybenzoic acid (44.8mg, 0.260mmol, Aldrich, St. Louis, Mo.) in di (NThe mixture of alkanes (1mL) was stirred for 2 h. The mixture was used directly in the next step without work-up.

And 5: 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone

The reaction mixture from the above step was treated with aqueous ammonia (0.5mL, 23.11mmol, j.t. baker) (30% in water) and the mixture was stirred at 100 ℃ for 5 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 5% EtOAc/hexanes, to give 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone (18mg, 0.049mmol, 37.5% yield). ¹HNMR(300MHz，CDCl₃)δ2.67(s，3H)2.70(s，3H)4.05(s，3H)5.08(s，2H)7.53(s，1H)8.16(d，J ═ 2.19Hz, 1H)8.25(dd, J ═ 11.91, 2.12Hz, 1H)8.91(s, 1H)13.36(s, 1H). M/z (ESI, cation) 370.0(M + H)⁺。

Step 6: 6- (3- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine

A mixture of 1- (methylsulfonyl) piperazine (13.34mg, 0.081mmol, Apollo), 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone (15mg, 0.041mmol) and titanium (iv) isopropoxide (0.048mL, 0.162mmol, Aldrich, St.Louis, MO) in tetrahydrofuran (0.5mL) was stirred at 75 ℃ for 25 h. The mixture was cooled down to 20 ℃ and CH was added₂Cl₂(1mL) followed by sodium triacetoxyborohydride (34.4mg, 0.162 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with aqueous ammonia (3mL, 30% in water) and CH₂Cl₂(2X 20 mL). The combined organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purify by elution to give 6- (3- (5-fluoro-6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine (4.8mg, 9.27 μmol, 23% yield). ¹H NMR(300MHz，CDCl₃) δ 1.44(d, J ═ 6.58Hz, 3H)2.46-2.69(m, 7H)2.77(s, 3H)3.23(t, J ═ 4.24Hz, 4H)3.55(q, J ═ 6.77Hz, 1H)4.03(s, 3H)5.42(s, 2H)8.04(d, J ═ 2.19Hz, 1H)8.20-8.37(m, 2H)8.70(d, J ═ 1.90Hz, 1H)11.90(s, 1H). M/z (ESI, cation) 518.2(M + H)⁺。

Example 284: 2- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) propan-2-ol

A mixture of 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone (11mg, 0.030mmol) and a 3.0M solution of methylmagnesium bromide in diethyl ether (10.65. mu.L, 0.089mmol, Aldrich, St.Louis, Mo.) in tetrahydrofuran (1mL) was stirred at 0 ℃ for 30 min. The reaction mixture was diluted with saturated NH4Cl (5mL) and CH₂Cl₂(2X 10 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purify by elution to give 2- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (5-fluoro-6-methoxypyridin-3-ylamino) pyrazin-2-yl) propan-2-ol (8.5mg, 0.022mmol, 74.1% yield). ¹H NMR(300MHz，CDCl₃) δ 1.63(s, 6H)2.66(s, 3H)3.66(s, 1H)4.03(s, 3H)5.01(s, 2H)7.45(s, 1H)8.11(d, J ═ 1.90Hz, 1H)8.22(dd, J ═ 12.13, 2.05Hz, 1H)8.39(s, 1H)12.66(s, 1H). M/z (ESI, cation) 386.1(M + H)⁺。

Example 285: 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone

Step 1: 3-bromo-5-chloro-N- (6-methoxypyridin-3-yl) pyrazin-2-amine

A mixture of 3-bromo-5-chloropyrazin-2-amine (624mg, 2.99mmol, Ark Phar.Inc), 6-methoxypyridin-3-ylboronic acid (1374mg, 8.98mmol, combi.Blocks), copper (II) acetate (896mg, 4.49mmol, Aldrich, St.Louis, MO) and N, N-diisopropylethylamine (2.083mL, 11.97mmol, Aldrich, St.Louis, MO) in dichloromethane (20mL) was stirred at room temperature for 48 h. Passing the mixture through CeliteThe pad was filtered and washed with EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes, to give 3-bromo-5-chloro-N- (6-methoxypyridin-3-yl) pyrazin-2-amine (165mg, 0.523mmol, 17.47% yield).¹H NMR(300MHz，CDCl₃) δ 3.95(s, 3H)6.79(d, J ═ 8.77Hz, 1H)6.92(s, 1H)7.77(dd, J ═ 8.84, 2.41Hz, 1H)8.01(s, 1H)8.29(d, J ═ 2.05Hz, 1H). M/z (ESI, cation) 316.9(M + H) ⁺。

Step 2: 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine

Will dissolve in II3-bromo-5-chloro-N- (6-methoxypyridin-3-yl) pyrazin-2-amine (83mg, 0.263mmol), copper (I) iodide (10mg, 0.053mmol, Aldrich), cesium fluoride (80mg, 0.526mmol, Alfa Aesar), tetrakis (triphenylphosphine) palladium (0) (30.4mg, 0.026mmol) and 2-methyl-4- (methylthio) -6- (tributylstannyl) pyrimidine (113mg, 0.263mmol) in an alkane (2mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys Optizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Ussala, Sweden) at 140 ℃ for 30 min. The reaction mixture was diluted with water (10mL) and CH₂Cl₂(2X 30 mL). The combined organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give 5-chloro-N- (6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (72mg, 0.192mmol, 73.0% yield).¹H NMR(300MHz，CDCl₃) δ 2.63(s, 3H)2.78(s, 3H)3.95(s, 3H)6.79(d, J-8.77 Hz, 1H)8.01(dd, J-8.70, 2.12Hz, 1H)8.17(d, J-5.55 Hz, 2H)8.39(s, 1H)12.21(s, 1H). m/z (ESI, cation) 375.0 (C.), ( M+H)⁺。

And step 3: 1- (5- (6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone

5-chloro-N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-amine (30mg, 0.080mmol), 2- (dicyclohexylphosphino) -2 ', 4 ', 6 ', -triisopropyl-biphenyl (7.63mg, 0.016mmol, Al drich), copper (I) iodide (17mg, 0.016mmol, Aldrich), palladium diacetate (1.8mg, 8.00. mu. mol, Aldrich), cesium fluoride (15mg, 0.160mmol, Alfa Aesar) and tributyl (1-ethoxyvinyl) tin (0.041mL, 0.120mmol, Aldrich) were combined at 100 deg.CThe mixture of alkanes (2mL) was stirred for 18 h. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2X 20 mL). The combined organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 10% EtOAc/CH₂Cl₂Purify by elution to give 1- (5- (6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone (19mg, 0.050mmol, 62.1% yield).¹H NMR(300MHz，CDCl₃) δ 2.66(s, 3H)2.71(s, 3H)2.80(s, 3H)3.96(s, 3H)6.82(d, J ═ 8.92Hz, 1H)8.14(dd, J ═ 8.92, 2.78Hz, 1H)8.25(s, 1H)8.45(d, J ═ 2.63Hz, 1H)8.91(s, 1H)12.79(s, 1H). M/z (ESI, cation) 383.0(M + H) ⁺。

And 4, step 4: 1- (5- (6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylsulfinyl) pyrimidin-4-yl) pyrazin-2-yl) ethanone

1- (5- (6-methoxypyridin-3-ylamino) -6- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyrazin-2-yl) ethanone (25mg, 0.065mmol) and 3-chloroperoxybenzoic acid (22.5mg, 0.131mmol, Aldrich) in dioxane at room temperatureThe mixture of alkanes (1mL) was stirred for 2 h. The reaction mixture was used directly in the next step without work-up.

And 5: 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone

The reaction mixture from the above step was treated with aqueous ammonia (0.5mL, 30% in water, j.t. baker). The reaction mixture was stirred at 100 ℃ for 4 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purify by elution to give 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone (16mg, 0.046mmol, 69.8% yield).¹H NMR(300MHz，CDCl₃) δ 2.66(s, 3H)2.70(s, 3H)3.96(s, 3H)5.10(s, 2H)6.81(d, J ═ 8.77Hz, 1H)7.53(s, 1H)8.09(s, 1H)8.15(dd, J ═ 8.62, 2.34Hz, 1H)8.46(d, J ═ 2.48Hz, 1H)8.88(s, 1H)13.14(s, 1H). M/z (ESI, cation) 352.1(M + H) ⁺。

Example 286: 6- (3- (6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine

A mixture of 1- (methylsulfonyl) piperazine (5.61mg, 0.034mmol, Apollo), 1- (6- (6-amino-2-methylpyrimidin-4-yl) -5- (6-methoxypyridin-3-ylamino) pyrazin-2-yl) ethanone (6mg, 0.017mmol) and titanium tetraisopropoxide (19.41mg, 0.068mmol, Aldrich) in tetrahydrofuran (0.5mL) was stirred at 75 ℃ for 48 h. The mixture was cooled down to 20 ℃ and CH was added₂Cl₂(1mL) followed by sodium triacetoxyborohydride (14.48mg, 0.068 mmol). The reaction mixture was stirred at room temperature for 5 h. Ammonia (1mL, 30% in water) was added and the mixture was washed with CH₂Cl₂(2×10mL) extracting. The combined organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purify by elution to give 6- (3- (6-methoxypyridin-3-ylamino) -6- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyrazin-2-yl) -2-methylpyrimidin-4-amine (5.2mg, 10.41 μmol, 61.0% yield).¹H NMR(300MHz，CDCl₃) δ 1.48(d, J ═ 6.87Hz, 3H)2.64(s, 3H)2.78(s, 4H)3.14-3.40(m, 4H)3.81(q, J ═ 6.72Hz, 1H)5.10(s, 2H)6.78(d, J ═ 8.77Hz, 1H)7.46(s, 1H)8.08(dd, J ═ 8.84, 2.70Hz, 1H)8.20(s, 1H)8.43(d, J ═ 2.63Hz, 1H). M/z (ESI, cation) 500.1(M + H) ⁺。

Example 287: (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine

Step 1: (E) -2- (3, 3-diethoxyprop-1-enyl) -1-fluoro-3-nitrobenzene

Will dissolve in II3, 3-diethoxy-1-propenylboronic acid pinacol ester (0.154mL, 0.600mmol, Frontier Scientific), 2-bromo-1-fluoro-3-nitrobenzene (110mg, 0.500mmol, Aldrich), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (40.8mg, 0.050mmol, Strem), and cesium carbonate (326mg, 1.00mmol, Aldrich) in alkane (3mL) and water (0.5mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an emryoptimizer microwave reactor (Personal Chemistry, Biotange AB, inc., Upssanlan, Sweden) at 120 ℃ for 20 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 20 mL). To be combinedThe organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give a crude material. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give (E) -2- (3, 3-diethoxyprop-1-enyl) -1-fluoro-3-nitrobenzene (82mg, 0.305mmol, 60.9% yield). ¹H NMR(300MHz，CDCl₃) δ 1.26(t, J ═ 7.02Hz, 6H)3.45-3.81(m, 4H)5.09(d, J ═ 4.09Hz, 1H)6.16-6.37(m, 1H) 6.76(d, J ═ 17.25Hz, 1H)7.29-7.53(m, 2H)7.57-7.75(m, 1H). M/z (ESI, cation) 270(M + H)⁺。

Step 2: (E) -3- (4-bromo-2-fluoro-6-nitrophenyl) propenal

A mixture of (E) -2- (3, 3-diethoxyprop-1-enyl) -1-fluoro-3-nitrobenzene (63.5mg, 0.22mmol), 1, 3-dibromo-5, 5-dimethylhydantoin (63.5mg, 0.222mmol, Aldrich) and 95% sulfuric acid (0.5mL, 7.14mmol) was stirred at room temperature for 4 h. Ice (5g) was added and the mixture was extracted with EtOAc (2X 20 mL). The combined organic extracts were washed with saturated NaCl (6mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give (E) -3- (4-bromo-2-fluoro-6-nitrophenyl) acrolein (46mg, 0.168mmol, yield 39.3%).¹H NMR(300MHz，CDCl₃) δ 7.47-7.58(m, 1H)7.58-7.71(m, 1H)8.10(d, J ═ 8.33Hz, 1H)8.15(s, 1H)9.50(s, 1H). M/z (ESI, cation) 273(M + H)⁺。

And step 3: 7-bromo-5-fluoroquinolines

(E) -3- (4-bromo-2-fluoro-6-nitrophenyl) acrolein (35mg, 0.128mmol), iron powder (0.018mL, 2.55mmol, Aldrich), and ammonium chloride (6.83mg, 0.128mmol, Aldrich) in ethanol (1mL) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an Emrys optizer microwave reactor (Personal Chemistry, Biotange AB, inc., Upssanlan, Sweden) at 120 ℃ for 5 min. Passing the mixture through Celite The pad was filtered and washed with EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc in hexanes, to give 7-bromo-5-fluoroquinoline (16mg, 0.071mmol, 55.4% yield).¹H NMR(300MHz，CDCl₃)7.20-7.34(m, 1H)7.59-7.74(m, 1H)7.90(d, J ═ 8.48Hz, 1H)8.58(d, J ═ 1.61Hz, 1H)8.95(d, J ═ 2.34Hz, 1H). M/z (ESI, cation) 227.9(M + H)⁺。

And 4, step 4: n- (diphenylmethylene) -5-fluoroquinolin-7-amines

7-bromo-5-fluoroquinoline (128mg, 0.566mmol), benzophenone imine (0.143mL, 0.849mmol, Aldrich), Pd (dba) at 110 deg.C₂A mixture of (32.6mg, 0.057mmol, Strem), 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (70.5mg, 0.113mmol, Aldrich) and sodium 2-methylpropan-2-olate (82mg, 0.849mmol, Aldrich) in toluene (4mL) was stirred for 5 h. The mixture was cooled to room temperature. The reaction mixture was washed with saturated NH₄Cl (10mL) was diluted and extracted with EtOAc (2X 40 mL). The combined organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow solid, which was used in the next step without purification.

And 5: 5-fluoroquinolin-7-amines

A mixture of N- (diphenylmethylene) -5-fluoroquinolin-7-amine (185mg, 0.566mmol) and hydrochloric acid (1.132mL, 1.132mmol) in THF (5mL) was stirred at room temperature for 3 h. The reaction mixture was washed with saturated NaHCO₃Diluted (5mL) and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (5mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow oil. The crude product was purified by silica gel chromatography, eluting with 80% EtOAc in hexanes, to give 5-fluoroquinolin-7-amine (82mg, 0.506mmol, 89% yield).¹H NMR(300MHz，CDCl₃)δ4.02(s，2H)711(dd, J ═ 9.65, 8.18Hz, 1H)7.29-7.40(m, 1H)7.45(d, J ═ 2.48Hz, 1H)7.76(d, J ═ 8.48Hz, 1H)8.53(d, J ═ 2.78Hz, 1H). M/z (ESI, cation) 163.1(M + H)⁺。

Step 6: (R) -N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine

A mixture of (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 146, step 6) (140mg, 0.220mmol), 5-fluoroquinolin-7-amine (35.7mg, 0.220mmol) and lithium bis (trimethylsilyl) amide (1.0M in THF; 0.661mL, 0.661mmol, Aldrich) in THF (3mL) was stirred at 0 deg.C for 1 h. The reaction mixture was washed with saturated NH ₄Cl (10mL) was diluted and extracted with EtOAc (2X 30 mL). The organic extracts were washed with saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was purified by silica gel chromatography eluting with EtOAc to give (R) -N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine (122mg, 0.157mmol, 71.2% yield).¹H NMR(300MHz， CDCl₃) δ 1.40(d, J ═ 6.72Hz, 3H)2.57(dd, J ═ 11.91, 4.17Hz, 4H)2.65(s, 3H)2.67(s, 3H)3.07-3.24(m, 4H)3.81(s, 3H)4.76-4.98(m, 4H)6.86(dd, J ═ 12.28, 8.62Hz, 4H)7.11-7.25(m, 9H)7.38-7.52(m, 1H)7.82(d, J ═ 8.48Hz, 1H)8.42(d, J ═ 2.19Hz, 1H)8.77(d, J ═ 2.34Hz, 1H)8.91(d, J ═ 2.49, 1H)9.14 Hz, 1H (d, 1H) 1.05H, 1H). M/z (ESI, cation) 778.1(M + H)⁺。

And 7: (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine

The (R) -N- (3- (4- (bi (4-methoxy benzyl) amino) -6-methyl-1,3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine (82mg, 0.105mmol) and trifluoroacetic acid (1mL, 13.46mmol, Aldrich) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in an oil bath at 75 ℃ for 14 h. The solvent was removed in vacuo. The residue was taken up in 10% MeOH/CH ₂Cl₂(40 mL). The reaction mixture was washed with saturated NaHCO₃(10mL), saturated NaCl (10mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purification by elution to give (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoroquinolin-7-amine (33mg, 0.061mmol, 58.2% yield).¹H NMR(300MHz，CDCl₃) δ 1.47(d, J ═ 6.72Hz, 3H)2.52-2.72(m, 7H)2.78(s, 3H)3.25(t, J ═ 4.17Hz, 4H)3.60(q, J ═ 6.53Hz, 1H)5.49(s, 2H)7.12-7.24(m, 1H)7.39-7.54(m, 1H)7.83(d, J ═ 8.33Hz, 1H)8.48(d, J ═ 2.19Hz, 1H)8.77(d, J ═ 2.05Hz, 1H)8.96(d, J ═ 2.34Hz, 1H)9.25(d, J ═ 1.90Hz, 1H)12.51(s, 1H). M/z (ESI, cation) 538.1(M + H)⁺。

Example 288: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Step 1: 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid

A stirred solution of diisopropylamine (2.152mL, 15.35mmol) in tetrahydrofuran (20mL) was treated with 1.6M n-butyllithium (9.60mL, 15.35mmol) in hexane at-40 ℃. The yellow solution was stirred at the same temperature for 1h and then cooled to-78 ℃. 4- (1- (6-Fluoropyridin-3-yl) ethyl) morpholine (2.69g, 12) was added via cannula over 20min 79mmol) in THF (15 mL). The dark red mixture was stirred at the same temperature for 1.5 h. Subsequently, a solution of triisopropyl borate (4.41mL, 19.19mmol) in THF (10mL) was slowly added to the mixture. The resulting mixture was stirred at the same temperature for 30min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the brown-yellow mixture was quenched with 1N NaOH (aq) (15mL) and stirred. The separated aqueous layer was removed, and the flask was washed with 1N NaOH (aq) (2X 20mL), and the organic layer was extracted with 1N NaOH (2X 10 mL). The aqueous layer was collected and carefully acidified with 5N HCl until acidic (pH 5 to about 6) and the resulting cloudy mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The product remained in the aqueous layer. The aqueous layer was frozen and the water was removed by freeze drying. The mixture was diluted with 1: 1 MeOH/DCM and placed in the sonicator for 5 min. The mixture was filtered through a fine fritted funnel and the filtrate was concentrated in vacuo to give 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid (3.120g, 12.28mmol, 96% yield) as a yellow solid.¹H NMR(400MHz，d₄-MeOH) δ 8.00(dd, J ═ 8.22, 2.54Hz, 1H)7.88(d, J ═ 2.35Hz, 1H)3.68(t, J ═ 4.69Hz, 4H)3.40-3.54(m, 1H)2.56(d, J ═ 10.76Hz, 2H)2.35-2.50(m, 2H)1.41(t, J ═ 6.65Hz, 3H). M/z (ESI, cation) 255.1(M + H) ⁺。

Step 2: 4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.433g, 1.126mmol), 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid (0.260g, 1.023mmol), potassium acetate (0.308g, 3.14mmol), Am-Phos (0.051g, 0.082mmol), bisAlkane (3mL) and water (0.5mL, 27.8mmol) were charged to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a CEM Explorer microwave apparatus for 10min at 120 ℃ while passing through Powermax(simultaneous heating and cooling technique) 100 watts of energy was supplied. The reaction mixture was diluted with saturated sodium bicarbonate (10mL) and extracted with chloroform (3X 10 mL). The organic extracts were combined and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was adsorbed onto a silica gel packed column and chromatographed via a silica gel column (40 g) eluting with 50% ethyl acetate/hexanes to give 4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.300g, 0.537mmol, 52.5% yield) as a pale yellow oil. ¹H NMR(400MHz，d₆-DMSO) δ 8.46(d, J ═ 9.59Hz, 1H)8.31(d, J ═ 1.57Hz, 1H)7.25(d, J ═ 7.63Hz, 4H)6.90(dd, J ═ 10.27, 8.71Hz, 4H)4.77(d, J ═ 13.30Hz, 3H)3.66-3.79(m, 6H)3.47-3.61(m, 5H)3.36(s, 4H)3.18(d, J ═ 5.09Hz, 1H)2.49-2.53(m, 3H)2.40(s, 2H)2.14-2.34(m, 2H). M/z (ESI, cation) 559.2(M + H)⁺。

And step 3: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.300g, 0.537mmol) and benzo [ d [ -d ] in a suitable solvent]A mixture of thiazol-5-amine (0.202g, 1.343mmol) in THF (10mL) was chilled to 0 deg.C. Subsequently, sodium bis (trimethylsilyl) amide (1.0M solution in THF, Aldrich; 2.148mL, 2.148mmol) was added to the mixture via syringe. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The reaction mixture was diluted with water (30mL) and the organic layer was extracted with chloroform (3X 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude bis-PMB protected product as a tan oil. This crude material was treated with trifluoroacetic acid (1.8mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was placed in a pre-heat bath (70 ℃) and allowed to stir for 10min under an inert atmosphere. Mixing the mixture with a solvent The heat source was removed and allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (10mL) and then sodium carbonate (1.5g) was added to the mixture with stirring. The mixture was filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Varian, 5-70% acetonitrile in water with trifluoroacetic acid as additive, 0.1% v/v in each solvent) to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-yl) benzo [ d [ -d ] as a tan solid]Thiazol-5-amine (0.015g, 0.033mmol, 6.23% yield).¹H NMR(400MHz，d₆-DMSO) δ 12.24(s, 1H)9.36(s, 1H)8.92(s, 1H)8.75(s, 1H)8.36(s, 1H)8.06(d, J ═ 8.61Hz, 1H)7.92(s, 1H)7.82(d, J ═ 8.61Hz, 2H)3.57(s, 4H) 3.29-3.46(m, 1H)2.50(d, J ═ 7.82Hz, 5H)2.34(s, 2H)1.36(d, J ═ 6.46Hz, 3H). M/z (ESI, cation) 449.1(M + H)⁺。

Example 289: 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (benzo [ d ] thiazol-5-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide

Step 1: 5- (1-bromoethyl) -2-fluoropyridine

A mixture of 6-fluoronicotinaldehyde (10.000g, 80mmol) in THF (300mL) was chilled to-10 ℃ in a dry ice/acetone bath, followed by the addition of methylmagnesium bromide (3M solution in ether, Aldrich; 27.4mL, 82mmol) to the reaction mixture via addition funnel. After addition, the ice bath was removed and the reaction mixture was stirred for 45min under an inert atmosphere. The mixture was chilled to-10 ℃ in a dry ice/acetone bath, followed by slow addition of methanesulfonyl chloride (6.50mL, 84mmol) to the reaction mixture via syringe. After addition, the ice bath was removed and the reaction mixture was stirred under an inert atmosphere for 2 h. The reaction mixture was quenched with water (100mL) and diluted with chloroform (300 mL). The organic layer was extracted with chloroform (3X 50 mL). To be combined with The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 5- (1-bromoethyl) -2-fluoropyridine as a tan oil (16.31g, 80mmol, 100% yield). This material was immediately sent to the next step of the synthesis to prevent decomposition.¹H NMR(400MHz，CDCl₃) δ 8.25(d, J ═ 2.35Hz, 1H)7.93(td, J ═ 8.02, 2.54Hz, 1H)6.90-7.11(m, 1H)5.21(q, J ═ 6.85Hz, 1H)2.06(d, J ═ 7.04Hz, 3H). M/z (ESI, cation) 205.9(M + H)⁺。

Step 2: 4- (1- (6-Fluoropyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

A mixture of 5- (1-bromoethyl) -2-fluoropyridine (17.65g, 87mmol) and piperazine-1-carboxylic acid tert-butyl ester (16.92g, 91mmol) in acetonitrile (300mL) was treated with potassium carbonate (14.35g, 104mmol) and potassium iodide (2.87g, 17.30 mmol). The mixture was placed in a preheated (70 ℃) bath and allowed to stir under an inert atmosphere overnight. The reaction mixture was diluted with chloroform (200mL) and water (100 mL). The organic layer was extracted with chloroform (3X 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (330g), eluting with 50% ethyl acetate/hexanes, to give tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (17.27g, 55.8mmol, 64.5% yield) as a yellow oil. M/z (ESI, cation) 310.1(M + H) ⁺。

And step 3: 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid

A solution of tert-butyl 4- (1- (6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (8.41g, 27.2mmol) in tetrahydrofuran (100mL) was chilled to-78 ℃ in a dry ice/acetone bath. Subsequently, n-butyllithium (1.6M in hexane; Aldrich; 18.69mL, 29.9mmol) was added to the mixture via cannula. The dark red solution was stirred for 1h at the same temperature, followed by the addition of triisopropyl borate (7.50mL, 32.6mmol) to the mixture. The resulting mixture was stirred at the same temperature (-78 ℃) for 30min, after which the ice bath was removed. After the reaction mixture had warmed to room temperature, brownThe yellow mixture was quenched with 1N NaOH (aq) (50mL) and stirred for 10 min. The separated aqueous layer was collected and the round bottom flask was washed with 1N NaOH (aq) (2X 10 mL). The aqueous layer was carefully acidified with 10% HCl until acidic (about pH 5 to 6) and the resulting cloudy mixture was extracted with 3: 1 dichloromethane/methanol (3X 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (5.507g, 15.59mmol, 57.4% yield) as a tan solid. ¹H NMR(400MHz，d₆-DMSO) δ 7.79-8.70(m, 2H)3.66(t, J ═ 6.36Hz, 1H)3.34(s, 4H)2.56(s, 3H)2.39(s, 4H)1.26-1.51(m, 12H). M/z (ESI, cation) 354.2(M + H)⁺。

And 4, step 4: 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

Will dissolve in II4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.140g, 5.56mmol) and 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (4.12g, 11.68mmol) in an alkane (25mL) were charged to a glass microwave reaction vessel. Subsequently, A-Phos (0.394g, 0.556mmol), potassium acetate (1.637g, 16.68mmol) and water (3mL) were added to the reaction mixture. The reaction mixture was stirred and heated in a CEM Voyager Microwave (large scale apparatus) at 120 ℃ for 20 min (160 watts, enabling Powermax characteristics). The mixture was diluted with dichloromethane (20mL), water (20mL) and brine solution (10 mL). The organic layer was collected by extraction with dichloromethane (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude product as a tan oil. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, through a silica gel column (220g), eluting with 100% ethyl acetate, to give 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridine as a tan solid -3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (3.65g5.55mmol, 99% yield).¹H NMR(400MHz，d₆-DMSO) δ 8.47(dd, J ═ 9.39, 2.35Hz, 1H)8.31(d, J ═ 1.57Hz, 1H)7.26(dd, J ═ 8.61, 3.33Hz, 4H)6.90(dd, J ═ 12.42, 8.71Hz, 4H)4.78(d, J ═ 12.91Hz, 4H)3.74(d, J ═ 8.02Hz, 6H)3.70(d, J ═ 6.85Hz, 1H)3.28(d, J ═ 6.06Hz, 4H)2.50-2.53(m, 3H)2.21-2.39(m, 4H)1.37(d, J ═ 1.76Hz, 15H). M/z (ESI, cation) 658.3(M + H)⁺。

And 5: n- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (3.65g, 5.55mmol) and trifluoroacetic acid (6.41mL, 83mmol) in dichloroethane (30mL) were charged to a glass microwave reaction vessel (80 mL). The reaction mixture was stirred and heated at 80 ℃ for 5min in a CEM Voyager type (large apparatus) microwave (100 Watts, enabling Powermax characteristics). The mixture was added to a round bottom flask and concentrated in vacuo. The crude residue was diluted with THF (10mL) and then benzo [ d ] was added with stirring ]Thiazol-5-amine (0.539g, 3.59mmol) was added to the reaction mixture. The mixture was chilled to 0 ℃ in an ice bath followed by the slow addition via syringe of sodium bis (trimethylsilyl) amide (1.0M in THF, Aldrich; 5.74mL, 5.74mmol) to the mixture. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The reaction mixture was diluted with saturated sodium bicarbonate (10mL) and extracted with chloroform (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a brown-yellow oil. The crude material was adsorbed onto a silica gel packed column and purified by chromatography over a silica gel column (80g) eluting with a 20% mixture of 10: 1 methanol and ammonium hydroxide/dichloromethane to give N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d [ -j (t-butyl) ethyl ] benzyl) acetate as a tan oil]Thiazol-5-amine (0.651g, 0.946mmol, 66.0% yield)。¹H NMR(400MHz，CDCl₃) δ 12.06(s, 1H)8.96(s, 1H)8.74(d, J ═ 2.54Hz, 1H)8.63(d, J ═ 1.96Hz, 1H)8.31(d, J ═ 2.35Hz, 1H)8.12(d, J ═ 1.76Hz, 1H)7.78(td, J ═ 8.12, 2.35Hz, 1H)7.60(dd, J ═ 8.61, 1.96Hz, 1H)7.14-7.28(m, 4H)6.80-6.91(m, 4H)4.76-4.91(m, 4H)3.72-3.82(m, 6H)3.37-3.51(m, 1H)2.86(dt, J ═ 12.67, 4.72, 4H) 2.55H (m, 2.55H) 2.32H (m, 2H) 2.32H). M/z (ESI, cation) 688.2(M + H) ⁺。

Step 6: 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (benzo [ d ] thiazol-5-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide

Reacting N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d]A mixture of thiazol-5-amine (0.300g, 0.436mmol) in dichloromethane (10mL) was chilled to 0 ℃ in an ice bath, and triethylamine (0.304mL, 2.181mmol) was added to the mixture. After 10min, dimethylcarbamoyl chloride (Aldrich; 0.141g, 1.308mmol) was added dropwise to the mixture via syringe. After addition, the ice bath was removed and the mixture was stirred overnight under an inert atmosphere. The mixture was diluted with chloroform (20mL) and water (10 mL). The organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and pre-filled with silica gel column (40g) by chromatography via SiliCycle siliasecep to dissolve in CH₂Cl₂Purified eluting with 20% MeOH to give urea as a tan oil. This material was diluted with trifluoroacetic acid (1.803mL, 23.40mmol) and stirred for 5 min. Subsequently, trifluoromethanesulfonic acid (0.214mL, 2.406mmol) was added to the mixture. The reaction mixture was placed in a preheated (70 ℃) bath and allowed to stir for 10min under an inert atmosphere. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The residue was diluted with dichloromethane (10mL) and then sodium carbonate (2.0g) was added to the mixture with stirring. After 5min, methanol (5mL) was added to the mixture and allowed to stir for 20 min. The mixture was filtered and vacuum And (5) concentrating. The mixture was recrystallized from ethyl acetate/diethyl ether. This gave 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (benzo [ d ] a yellow solid]Thiazol-5-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide (0.070g, 0.135mmol, 61.7% yield).¹H NMR(400 MHz，d₆-DMSO) δ 12.24(s, 1H)9.36(s, 1H)8.92(s, 1H)8.37(s, 1H)7.91(s, 1H)8.05(s, 1H)7.83(s, 2H)3.53(m, 1H)3.10(s, 4H)2.70(s, 6H)2.43-2.55(m, 3H)2.36(d, J ═ 4.50Hz, 4H)1.38(d, J ═ 6.06Hz, 3H). M/z (ESI, cation) 519.1(M + H)⁺。

Example 290: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Step 1: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Reacting N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d]A stirred mixture of thiazol-5-amine (0.350g, 0.509mmol) in dichloromethane (10mL) was treated with triethylamine (0.355mL, 2.54 mmol). After 10min, methanesulfonyl chloride (Aldrich; 0.119mL, 1.526mmol) was added slowly to the mixture via syringe. After addition, the reaction mixture was placed in a preheated (70 ℃) bath and allowed to stir for 1.5h under an inert atmosphere. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was diluted with chloroform (20mL) and water (10mL), and the organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (40g) eluting with 20% methanol/dichloromethane to give the bis-PMB as a tan oil And (4) protecting the material. This material was diluted with trifluoroacetic acid (1.8mL, 23.36mmol) and allowed to stir for 5 min. Subsequently, trifluoromethanesulfonic acid (0.2mL, 2.252mmol) was added to the mixture. The mixture was placed in a preheated (70 ℃) bath and allowed to stir for 10min under an inert atmosphere. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The mixture was diluted with dichloromethane (10mL) and sodium carbonate (1.00g) was added to the mixture, which was then allowed to stir for 5 min. Subsequently, methanol (3mL) was added to the mixture and allowed to stir for 20 min. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was recrystallized from ethyl acetate/diethyl ether to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] as a tan solid]Thiazol-5-amine (0.035g, 0.067mmol, 17.71% yield).¹H NMR(400MHz，d₆-DMSO) δ 12.23(s, 1H)9.36(s, 1H)8.92(s, 1H)8.74(s, 1H)8.39(s, 1H)8.05(s, 1H)7.91(s, 1H)7.79(m, 2H)3.59(m, 1H)3.10(s, 4H)2.86(s, 3H)2.50(d, J ═ 8.80Hz, 4H)1.99(s, 3H)1.38(d, J ═ 6.06Hz, 3H). M/z (ESI, cation) 526.0(M + H)⁺。

Examples 291 and 292: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The isomeric mixture of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine was prepared by a procedure similar to example 288 using 2-methoxy-3-fluoro-5-aminopyridine instead of benzo [ d ] thiazol-5-amine in step 2. Chiral SFC preparative chromatography was used to separate the isomers. The following conditions were used:

column: chiralcel OJ-H (3X 15cm)

A: liquid CO₂

B: 25% 1: 1 Heptane: ethanol (0.2% DEA), isocratic

Flow rate: 80mL/min, 220 nm.

The two separate peaks containing the two enantiomers were collected, concentrated and dried under high vacuum to give the two enantiomers. Absolute stereochemistry was not determined.

First elution peak: (isomer 1; example 291)

¹H NMR(400MHz，CDCl₃) δ 11.90(s, 1H)8.73(d, J ═ 2.35Hz, 1H)8.29(td, J ═ 6.16, 2.15Hz, 2H)8.04(d, J ═ 2.15Hz, 1H)5.52(s, 2H)4.02(s, 3H)3.71(t, J ═ 4.60Hz, 4H)3.40(q, J ═ 6.72Hz, 1H)2.57(s, 3H)2.51(s, 2H)2.39-2.45(m, 2H)1.41(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 441.1(M + H)⁺。

Second elution peak: (isomer 2; example 292)

¹H NMR(400MHz，CDCl₃) δ 11.91(s, 1H)8.72(d, J ═ 2.35Hz, 1H)8.26-8.31(m, 2H)8.04(d, J ═ 2.35Hz, 1H)5.65(s, 2H)4.03(s, 3H)3.69-3.76(m, 4H)3.39(q, J ═ 6.65Hz, 1H)2.49-2.60(m, 5H)2.39-2.48(m, 2H)1.42(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 441.1(M + H) ⁺。

Example 293: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Step 1: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methylpiperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

(S) -tert-butyl 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylate (0.300g, 0.447mmol) and benzo [ d [ -d]A mixture of thiazol-5-amine (0.101g, 0.670mmol) in THF (10mL) was chilled to 0 deg.C in an ice bath, then sodium bis (trimethylsilyl) amide (1.0M in THF, Aldrich; 1.563mL, 1.563mmol) was added slowly to the mixture via syringe. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The reaction mixture was diluted with saturated sodium bicarbonate (10mL) and extracted with chloroform (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as a brown-yellow oil. The crude material was adsorbed onto silica gel and purified by chromatography through a silica gel column (40g) eluting with 100% ethyl acetate to give the bis-PMB protected material as a tan oil (0.056 g). The crude residue was diluted with trifluoroacetic acid (0.9mL) and trifluoromethanesulfonic acid (0.1 mL). The mixture was placed in a preheated (70 ℃) bath and allowed to stir for 10min under an inert atmosphere. The mixture was removed from the heating bath and allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The mixture was diluted with DCM (10mL) and stirred while sodium carbonate (1.0g) was slowly added to the mixture. After 2min, methanol (3mL) was added to the mixture and allowed to stir for an additional 20 min. The mixture was filtered through a fine sintered funnel. The organic layer was concentrated in vacuo. This gives N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methylpiperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] a yellow solid ]Thiazol-5-amine (0.206g, 0.446mmol, 100% yield).¹H NMR(300MHz，CDCl₃) δ 12.06(s, 1H)8.98(s, 1H)8.74(d, 1H)8.66(s, 1H)8.31(d, 1H)7.36range (m, 1H)5.44(s, 2H)2.61(s, 9H)1.52(s, 3H)1.25(s, 6H). M/z (ESI, cation) 462.1(M + H)⁺。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d ] thiazol-5-amine

Reacting N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methylpiperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d]A mixture of thiazol-5-amine (0.100g, 0.217mmol) in THF (5mL) was chilled to 0 deg.C in an ice bath, followed by addition of sodium carbonate (0.115g, 1.083mmol) to the mixture while stirring. After 10min, methanesulfonyl chloride (0.051mL, 0.650mmol) was added slowly to the mixture via syringe. After addition, the ice bath was removed and the mixture was stirred overnight under an inert atmosphere. The mixture was diluted with chloroform (20mL) and water (10 mL). The organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography, via a silica gel column (25g), eluting with a 20% mixture of 10: 1 methanol/ammonium hydroxide in dichloromethane to give N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) benzo [ d [ -d ]Thiazol-5-amine (0.012g, 0.022mmol, 10.26% yield).¹H NMR(400MHz，CDCl₃) δ 12.02(s, 1H)8.92(s, 1H)8.65(s, 1H)8.60(s, 1H)8.26(d, J ═ 2.35Hz, 1H)7.79-7.83(m, 1H)7.72(dd, J ═ 8.61, 1.56Hz, 1H)5.55(s, 2H)4.05(q, J ═ 7.04Hz, 1H)3.21(s, 2H)3.11(s, 1H)2.87(s, 2H)2.61-2.73(m, 4H)2.47-2.60(m, 4H)1.34-1.46(m, 3H)1.02-1.22(m, 3H). M/z (ESI, cation) 540.0(M + H)⁺。

Example 294: 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide

Step 1: 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

Will dissolve in II4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.300g, 0.780mmol) and 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (0.385g, 1.091mmol) in an alkane (3mL) were charged to a glass microwave reaction vessel. Subsequently, A-Phos (0.055g, 0.078mmol), potassium acetate (0.230g, 2.339mmol) and water (0.5mL) were added to the reaction mixture. The reaction mixture was stirred and heated in a CEM Voyager microwave for 10min at 120 deg.C (120 watts, enabling Powermax characteristics). The mixture was diluted with dichloromethane (10mL), water (10mL) and brine (5 mL). The organic layer was collected by extraction with dichloromethane (3X 10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to give the crude material as a brown-yellow oil. The crude material was adsorbed onto silica gel and purified by chromatography, through a silica gel column (40g), eluting with 100% ethyl acetate, to give tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (0.513g, 0.780mmol, 100% yield) as a tan solid. ¹H NMR(400MHz，CDCl₃) δ 8.19-8.32(m, 1H)7.91(d, J ═ 8.02Hz, 1H)7.22(dd, J ═ 8.61, 2.93Hz, 4H)6.83-6.97(m, 4H)4.82(d, J ═ 9.39Hz, 4H)3.76-3.83(m, 6H)3.67-3.71(m, 3H)3.40(s, 4H)3.01(s, 1H)2.55(s, 3H)2.45(s, 2H)2.37(s, 2H)2.04-2.07(m, 3H)1.38-1.53(m, 9H). M/z (ESI, cation) 658.3(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) piperazine-1-carboxylate (0.518g, 0.788mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.280g, 1.969mmol) in THF (10mL) was chilled to 0 ℃ in an ice bath, followed by bis (trimethyl) via syringeSilyl) amide sodium (1.0M in THF, Aldrich; 3.15mL, 3.15mmol) was slowly added to the mixture. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The reaction mixture was diluted with saturated sodium bicarbonate (10mL) and extracted with chloroform (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as a brown-yellow oil. The crude material was adsorbed onto silica gel and purified by chromatography through a silica gel column (80g) with a 20% mixture of 10: 1 methanol/ammonium hydroxide in dichloromethane to give an intermediate as a tan oil. The residue was diluted with trifluoroacetic acid (5mL, 64.9mmol) and trifluoromethanesulfonic acid (0.5mL, 5.63mmol) with stirring. The flask was placed in a preheated (70 ℃) bath and allowed to stir for 10 min. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (10mL) and subsequently sodium carbonate (0.500g) was added to the mixture with stirring. After 2min, methanol (2mL) was added to the mixture and allowed to stir for 20 min. The mixture was filtered and the filtrate was concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and purified by chromatography over a silica gel column (40g), eluting with a 20% mixture of 10: 1 methanol/ammonium hydroxide in dichloromethane, to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.141g, 0.321mmol, 31.3% yield) as a tan solid. M/z (ESI, cation) 440.1(M + H) ⁺。

And step 3: 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide

A mixture of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.141g, 0.321mmol) in dichloromethane (5mL) was chilled to 0 ℃ in an ice bath before triethylamine (0.224mL, 1.604mmol) was added to the mixture with stirring. After 10min, dimethylcarbamoyl chloride (Aldrich; 0.104g, 0.962mmol) was added slowly via syringe to the mixture. After the addition of the water-soluble organic acid,the ice bath was removed and the mixture was stirred overnight under an inert atmosphere. The mixture was diluted with chloroform (20mL) and water (10 mL). The organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography on a silica gel column (25g) eluting with a 20% mixture of 10: 1 methanol/ammonium hydroxide dichloromethane to give 4- (1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -N, N-dimethylpiperazine-1-carboxamide as a tan solid (0.070g, 0.137mmol, 42.7% yield). ¹H NMR(400MHz，CDCl₃) δ 12.34(s, 1H)9.40(d, J ═ 2.15Hz, 1H)8.17-8.23(dd, 1H)8.12(d, J ═ 2.54Hz, 1H)8.09(d, J ═ 2.15Hz, 1H)4.04(s, 3H)3.10-3.98(m, 9H)2.85(s, 6H)2.56(s, 3H)1.88(d, J ═ 6.85Hz, 3H). M/z (ESI, cation) 533(M + Na)⁺。

Example 295: n- (5-fluoro-6-methoxypyridin-3-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

Step 1: 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester

Will dissolve in II6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.200g, 0.791mmol) and 5- ((R) -1- ((S) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (0.407g, 1.108mmol) in an alkane (3mL) were charged to a glass microwave reaction vessel. Subsequently, A-Phos (0.056g, 0.079mmol), potassium acetate (0.233g, 2.374mmol) and water (0.5mL) were added to the reaction mixture. In thatThe reaction mixture was stirred and heated in a CEM Voyager microwave for 10min at 120 deg.C (120 watts, enabling Powermax characteristics). The mixture was diluted with dichloromethane (10mL), water (10mL) and brine solution (5 mL). The organic layer was collected by extraction with dichloromethane (3X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as a brown-yellow oil. The crude material was adsorbed onto silica gel and purified by chromatography over a silica gel column (40g), eluting with 100% ethyl acetate followed by 10% methanol in dichloromethane, to give 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester as a tan solid (0.342g, 0.634mmol, 80% yield). ¹H NMR(400MHz，CDCl₃) δ 8.26-8.35(m, 3H)5.86(dd, J ═ 10.37, 2.35Hz, 1H) 4.19(d, J ═ 11.74Hz, 2H)3.83(d, J ═ 2.54Hz, 1H)2.89(s, 3H)2.54(d, J ═ 2.93Hz, 2H)2.16(s, 1H)2.11(s, 1H)2.07(d, J ═ 17.80Hz, 1H)1.81(d, J ═ 11.54Hz, 2H)1.59-1.75(m, 3H)1.39-1.49(m, 15H)1.02(d, J ═ 5.67Hz, 3H). M/z (ESI, cation) 540.2(M + H)⁺。

Step 2: 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester

A mixture of 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester (0.323g, 0.599mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.170g, 1.197mmol) in THF (15mL) was chilled to-20 ℃ in a dilute dry ice/acetone bath, followed by slow addition of lithium bis (trimethylsilyl) amide (1.0M in THF, Aldrich; 1.796mL, 1.796mmol) via syringe to the reaction mixture. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The mixture was diluted with chloroform (20mL) and water (10 mL). The organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Adsorbing the coarse material to silica gel packing On column and purified by chromatography over silica gel column (80g) eluting with 100% EtOAc to give 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester as a tan solid (0.155g, 0.234mmol, 39.1% yield).¹H NMR(400MHz，CDCl₃) δ 12.63(s, 1H)9.71(d, J ═ 2.15Hz, 1H)8.32(dd, J ═ 12.52, 2.15Hz, 1H)8.22(s, 1H)8.17(d, J ═ 2.35Hz, 1H)8.03(d, J ═ 2.15Hz, 1H)5.80(dd, J ═ 10.56, 2.15Hz, 1H)4.12(s, 2H)3.96(s, 3H)3.76(d, J ═ 2.54Hz, 1H)3.53(m, 1H)3.23(m, 1H)2.84(s, 5H)2.41(m, 1H)2.08(s, 1H)2.03(s, 1H)1.97(s, 1H)1.64(s, 1H) 3.85 (d, 1H) 3.87 (d, 1H) 2.6H) 3.87 (d, 1H). M/z (ESI, cation) 662.2(M + H)⁺。

And step 3: n- (5-fluoro-6-methoxypyridin-3-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

A mixture of 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl ester (0.180g, 0.272mmol) and trifluoroacetic acid (0.314mL, 4.08mmol) in DCM (10mL) was treated with trifluoromethanesulfonic acid (0.01mL) and allowed to stir under an inert atmosphere for 1H. The mixture was concentrated in vacuo, then THF (10mL) was added to the residue and stirred for 5 min. Subsequently, sodium carbonate (0.500g) was added to the mixture and allowed to stir for a further 5min under an inert atmosphere. Subsequently, methanesulfonyl chloride (0.064mL, 0.816mmol) was slowly added to the mixture via syringe. The mixture was allowed to stir overnight under an inert atmosphere. The mixture was diluted with DCM (20mL), water (20mL) and brine solution (10 mL). The organic layer was extracted with DCM (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol and dichloromethane to give N- (5-fluoro-6-methoxypyridin-3-yl) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purine as a tan solid (iv) Proten-6-yl) pyridin-2-amine (0.007g, 0.013mmol, 4.63% yield).¹H NMR(400MHz，CDCl₃) δ 12.69(s, 1H)9.84(s, 1H)8.38(dd, J ═ 12.42, 2.05Hz, 1H)8.28(d, J ═ 2.15Hz, 1H)8.22(s, 1H)8.11(d, J ═ 2.15Hz, 1H)7.26(s, 8H)4.16(dq, J ═ 14.18, 6.94Hz, 1H)4.04(s, 3H)3.30(s, 2H)3.14-3.21(m, 1H)2.93-3.06(m, 4H)2.85(dd, J ═ 10.76, 7.24Hz, 1H)2.69-2.78(m, 4H)2.55-2.64(m, 1H)1.54(d, J ═ 6.85H) 1.13 (d, 13H) 3.13 Hz. M/z (ESI, cation) 556.1(M + H)⁺。

Example 296: n- (5-fluoro-6-methoxypyridin-3-yl) -5- ((S) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine

The title compound was prepared in analogy to the procedure described in example 295 using 5- ((S) -1- ((S) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid, 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine and 5-fluoro-6-methoxypyridin-3-amine and was isolated as a tan solid (38%).¹H NMR(400MHz，CDCl₃) δ 9.60(s, 1H)8.24(d, J ═ 1.37Hz, 2H)8.11(s, 1H)7.97(s, 1H)4.01(s, 5H) 3.76(s, 4H)2.89(s, 5H)2.61(s, 4H)1.88(s, 3H)1.70(s, 3H). M/z (ESI, cation) 556.1(M + H) ⁺。

Example 297: (R) -N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine

Step 1: 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

Will dissolve in II6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (0.250g, 0.989mmol) and (R) -5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (0.489g, 1.385mmol) in an alkane (3mL) were charged to a glass microwave reaction vessel. Subsequently, A-Phos (0.070g, 0.099mmol), potassium acetate (0.291g, 2.97mmol) and water (0.5mL) were added to the reaction mixture. The reaction mixture was stirred and heated in a CEM Voyager microwave for 10min at 120 deg.C (120 watts, enabling Powermax characteristics). The mixture was diluted with dichloromethane (10mL), water (10mL) and brine solution (5 mL). The organic layer was collected by extraction with dichloromethane (3X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as a brown-yellow oil. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, via silica gel column (40g), eluting with 100% ethyl acetate, to give tert-butyl 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (0.400g, 0.761mmol, 77% yield) as a pale yellow solid. ¹H NMR(400MHz，CDCl₃) δ 8.20-8.29(m, 3H)5.78(dd, J ═ 10.37, 2.35Hz, 1H)3.76(s, 1H)3.55(d, J ═ 6.65Hz, 1H)3.34(s, 5H)2.82(s, 3H)2.33(d, J ═ 5.09Hz, 5H)1.95-2.13(m, 3H)1.56-1.81(m, 5H)1.33-1.40(m, 9H). M/z (ESI, cation) 526.2(M + H)⁺。

Step 2: 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4- ((1R) -1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (0.673g, 1.280mmol) in THF (15mL) was taken with 5-fluoro-6-methoxypyridin-3-amine (0) via syringe under an inert atmosphere.364g, 2.56mmol) in THF (10 mL). The mixture was chilled to-20 ℃ in a dilute dry ice/acetone bath, then sodium bis (trimethylsilyl) amide (1.0M in THF, Aldrich; 3.84mL, 3.84mmol) was slowly added to the reaction mixture via syringe. After addition, the ice bath was removed and the mixture was stirred under an inert atmosphere for 1 h. The mixture was diluted with chloroform (20mL) and water (10 mL). The organic layer was extracted with chloroform (3X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, through a silica gel column (80g), eluting with 100% ethyl acetate, to give tert-butyl 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (0.459g, 0.709mmol, 55.3% yield) as a tan solid. ¹H NMR(400MHz，CDCl₃) δ 12.61(s, 1H)9.65(t, J ═ 1.96Hz, 1H)8.31(dd, J ═ 12.52, 2.35Hz, 1H)8.18-8.23(m, 2H)8.03(d, J ═ 2.35Hz, 1H)5.80(dd, J ═ 10.47, 2.05Hz, 1H)3.96(s, 3H)3.76(s, 1H)3.55(d, J ═ 6.85Hz, 1H)3.36(s, 4H)2.85(s, 3H)2.40(d, J ═ 3.33Hz, 4H)2.07(s, 1H)2.02(s, 1H)1.97(s, 1H)1.54-1.81(m, 2H)1.41 (t, 65 ═ 1.65 (t, J ═ 1H) 1.19 (d, 1H) 1.65 (d, 1H) 1.6H). M/z (ESI, cation) 648.2(M + H)⁺。

And step 3: (R) -N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine

A mixture of tert-butyl 4- ((1R) -1- (6- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (0.450g, 0.695mmol) and trifluoroacetic acid (0.803mL, 10.42mmol) in DCM (25mL) was treated with trifluoromethanesulfonic acid (0.01mL) and allowed to stir under an inert atmosphere for 1H. The mixture was concentrated in vacuo. The residue was diluted with DCM (10mL), then sodium carbonate (2.50g) was added to the mixture and allowed to stir for 10 min. Subsequently, methanesulfonyl chloride (0.271mL, 3.47mmol) was slowly added to the mixture via syringe. Under inert gas The mixture was allowed to stir overnight under an atmosphere. The mixture was diluted with dichloromethane (20mL), water (20mL) and brine solution (10 mL). The organic layer was extracted with dichloromethane (3X 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Preparative HPLC on reversed phase using Phenomenex Luna column, 10 micron, C18(2),250X 50mm (Varian, 5-70% acetonitrile in water with trifluoroacetic acid as additive, 0.1% v/v in each solvent) and then further purified by normal phase silica gel chromatography on an Interchim puriflash (25g) column eluting with 10% methanol in dichloromethane to give N- (5-fluoro-6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) -5- ((R) -1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-amine as a pale yellow solid (0.010g, 0.018mmol, 2.66% yield).¹H NMR(400MHz，CDCl₃) δ 12.69(s, 1H)9.77(d, J ═ 1.96Hz, 1H)8.39(dd, J ═ 12.52, 2.15Hz, 1H)8.32(d, J ═ 2.15Hz, 1H)8.21(s, 1H)8.11(d, J ═ 2.15Hz, 1H)4.04(s, 3H)3.67-3.73(m, 1H)3.26(t, J ═ 4.69Hz, 4H)2.94(s, 3H)2.77(s, 3H)2.62-2.71(m, 4H)1.51(d, J ═ 6.65Hz, 3H). M/z (ESI, cation) 542.1(M + H) ⁺。

Example 298: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) cyclopropanol

Step 1: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinic acid methyl ester

5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (example 143, 0.200g, 0.336mmol), bisA slurry of manganese oxide (0.584g, 6.72mmol), methanol (0.068mL, 1.679mmol), acetic acid (0.029mL, 0.504mmol) and sodium cyanide (0.082g, 1.679mmol) in 4mL THF was stirred rapidly overnight. Manganese dioxide (0.584g, 6.72mmol) was added and the reaction was sealed and stirred rapidly for 3 days. The reaction was passed through CeliteFilter (celite) and rinse with 10% MeOH in DCM. The residue was adsorbed onto 2g silica gel, dried and purified by silica gel chromatography (40g column) using 0-100% EtOAc/hexanes. The fractions containing the product were concentrated to give methyl 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinate (0.107g, 0.171mmol, 50.9% yield) as an orange solid. M/z (ESI, cation) 626(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ12.33(br.s.，1H)，9.41(d，J＝2.3Hz，1H)，8.92(d，J＝2.3Hz，1H)，7.98(d，J＝2.3Hz，1H，)7.90-7.97(m，1H)，7.16-7.25(m，4H)，6.82-6.92(m，4H)，4.90(s，2H)，4.84(s，2H，)4.04(s，3H)，3.92(s，3H)，3.82(s，3H)，3.79(s，3H)，2.61(s，3H)。

Step 2: 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinic acid methyl ester

A solution of methyl 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinate (0.965g, 1.542mmol) and trifluoromethanesulfonic acid (0.685mL, 7.71mmol) in 6mL TFA was heated at 80 deg.C for 30min in a flask equipped with a reflux condenser and drying tube. The dark red reaction was cooled and trifluoromethanesulfonic acid (0.685mL, 7.71mmol) was added and the reaction was heated again to 80 ℃. After 30min, the reaction was judged to be complete. The reaction was cooled to 0 ℃ and ice was added in portions along with solid sodium bicarbonate with rapid stirring. DCM was added. After complete quenching of the acid, the thick mixture was extracted with 3 × 10% iPrOH/DCM, 2 × 10% iPrOH/EtOAc (EtOAc layer was washed with 1 × brine). The combined organic extracts are dried over sodium sulfate andfiltered and concentrated in vacuo. The solid was suspended in ether, sonicated and filtered, washed 3 times with ether to give methyl 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinate as an orange solid (0.400g, 1.038mmol, 67.3% yield). M/z (ESI, cation) 386(M + H) ⁺。¹H NMR(400MHz，d₆-DMSO)δ12.37(s，1H)，9.26(d，J＝2.3Hz，1H)，8.83(d，J＝2.3Hz，1H)，8.41(d，J＝2.3Hz，1H)，8.31(dd，J＝12.4，2.2Hz，1H)，8.01(br.s.，1H)，7.84(br.s.，1H)，3.95(s，3H)，3.88(s，3H)，2.46(s，3H)。

And step 3: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) cyclopropanol

To a slurry of methyl 5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinate (0.400g, 1.038mmol) and titanium (iv) isopropoxide (0.365mL, 1.246mmol) in 8mL THF was added a solution of ethylmagnesium bromide in THF (5.61mL, 5.61mmol) at ambient temperature over 2-3 min. The reaction was dark brown and warmed up under bubbling. The reaction was cooled briefly with an ice bath and then allowed to stir at ambient temperature. After 1h, an additional 2.4 equivalents of 1.0M ethyl magnesium bromide in THF were added at ambient temperature. After 30min, the reaction was cooled to 0 ℃ and quenched with ice and NH₄And (4) quenching by a saturated Cl aqueous solution. Reacting the reactant in NH₄The mixture was partitioned between saturated aqueous Cl and DCM. The aqueous layer was extracted 3 times with DCM and once with ethyl acetate and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by RPHPLC (gradient, acetonitrile + 0.1% TFA/water + 0.1% TFA) afforded 0.070g of a viscous orange film. The material is put into NaHCO₃Saturated aqueous solution and 10% iPrOH/DCM treatment. The aqueous layer was extracted 3 times with 10% iPrOH/DCM and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) cyclopropanol (0.027g, 0.070mmol, 7% yield) as a yellow solid. m/z (ESI, cation) 384 (M+H)⁺。¹H NMR(400MHz，d6-DMSO)δ11.90(s，1H)，8.82(d，J＝2.5Hz，1H)，8.29-8.48(m，2H)，8.20(d，J＝2.5Hz，1H)，7.91(br.s.，1H)，7.75(br.s.，1H)，6.03(s，1H)，3.93(s，3H)，2.44(s，3H)，1.04-1.13(m，2H)，0.86-0.98(m，2H)。

Example 299: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (isopropylamino) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (example 271, 0.270g, 0.443mmol), titanium (iv) isopropoxide (0.519mL, 1.772mmol) and isopropylamine (0.152mL, 1.772mmol) in 3mL THF was sealed and heated to 60 ℃ overnight. The reaction was cooled, diluted with 3mL of DCM and treated with sodium triacetoxyborohydride (0.375g, 1.772 mmol). After 1h, sodium cyanoborohydride (0.111g, 1.772mmol) was added. After 3h, the reaction was complete. Using ice, water and concentrated NH to react₄OH and DCM treatment. The organic layer was removed. Extraction was attempted only with the emulsion possible, so the material was filtered through celite. The aqueous layer was extracted with 1 × DCM. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.331g of an orange oil containing impure 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (isopropylamino) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine. M/z (ESI, cation) 653(M + H) ⁺. In a sealed vessel, the impure material was treated with 2mL TFA and triflic acid (0.197mL, 2.214mmol) and heated to 80 ℃ for 30 min. The reaction was cooled and poured onto ice and basified with 10N NaOH. The material was extracted 3 times with DCM and once with 10% iPrOH/DCM. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was suspended in MeOH and passedFiltered and washed with MeOH. The solid was dried in vacuo to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (1- (isopropylamino) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.145g, 0.352mmol, 79% yield) as an orange solid. M/z (ESI, cation) 413(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.91(s，1H)，8.77(br.s.，1H)，8.28-8.49(m，3H)，7.89(br.s.，1H)，7.74(br.s.，1H)，3.93(s，3H)，3.76-3.91(m，1H)，3.26-3.32(m，1H)，2.44(s，3H)，1.27(b r.s.，3H)，0.84-1.08(m，6H)。

Example 300: 4- (5- (1-aminocyclopropyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinonitrile

Hydroxylammonium chloride (0.700g, 10.07mmol), 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (example 143, 2.00g, 3.36mmol) and pyridine (0.815mL, 10.07mmol) in 15mL of DMF dark brown solution were stirred for 2 h. The reaction was partitioned between water and EtOAc. The organic layer was washed 2 times with water, once with a saturated aqueous solution of NaCl, and the organic was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.0g of an orange solid. This solid was treated with acetic anhydride (15.84mL, 168mmol) and the flask was fitted with a water-cooled reflux condenser and placed in an oil bath. The reaction was heated to reflux for 5h and then cooled and stirred overnight. The slurry was treated with 80mL MeOH, filtered and dried in vacuo to give 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinonitrile as a green-brown solid (1.50g, 2.53mmol, 75% yield). M/z (ESI, cation) 593(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ12.46(s，1H)，8.99(d，J＝2.3Hz，1H)，8.52(d，J＝2.3Hz，1H)，7.99(d，J＝2.3Hz，1H)，7.92(dd，J＝11.7，2.2Hz，1H)，7.12-7.25(m，4H)，6.82-6.94(m，4H)，4.88(s，2H)，4.82(s，2H)，4.04(s，3H)，3.82(s，3H)，3.81(s，3H)，2.61(s，3H)。

Step 2: 4- (5- (1-Aminocyclopropyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate salt

To a dark brown slurry of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinonitrile (0.210g, 0.354mmol) in 7mL THF was added titanium (IV) isopropoxide (0.125mL, 0.425mmol) and the reaction was cooled to-78 ℃. A1.0M solution of ethylmagnesium bromide in THF (2.268mL, 2.268mmol) was added slowly dropwise and the reaction stirred at-78 deg.C for 1 h. The reaction was allowed to warm to ambient temperature. After 2h, boron trifluoride diethyl etherate (0.108mL, 0.850mmol) was added. After 1h, boron trifluoride diethyl etherate (0.108mL, 0.850mmol) was added again. After 1h, quench the reaction by adding 1N NaOH and treat with EtOAc. The aqueous layer was extracted 3 times with EtOAc and 1 time with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting impure mixture is combined with additional impure material for use in the next reaction. 0.334g of the impure mixture containing 4- (5- (1-aminocyclopropyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine was dissolved in 2mL TFA and treated with trifluoromethanesulfonic acid (0.238mL, 2.68mmol) and the reaction was sealed and heated to 80 ℃ for 0.5 h. The reaction was cooled, poured onto ice, and treated with 10N NaOH until basic. The aqueous solution was extracted 3 times with DCM, 1 time with 10% iPrOH/DCM, dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO/TFA and subjected to reverse phase HPLC, 10-60% ACN/H ₂O (+ 0.1% TFA) purification; the product-containing fractions were concentrated in vacuo to give 4- (5-(1-Aminocyclopropyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate (0.010g, 0.020mmol, 3.76% yield). M/z (ESI, cation) 383(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ12.03(s，1H)，8.94(d，J＝2.5Hz，1H)，8.53(br.s.，3H)，8.38-8.49(m，2H)，8.30(dd，J＝12.7，2.2Hz，1H)，7.96(br.s.，1H)，7.84(br.s.，1H)，3.94(s，3H)，2.46(s，3H)，1.26-1.35(m，2H)，1.14-1.23(m，2H)。

Example 301: 4- (5- (3-aminopentan-3-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a slurry of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinonitrile (example 143, 0.205g, 0.346mmol) in 7mL THF at 0 deg.C was added titanium tetraisopropoxide (0.122mL, 0.415mmol) followed by 1.0M ethylmagnesium bromide in THF (2.214mL, 2.214 mmol). The reaction became dark brown. After 30min, boron trifluoride diethyl etherate (0.210mL, 1.660mmol) was added. The reaction was warmed to ambient temperature and after 15min, quenched with 10N NaOH. The aqueous solution was extracted 3 times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.234 g. This material was treated with 2mL TFA and triflic acid (O.154mL, 1.730 mmol). The reaction was sealed and heated to 80 ℃ for 30 min. The reaction was cooled and poured onto ice, basified with 10N NaOH and extracted 3 times with DCM. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting material was treated with DMSO and TFA, by RPHPLC, 10-60% ACN/H ₂O (+ 0.1% TFA) purification; the product-containing fractions were concentrated and washed with NaHCO₃Saturated aqueous solution and DCM. The aqueous layer was extracted 3 times with 10% IPA/DCM and the combined organics were treated with sulfuric acidSodium was dried, filtered and concentrated in vacuo to give 4- (5- (3-aminopentan-3-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.010g, 0.044mmol, 12.62% yield) as a yellow solid. M/z (ESI, cation) 413(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.92(s，1H)，8.88(d，J＝2.5Hz，1H)，8.35-8.46(m，3H)，7.88(br.s.，1H)，7.72(b r.s.，1H)，3.93(s，3H)，2.44(s，3H)，1.53-1.84(m，4H)，0.69(t，J＝7.3Hz，6H)。

Example 302: (R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 3-bromo-2-methoxy-5-nitropyridine

To a 50mL dry methanol cloudy mixture of 3-bromo-2-chloro-5-nitropyridine (Atlantic Scitech, Linden, NJ, 5.10g, 21.48mmol) was added dropwise 5.4M sodium methoxide in methanol (7.96mL, 43.0mmol) through an addition funnel at 0 deg.C (ice/water bath). The reaction became clear and a thick precipitate formed subsequently. The ice/water bath was removed and the reaction was warmed to ambient temperature, washed with water and NH₄Saturated aqueous Cl and DCM quench. The aqueous layer was extracted 2 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-2-methoxy-5-nitropyridine (5.07g, 21.76mmol, quantitative yield) as a pale yellow solid. M/z (ESI, cation) 233(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ9.02(d，J＝2.3Hz，1H)，8.63(d，J＝2.5Hz，1H)，4.15(s，3H)。

Step 2: 5-isopropyl-6-methoxypyridin-3-amine

Argon was passed over potassium carbonate (4.45g, 32.2mmol), ethyl propenyl trifluoro-benzenePotassium borate (3.18g, 21.46mmol), bis (4- (di-tert-butylphosphino) -N, N-dimethylaniline) dichloropalladium (Aldrich, St. Louis, MO, 0.152g, 0.215mmol) and 3-bromo-2-methoxy-5-nitropyridine (2.50g, 10.73mmol) in 50mL of bisA slurry of alkane and 20mL of water was bubbled for 5 min. The reaction was sealed and heated to 80 ℃ for 1 h. The dark red reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted 3 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a red solid which was used without further purification. The solid was treated with 10% palladium on carbon (50% water wet) (2.62g, 2.464mmol) and 75mL MeOH, equipped with a hydrogen balloon and stirred rapidly for 3 h. The reaction was flushed with nitrogen through Celite(celite) filtration, washing with 400mL MeOH and concentration in vacuo to give 5-isopropyl-6-methoxypyridin-3-amine as a brown oil (1.81g, 10.89mmol, quantitative yield). M/z (ESI, cation) 167(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ7.51(d，J＝2.9Hz，1H)，6.94(d，J＝2.7Hz，1H)，3.90(s，3H)，3.13(m，1H)，1.14-1.22(m，6H)。

And step 3: (R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a solution of (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (examples 145 and 146)0.380g, 0.598mmol) and 5-isopropyl-6-methoxypyridin-3-amine (0.149g, 0.897mmol) in 3mL THF was added 1.0M lithium bis (trimethylsilyl) amide dissolved in THF (2.69mL, 2.69mmol) dropwise via syringe over 1min at 0 ℃. The dark red reaction was stirred for 30min and by addition of NH₄Saturated aqueous Cl solution. Reacting the reactant in waterAnd DCM. The aqueous layer was extracted 3 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80g column) eluting the desired product with 20-100% EtOAc/hexanes followed by 10% MeOH/EtOAc. Fractions containing the product were concentrated to give (R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.097g, 0.124mmol, 21% yield) as a red oil. M/z (ESI, cation) 782(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ11.59(s，1H)，8.70(d，J＝2.2Hz，1H)，8.15-8.29(m，2H)，7.77(d，J＝2.5Hz，1H)，7.15-7.25(m，4H)，6.77-6.96(m，4H)，4.71-4.97(m，4H)，3.95(s，3H)，3.82(s，3H)，3.79(s，3H)，3.53(q，J＝6.8Hz，1H)，3.11-3.20(m，5H)，2.69(s，3H)，2.47-2.63(m，7H)，1.38(d，J＝6.7Hz，3H)，1.21(d，J＝6.8Hz，6H)。

And 4, step 4: (R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A dark red solution of (R) -4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.097g, 0.124mmol) and trifluoromethanesulfonic acid (0.055mL, 0.620mmol) in 1mL TFA was sealed and heated to 80 ℃ for 30 min. The reaction was cooled with ice, then quenched with 10N NaOH until basic and partitioned between water and DCM. The aqueous layer was extracted 2 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in DMSO (plus a few drops of TFA) and purified by RPHPLC, 10-80% ACN/H2O (plus 0.1% TFA); the product-containing fractions were concentrated to dryness and subsequently treated with NaHCO₃Saturated aqueous solution and DCM. The aqueous layer was extracted 3 times with DCM and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give (R) -one as a yellow solid4- (2- (5-isopropyl-6-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.021g, 0.039mmol, 31% yield). M/z (ESI, cation) 542(M + H) ⁺。 ¹H NMR(400MHz，CDCl₃)δ11.58(br.s.，1H)，8.69(br.s.，1H)，8.17-8.34(m，2H)，7.92(br.s.，1H)，5.38(br.s.，2H)，3.97(s，3H)，3.47-3.62(m，1H)，3.11-3.31(m，5H)，2.77(br.s.，3H)，2.49-2.68(m，7H)，1.44(d，J＝6.1Hz，3H)，1.27(d，J＝6.8Hz，6H)。

Example 303: 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5- (ethylsulfinyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Argon was passed through 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 313, step 2)0.318g, 0.528mmol), (R) -1- [ (S) -2- (dicyclohexylphosphino) ferrocenyl]Ethyl di-tert-butylphosphine (Aldrich, St. Louis, MO, 0.029g, 0.053mmol), diacetoxypalladium (0.012g, 0.053mmol) and sodium ethanethiol (0.156g, 1.849mmol) in 3mL DME slurry was bubbled for 1 min. The reaction was sealed and heated to 110 ℃ overnight. With (R) -1- [ (S) -2- (dicyclohexylphosphino) ferrocenyl]Ethyl di-tert-butylphosphine (0.029g, 0.053mmol), diacetoxypalladium (0.012g, 0.053mmol) and sodium ethanethiol (0.156g, 1.849mmol) were supplemented with argon, sealed and heated overnight. The reaction was cooled and adsorbed from DCM onto 2g silica gel and purified by silica gel chromatography, 40g, 0-50% EA in hexanes. The product-containing fractions were combined and concentrated to give 0.249g of a yellow solid. Adsorb material from DCM Onto 1.5g silica gel and purified by silica gel chromatography, 40g, 0 to 5% EtOAc/DCM to give 4- (5- (ethylsulfinyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.090g, 0.140mmol, 27% yield). M/z (ESI, cation) 644(M + H)⁺。 ¹H NMR(400MHz，CDCl₃)δ11.75(br，s.，1H)，8.76(d，J＝2.5Hz，1H)，8.18-8.24(m，1H)，8.02(d，J＝2.3Hz，1H)，7.88-7.98(m，1H)，7.12-7.24(m，4H)，6.81-6.94(m，4H)，4.87(s，2H)，4.82(s，2H)，4.04(s，3H)，3.82(s，3H)，3.80(s，3H)，2.91(q，J＝7.4Hz，2H)，2.59(s，3H)，1.37(t，J＝7.3Hz，3H)。

Step 2: 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To 4- (5- (ethylsulfinyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.090g, 0.140mmol) in 2mL MeOH, 2mL of bisA slurry of alkane and 1mL of water was added to potassium peroxymonosulfate complex salt (0.172g, 0.280 mmol). The bright yellow slurry was stirred rapidly overnight. The reaction was washed with saturated NaHCO₃And DCM. The aqueous layer was extracted 3 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25g column) using 20 to 100% EtOAc/hexanes. Fractions containing product were concentrated to give 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.066g, 0.100mmol, 71.6% yield) as a yellow solid. M/z (ESI, cation) 660(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ11.91(s，1H)，8.80(d，J＝2.7Hz，1H)，8.43(d，J＝2.7Hz，1H)，8.15-8.33(m，2H)，7.14-7.25(m，4H)，6.80-6.93(m，4H)，4.87(s，2H)，4.83(s，2H)，4.02(s，3H)，3.82(s，3H)，3.79(s，3H)，3.07-3.22(m，1H)，2.82-2.94(m，1H)，2.62(s，3H)，1.28(t，J＝7.4Hz，3H)。

And step 3: 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.066g, 0.100mmol) in trifluoromethanesulfonic acid (0.089mL, 1.000mmol) and 1.5mL TFA was sealed and heated to 70 ℃ for 30min, cooled and treated with ice and 10N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted 5 times with DCM and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting yellow solid was suspended in 1mL EtOAc, filtered, washed 2 times with diethyl ether, and dried in vacuo to give 4- (5- (ethylsulfonyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.029g, 0.069mmol, 69% yield) as a yellow solid. M/z (ESI, cation) 420(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.87(s，1H)，8.73(d，J＝2.7Hz，1H)，8.52(d，J＝2.7Hz，1H)，8.41(d，J＝2.5Hz，1H)，8.33(d，J＝2.7Hz，1H)，7.98(br.s.，1H)，7.83(br.s.，1H)，3.95(s，3H)，3.06-3.21(m，1H)，2.73-2.89(m，1H)，2.44(s，3H)，1.09(t，J＝7.3Hz，3H)。

Example 304: n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide

Step 1: 6- (2-fluoro-3-pyridinyl) -2-methyl-4-pyrimidinamine

At 110 ℃, adding 6-chloro-2- Methyl-4-pyrimidinamine (SynChem, Inc., Des Plaines, IL) (0.500g, 3.48mmol), 2-fluoropyridin-3-yl boronic acid (0.589g, 4.18mmol), PdCl₂(dppf) Complex with methylene chloride (0.199g, 0.244mmol) and 2M Na₂CO₃(aqueous solution, 5.22mL, 10.45mmol) of bisThe mixture of alkanes (17mL) was stirred overnight. After cooling to room temperature, water was added and the mixture was passed through Celite(celite) filtration. The mixture was extracted with EtOAc (3 ×). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (40g) to dissolve in CH₂Cl₂To provide 6- (2-fluoro-3-pyridinyl) -2-methyl-4-pyrimidinamine as an off-white solid (0.173g, 0.85mmol, 24% yield). M/z (ESI, cation) 205.1(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ8.52-8.62(m，1H)；8.27-8.34(m，1H)；7.44-7.61(m，2H)；7.00(br.s.，1H)；6.75-6.83(m，1H)；2.39(s，3H)。

Step 2: n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide

To a solution of N- (5-amino-2-chloro-3-pyridinyl) methanesulfonamide (example 330, step 2) (0.085g, 0.384mmol) in THF (5.0mL) at 0 deg.C was added NaHMDS (2M solution in THF) (0.959mL, 1.918 mmol). After addition, at 0 ℃ under N ₂The reaction mixture was then stirred for an additional 30 minutes. 6- (2-fluoro-3-pyridyl) -2-methyl-4-pyrimidinamine (0.094g, 0.460mmol) was added to the reaction mixture and the reaction mixture was allowed to continue at 0 ℃ for 10 minutes and then slowly warmed at room temperature. After 1 hour at room temperature, more NaHMDS (2M solution in THF) (0.50mL, 1.0mmol) was added. After another 1 hour, the reaction mixture was buffered at pH 7 (1M TRIS-HCl)And CH₂Cl₂Are distributed among the devices. The layers are separated and substituted with CH₂Cl₂(3X) extract the aqueous layer. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude product was purified by HPLC to give N- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide (0.0190g, 0.047mmol, 12.20% yield). M/z (ESI, cation) 406.1(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ12.68(s，1H)；9.66(s，1H)；8.61(d，J＝2.74Hz，1H)；8.41(d，J＝2.54Hz，1H)；8.32(dd，J＝4.89，1.76Hz，1H)；8.10-8.14(m，1H)；7.09(s，2H)；7.02(dd，J＝7.82，4.69Hz，1H)；6.78(s，1H)；3.13(s，3H)；2.52(s，3H)。

Example 305: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

Step 1: 4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -1-piperazinecarboxylic acid tert-butyl ester

Will dissolve in II6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (example 177) (0.766g, 1.996mmol), (5- ((1R) -1- (4- (tert-butoxycarbonyl) -1-piperazinyl) ethyl) -2-fluoro-3-pyridinyl) boronic acid (example 146, step 4) (0.705g, 1.996mmol), PdCl in a mixture of an alkane (16.6mL) and water (3.3mL) ₂AmPhos (0.071g, 0.100mmol) and KOAc (0.588g, 5.99mmol) were sparged with nitrogen and subsequently heated at 100 ℃ for 2.5 h. Subsequently, the yellow reaction mixture is reacted in CH₂Cl₂(60mL) and water (50 mL). The organic layer was separated and washed with CH₂Cl₂(2×50mL) The aqueous layer was extracted. The combined organic extracts were then passed over Na₂SO₄Dried and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (80g) eluting with a gradient of 0% to 100% EtOAc in hexanes to provide tert-butyl 4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -1-piperazinecarboxylate (0.570g, 0.868mmol, 43.5% yield) as a light yellow foam. M/z (ESI, cation) 657.2(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.43(d，J＝8.22Hz，1H)；8.18(s，1H)；7.18(d，J＝7.24Hz，4H)；6.82-6.89(m，5H)；4.75(br.s.，4H)；3.79(s，6H)；3.60(d，J＝7.04Hz，1H)；3.43(br.s.，4H)；2.63(s，3H)；2.30-2.53(m，4H)；1.44(s，12H)。

Step 2: 6- (2-fluoro-5- ((1R) -1- (1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

Tert-butyl 4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -1-piperazinecarboxylate (0.57g, 0.87mmol) in CH at 0 deg.C₂Cl₂(4.3mL) the mixture was treated with TFA (1.29mL, 17.36 mmol). The reaction mixture was allowed to warm to room temperature. After 90 minutes, the reaction mixture was concentrated and the residue was dissolved in CH ₂Cl₂And saturated NaHCO₃(aqueous solution). The layers are separated and substituted with CH₂Cl₂(2X) extract the aqueous layer. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give 6- (2-fluoro-5- ((1R) -1- (1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.41g, 0.74mmol, 85% yield). M/z (ESI, cation) 557.2(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ8.41(dd，J＝9.29，2.45Hz，1H)；8.14-8.18(m，1H)；7.18(d，J＝7.43Hz，4H)；6.86(d，J＝8.61Hz，4H)；6.83(br.s，1H)；4.74(br.s.，4H)；3.79(s，6H)；3.57(q，J＝6.78Hz，1H)；2.96(m，4H)；2.62(s，3H)；2.57(br.s.，2H)；2.44-2.51(m，2H)；1.40(d，J＝6.85Hz，3H)。

And step 3: 6- (2-fluoro-5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

6- (2-fluoro-5- ((1R) -1- (1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.448g, 0.805mmol) in CH is reacted at-20 deg.C₂Cl₂(4mL) solution with NEt₃(1.122mL, 8.05mmol) followed by methanesulfonyl chloride (0.190mL, 2.414 mmol). The mixture was stirred for 30 minutes at-20 ℃ and then 1M NaOH (aq) and CH were added₂Cl₂. The layers are separated and substituted with CH₂Cl₂(2X) extract the aqueous layer. The crude material was adsorbed onto a silica gel packed column and purified by chromatography over a silica gel column (12g) eluting with a gradient of 75% to 100% EtOAc in hexanes to provide 6- (2-fluoro-5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.317g, 0.499mmol, 62.1% yield) as a white foam. M/z (ESI, cation) 635.2(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ8.46(d，J＝9.00Hz，1H)；8.18(s，1H)；7.17(d，J＝7.63Hz，4H)；6.83-6.89(m，5H)；4.74(br.s.，4H)；3.80(s，6H)；3.65(m，1H)；3.18-3.30(m，4H)；2.77(s，3H)；2.64(s，5H)；2.50-2.58(m，2H)；1.44(d，J＝6.65Hz，3H)。

And 4, step 4: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

Lithium bis (trimethylsilyl) amide (1.0M solution in THF) (1.42mL, 1.42mmol) was added to a solution of 6- (2-fluoro-5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.300g, 0.47mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, inc. northbrunsick, NJ) (0.101g, 0.71mmol) in THF (1.5mL) at-10 ℃. More bis (trimethyl) is addedLithium silyl) amide (1.0M solution in THF) (1.42mL, 1.42mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.101g, 0.71mmol) and the reaction mixture was stirred for an additional 1 h. Adding saturated NH₄Cl (aq) and the mixture was extracted with EtOAc (3 ×). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography, pre-packed with silica gel column (40g) via a Redi-Sep, eluting with a gradient of 0% to 100% EtOAc in hexanes, to afford 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.200g, 0.264mmol, 55.9% yield) as a brown foam. M/z (ESI, cation) 757.2(M + H) ⁺。¹H NMR(400MHz，CDCl₃)δ11.92(br.s.，1H)8.24(dd，J＝12.52，2.15Hz，1H)8.13(d，J＝1.57Hz，1H)8.03(d，J＝2.15Hz，1H)7.50(br.s.，1H)7.19(d，J＝6.46Hz，4H)6.87(d，J＝8.61Hz，5H)6.52(br.s.，1H)4.79(br.s.，4H)4.01(s，3H)3.79(s，6H)3.44(br.s.，1H)3.17(br.s.，4H)2.75(s，3H)2.66(s，3H)2.40-2.59(m，4H)1.34(b r.s.，3H)。

And 5: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

A solution of 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.200g, 0.264mmol) in TFA (2mL) was treated with a few drops of trifluoromethanesulfonic acid at room temperature. The solution was heated to 80 ℃ for 90 minutes. The reaction mixture was cooled to room temperature and then concentrated. Several ice cubes were added, followed by saturated NaHCO₃(aqueous solution) followed by addition of CH₂Cl₂. The mixture was filtered and the layers were separated. The aqueous layer is replaced by CH₂Cl₂(2X) extracting. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. Adsorbing the crude material on a silica gel packed column andby chromatography, through a silica gel column (12g) to dissolve in CH₂Cl₂To provide 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- (4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine as a yellow solid (0.110g, 0.213mmol, 81% yield). M/z (ESI, cation) 517.1(M + H) ⁺。 ¹H NMR(400MHz，d₆-DMSO)δ12.17(br.s，1H)；8.35(dd，J＝13.01，2.25Hz，1H)；8.22(d，J＝2.15Hz，1H)；8.17(d，J＝2.35Hz，1H)；7.95-7.98(m，1H)；7.04(s，2H)；6.80(s，1H)；3.94(s，3H)；3.61(q，J＝6.78Hz，1H)；3.11(t，J＝4.99Hz，4H)；2.87(s，3H)；2.53-2.58(m，5H)；2.43-2.50(m，2H)；1.38(d，J＝6.85Hz，3H)。

Example 306: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

Step 1: (3S) -4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylic acid tert-butyl ester

(5- ((1R) -1- ((2S) -4- (tert-Butoxycarbonyl) -2-methyl-1-piperazinyl) ethyl) -2-fluoro-3-pyridinyl) boronic acid (example 272, step 2) (0.530g, 1.443mmol), 6-chloro-N, N-bis (4-methoxybenzyl) -2-methylpyrimidin-4-amine (example 177) (0.554g, 1.443mmol), PdCl₂(AmPhos)₂(0.102g, 0.144mmol) and KOAc (0.425g, 4.33mmol) were charged to a glass microwave reaction vessel. The tube was sealed and evacuated and backfilled with nitrogen. Adding twoAlkane (3.75mL) and water (0.375mL) and argon (gas) was bubbled through the mixture for 5 minutes. At 12The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, inc., Upssala, Sweden) for 20 minutes at 0 ℃. The crude material was adsorbed onto a silica gel packed column and purified by chromatography over a silica gel column (40g) eluting with a gradient of 0% to 100% EtOAc in hexanes to provide tert-butyl (3S) -4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylate as a yellow oil (0.240g, 0.358mmol, 24.79% yield). M/z (ESI, cation) 671.3(M + H) ⁺。 ¹H NMR(400MHz，CDCl₃)δ8.40(dd，J＝9.39，2.54Hz，1H)；8.13(d，J＝1.37Hz，1H)；7.18(d，J＝8.02Hz，4H)；6.80-6.90(m，5H)；4.50-5.03(m，4H)；4.03(d，J＝5.28Hz，1H)；3.73-3.84(m，6H)；3.24-3.57(m，3H)；3.08-3.22(m，1H)；2.69-2.81(m，1H)；2.61(s，3H)；2.29-2.51(m，2H)；1.37-1.48(m，12H)；1.02(d，J＝6.26Hz，3H)。

Step 2: 6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

(3S) -tert-butyl 4- ((1R) -1- (5- (6- (bis (4-methoxybenzyl) amino) -2-methyl-4-pyrimidinyl) -6-fluoro-3-pyridinyl) ethyl) -3-methyl-1-piperazinecarboxylate (0.240g, 0.358mmol) of CH at 0 deg.C₂Cl₂(5mL) the solution was treated with TFA (0.53mL, 7.16 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated and resuspended in CH₂Cl₂In and with NaHCO₃Aqueous (saturated) treatment. The layers are separated and substituted with CH₂Cl₂(2X) extract the aqueous layer. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give 6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.200g, 0.350mmol, 98% yield) as a pale yellow oil. M/z (ESI, cation) 571.3(M + H)⁺。¹HNMR(400MHz，CDCl₃)δ8.39(dd，J＝9.39，2.35Hz，1H)；8.12(s，1H)；7.18(d，J＝7.82Hz，4H)；6.79-6.89(m，5H)；4.74(br.s.，4H)；4.16(q，J＝6.98Hz，1H)；3.79(s，6H)；2.80-2.99(m，4H)；2.53-2.63(m，4H)；2.23-2.41(m，2H)；1.47(s，3H)；1.08(d，J＝6.26Hz，3H)。

And step 3: 6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.200g, 0.350mmol) in CH is reacted at-20 deg.C ₂Cl₂(3mL) solution with NEt₃(0.488mL, 3.50mmol) followed by methanesulfonyl chloride (0.083mL, 1.051 mmol). The mixture was stirred at-20 ℃ for 30 minutes. Followed by the addition of 1M NaOH (aq) and CH₂Cl₂. The layers are separated and substituted with CH₂Cl₂(2X) extract the aqueous layer. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (12g) eluting with a gradient of 60% to 100% EtOAc in hexanes to provide 6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.130g, 0.200mmol, 57.2% yield) as a white foam. M/z (ESI, cation) 649.2(M + H)⁺。 ¹H NMR(400MHz，CDCl₃)δ8.42(dd，J＝9.29，2.45Hz，1H)；8.14(d，J＝1.17Hz，1H)；7.18(d，J＝7.82Hz，4H)；6.81-6.89(m，5H)；4.74(br.s.，4H)；4.04(q，J＝6.78Hz，1H)；3.79(s，6H)；3.28-3.37(m，1H)；3.16-3.24(m，1H)；3.12(dd，J＝10.95，2.93Hz，1H)；2.85-3.01(m，2H)；2.77(s，3H)；2.63-2.70(m，2H)；2.62(s，3H)；1.44(d，J＝6.85Hz，3H)；1.10(d，J＝6.26Hz，3H)。

And 4, step 4: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine

A solution of 6- (2-fluoro-5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.130g, 0.200mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.043g, 0.301mmol) in THF (2.00mL) was treated with lithium bis (trimethylsilyl) amide (1.0M solution in THF) (0.60mL, 0.60mmol) at-10 ℃. After 30 min, more lithium bis (trimethylsilyl) amide (1.0M solution in THF) (0.60mL, 0.60mmol) was added and the reaction mixture was stirred for a further 30 min at-10 ℃. Adding saturated NH ₄Cl (aq) and the mixture was taken up with CH₂Cl₂(3X) extracting. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography over a silica gel column (4g) eluting with a gradient of 0% to 100% EtOAc in hexanes to provide 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.050g, 0.065mmol, 32.4% yield) as a brown oil. M/z (ESI, cation) 771.2(M + H)⁺. And 5: 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine

A mixture of 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -2-methyl-4-pyrimidinamine (0.050g, 0.065mmol) in TFA (1mL) was treated with trifluoromethanesulfonic acid (5.76 μ L, 0.065mmol) and heated to 80 ℃ for 1 h. The reaction mixture was concentrated and subsequently ice was added to the brown residue. Adding saturated NaHCO ₃(aqueous solution) followed by addition of CH₂Cl₂. The layers are separated and substituted with CH₂Cl₂(2X) extract the aqueous layer. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. Adsorbing the crude material on a silica gel packed column and passing throughChromatography through silica gel column (4g) to dissolve in CH₂Cl₂To provide 6- (2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -5- ((1R) -1- ((2S) -2-methyl-4- (methylsulfonyl) -1-piperazinyl) ethyl) -3-pyridinyl) -2-methyl-4-pyrimidinamine (0.010g, 0.019mmol, 29.1% yield) as a brown solid. M/z (ESI, cation) 531.2(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ12.14(s，1H)；8.36(dd，J＝12.91，2.35Hz，1H)；8.22-8.25(m，1H)；8.16(d，J＝2.35Hz，1H)；7.95(dd，J＝1.96，0.39Hz，1H)；7.04(s，2H)；6.79(s，1H)；4.02(q，J＝6.65Hz，1H)；3.94(s，3H)；3.05-3.20(m，2H)；2.77-2.95(m，5H)；2.53(br.s.，3H)；2.45(dd，J＝11.35，5.28Hz，1H)；1.40(d，J＝6.65Hz，3H)；1.10(d，J＝6.26Hz，3H)。

Example 307: n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyrazinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide

Step 1: 6- (3-fluoro-2-pyrazinyl) -2-methyl-4-pyrimidinamine

6-chloro-2-methyl-4-pyrimidinamine (SynChem, Inc., Des Plaines, IL) (0.223g, 1.550mmol), PdCl2(10.99mg, 0.062mmol), tri-tert-butylphosphine tetrafluoroborate (0.036g, 0.124mmol), CuI (0.024g, 0.124mmol), and CsF (0.471g, 3.10mmol) were charged into a microwave tube. Sealing the tube and evacuating and using N₂Backfilling 5 times. Argon was bubbled through the tube and 2-fluoro-3- (tributylstannyl) pyrazine (F. Toudic et al Tetrahedron, 2003, 29, 6375-6384; 1.80g, 4.65mmol) dissolved in DMF (4mL) was added and argon (gas) was bubbled through the solution for 5 minutes. The mixture was heated to 60 ℃ and stirred for 18 h. Water and EtOAc were added and the mixture was passed through Celite (celite) filtration. The layers were separated and the aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (40g) to dissolve in CH₂Cl₂Gradient elution from 0% to 3% MeOH. The product was further purified by HPLC (10 to 90% CH)₃CN and having 0.1% NH₄H of OH₂O, flow rate equal to about 45mL/min) to give 6- (3-fluoro-2-pyrazinyl) -2-methyl-4-pyrimidinamine (0.077g, 0.375mmol, 24.21% yield) as a white solid. M/z (ESI, cation) 206.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ9.54(d，J＝4.50Hz，1H)；8.53(d，J＝8.22Hz，1H)；7.26(s，1H)；5.58(br.s.，2H)；2.63(s，3H)。

Step 2: n- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyrazinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide

To a solution of N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (example 330, step 2) (0.091g, 0.413mmol) in THF (2.5mL) at 0 deg.C was added NaHMDS (1.0M solution in THF) (1.876mL, 1.876 mmol). After addition, at 0 ℃ under N₂The reaction mixture was then stirred for a further 30 min. 6- (3-Fluoropyrazin-2-yl) -2-methylpyrimidin-4-amine (0.077g, 0.375mmol) was added to the reaction mixture. The reaction mixture was stirred for a further 10min at 0 ℃ and then slowly warmed to room temperature. After 1 hour, the reaction mixture was washed with CH in pH 7 buffer (1M TRIS-HCl) ₂Cl₂Are distributed among the devices. The aqueous layer is replaced by CH₂Cl₂(3X) extracting. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude product was purified by HPLC (10-90% CH)₃CN and having 0.1% NH₄H of OH₂O, flow rate equal to about 5 mL/min). Fractions containing the desired product were concentrated in vacuo. The crude material was further chromatographed through a silica gel column (4g) to dissolve in CH₂Cl₂To provide a yellow solid, eluting with a gradient of 0% to 10% MeOHN- (5- ((3- (6-amino-2-methyl-4-pyrimidinyl) -2-pyrazinyl) amino) -2-chloro-3-pyridinyl) methanesulfonamide (0.0080g, 0.020mmol, 5.24% yield). M/z (ESI, cation) 407.0(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ10.12(s，1H)；8.85(s，2H)；8.35(s，1H)；8.23-8.30(m，1H)；7.22(s，1H)；6.87(b r.s.，1H)；3.14(s，3H)；2.42(s，3H)。

Example 308: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

Methylmagnesium bromide (1.4M in 3: 1 toluene/THF) (Aldrich, St. Louis, MO; 1.787mL, 2.502mmol) was added (dropwise over 10 min) to a yellow-brown solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) nicotinaldehyde (example 144, step 1; 451.7mg, 0.782mmol) in THF (5.0mL) at 0 deg.C and the resulting brown solution was stirred for 1h at 0 deg.C. Saturated ammonium chloride (10mL) and water ((10mL) were then added, THF was removed in vacuo and the resulting mixture was extracted with EtOAc (2 × 60mL), the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo the residue was triturated with hexane (10mL) to give 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (331.1mg, 0.558mmol, 71.3% yield) as a yellow-brown solid M/z (ESI, cation) 594.2(M + H) ⁺。

Step 2: methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester

Methanesulfonyl chloride (0.164mL, 2.119mmol) was added to 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (331.1mg, 0.558mmol) and triethylamine (0.350mL, 2.510mmol) in CH at 0 deg.C₂Cl₂(7.5mL) and the resulting mixture was stirred at 0 ℃ for 30 min. Subsequently, the reaction mixture is reacted with CH₂Cl₂(40mL) and water (30 mL). The organic layer was separated and washed with CH₂Cl₂The aqueous layer was extracted (30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester (356.1mg, 0.530mmol, 95% yield) as a yellow-brown solid, which was used directly in step 3.

And step 3: n, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Triethylamine (0.327mL, 2.345mmol) and 3- (methylsulfonyl) azetidine (PharmaBlock, Carrboro, NC; 241mg, 1.786mmol) were added successively to methanesulfonic acid 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl ester (375mg, 0.558mmol) of CH₂Cl₂(5.5mL) and the resulting mixture was stirred at 25 ℃ for 21 h. Subsequently, the reaction mixture was concentrated in vacuo and purified by chromatography (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes) to give N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow oil (141.0mg, 0.198mmol, 35.5% yield). M/z (ESI, cation) 711.3(M + H)⁺。

And 4, step 4: 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate

An orange solution of N, N-bis (4-methoxybenzyl) -4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (70.0mg, 0.098mmol) and trifluoromethanesulfonic acid (0.030mL, 0.338mmol) in TFA (1.5mL) was stirred at 75 ℃ for 18 h. Subsequently, the resulting mixture was cooled to 25 ℃ and concentrated in vacuo. The residue was taken up in DMSO (2.0mL) and purified by rpHPLC (Phenomenex Luna 5. mu. m C1830. mu.1830X 150mm, 35mL/min, 5 to 100% CH ₃CN/H₂O (plus 0.1% TFA, two solvents) was purified to provide 4- (2- (6-methoxypyridin-3-ylamino) -5- (1- (3- (methylsulfonyl) azetidin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine 2, 2, 2-trifluoroacetate as an orange solid (43.6mg, 0.075mmol, 76% yield).¹H NMR(400MHz，d₄-MeOH)δ9.10(d，J＝2.5Hz，1H)，8.70(d，J＝2.7Hz，1H)，8.40(d，J＝2.5Hz，1H)，8.19(dd，J＝9.0，2.7Hz，1H)，7.07(d，J＝9.0Hz，1H)，4.65(q，J＝6.7Hz，1H)，4.54-4.61(m，1H)，4.38-4.53(m，4H)，4.02(s，3H)， 3.05(s，3H)，2.66(s，3H)，2.52(s，3H)，1.67(d，J＝6.8Hz，3H)。¹⁹FNMR(376MHz，d₄MeOH) delta-79.11 (s, 3F). M/z (ESI, cation) 471.3(M + H)⁺。

Example 309: (R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Sodium bis (trimethylsilyl) amide (1.0M in THF) (Aldrich, st. louis, MO; 0.777mL, 0.777mmol) was added to (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 146, step 6)141.2mg, 0.222mmol) and 6-chloropyridin-3-amine (Aldrich, st. louis, MO) at 0 ℃; 57.1mg, 0.444mmol) in THF (2.5mL) and the resulting dark brown solution was stirred at 0 deg.C for 30 min. Followed by NH ₄Saturated aqueous Cl (2mL) quenched excess sodium bis (trimethylsilyl) amide and the reaction mixture was quenched in EtOAc (50mL) with NH₄The mixture was partitioned between saturated aqueous Cl (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 20 mL). The combined organic extracts were washed successively with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) afforded (R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (125.0mg 0.168mmol, 76% yield) as a yellow-brown oil.¹H NMR(400MHz，CDCl₃) δ 12.12(s, 1H), 8.74(d, J ═ 2.2Hz, 1H), 8.50(s, 1H), 8.28(s, 1H), 8.18-8.24(m, 1H), 7.21(td, J ═ 5.7, 2.4Hz, 5H), 6.89(s, 2H), 6.85(d, J ═ 8.6Hz, 2H), 4.74-4.93(m, 4H), 3.81(s, 3H), 3.79(s, 3H), 3.52-3.59(m, 1H), 3.15(br.s., 4H), 2.67(s, 3H), 2.60(s, 3H), 2.47-2.58(m, 4H), 1.38(d, J ═ 6.7Hz, 3H). M/z (ESI, cation) 744.2(M + H)⁺。

Step 2: (R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A brown solution of (R) -4- (2- (6-chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (125.0mg, 0.168mmol) and trifluoromethanesulfonic acid (0.15mL, 1.689mmol) in TFA (1.5mL) was stirred at 75 ℃ for 1.5 h. Followed byThe mixture was cooled to 25 ℃ and concentrated in vacuo. The residue is taken up in CH₂Cl₂(50mL), and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (40 mL). The organic layer was separated and washed with CH₂Cl₂The aqueous layer was extracted (2X 30 mL). Subsequently, all organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 10% MeOH/CH)₂Cl₂) (R) -4- (2- (6-Chloropyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine was obtained as a yellow solid (52.8mg, 0.105mmol, 62.4% yield).¹H NMR(400MHz，d₆-DMSO) δ 12.16(s, 1H), 8.88(d, J ═ 2.7Hz, 1H), 8.74(d, J ═ 2.5Hz, 1H), 8.48(dd, J ═ 8.7, 2.8Hz, 1H), 8.35(d, J ═ 2.3Hz, 1H), 7.45(d, J ═ 8.8Hz, 1H), 3.59(q, J ═ 6.8Hz, 1H), 3.09(t, J ═ 4.5Hz, 4H), 2.86(s, 3H), 2.56(br.s., 2H), 2.46(s, 3H), 2.41-2.45(m, 2H), 1.36(d, J ═ 6.7Hz, 3H). M/z (ESI, cation) 504.1(M + H) ⁺。

Example 310: (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine 2, 2, 2-trifluoroacetate

Step 1: (R) -N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine

Sodium bis (trimethylsilyl) amide (1.0M in THF) (Aldrich, St. Louis, MO; 0.863mL, 0.863mmol) was added to (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 146, step 6)156.7mg, 0.246mmol) and quinolin-7-amine (Ark Pharm, L)ibertyville, IL; 71.1mg, 0.493mmol) in THF (2.5mL) and the resulting dark brown solution was stirred at 0 deg.C for 2 h. Followed by NH₄Saturated aqueous Cl (2mL) quenched excess sodium bis (trimethylsilyl) amide and the reaction mixture was quenched in EtOAc (50mL) with NH₄The mixture was partitioned between saturated aqueous Cl (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 20 mL). The combined organic extracts were washed successively with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 6% MeOH/CH) ₂Cl₂) (R) -N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine (189mg, 0.249mmol, 101% yield) was obtained as a yellow-orange foam, which was used directly in step 2. M/z (ESI, cation) 760.3(M + H)⁺。

Step 2: (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine 2, 2, 2-trifluoroacetate

A brown solution of (R) -N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine (170.8mg, 0.225mmol) and trifluoromethanesulfonic acid (0.2mL, 2.252mmol) (10% v/v with TFA) in TFA (2.0mL) was stirred at 75 ℃ for 1.5 h. Subsequently, the reaction mixture was cooled to 25 ℃ and concentrated in vacuo. The residue is taken up in CH₂Cl₂(50mL), and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (40 mL). The organic layer was separated and washed with CH₂Cl₂The aqueous layer was extracted (2X 30 mL). Subsequently, all organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in DMSO (2.0mL) and purified by rpHPLC (Phenomenex Luna 5. mu. m C1830X 150mm, 45mL/min, 10 to 100% CH ₃CN/H₂O (plus 0.1% TFA, two solvents) to afford (R) -N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-2-yl) quinolin-7-amine as a yellow-orange solid2, 2, 2-Trifluoroacetate (52.0mg, 0.082mmol, 36.5% yield).¹H NMR(400MHz，d₄-MeOH)δ9.52(d，J＝1.8Hz，1H)，9.18(d，J＝2.5Hz，1H)，8.99(d，J＝8.2 Hz，1H)，8.96(dd，J＝5.6，1.3Hz，1H)，8.68(d，J＝2.5Hz，1H)，8.25(d，J＝9.2Hz，1H)，8.04(dd，J＝9.0，2.0Hz，1H)，7.83(dd，J＝8.0，5.7Hz，1H)，4.70(q，J＝7.0Hz，1H)，3.55(br.s.，4H)，2.94(s，3H)，2.65(s，4H)，2.58(s，3H)，1.89(d，J＝6.8Hz，3H)。¹⁹F NMR(376MHz，d₄MeOH) delta-77.36 (s, 3F). M/z (ESI, cation) 520.2(M + H)⁺。

Example 311: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropan-1-ol

Step 1: 2- (6-Fluoropyridin-3-yl) acetic acid tert-butyl ester

(2-tert-butoxy-2-oxoethyl) zinc (II) chloride (0.5M in ether) (Riekemetals, Inc., Lincoln, NE; 73.9mL, 36.9mmol) was added to a mixture of 5-bromo-2-fluoropyridine (Acros, Morris Plains, N J; 2.92mL, 28.4mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St.Louis, MO 0.201g, 0.284mmol) in THF (150mL) and the resulting yellow solution was stirred in a flask fitted with an air-cooled reflux condenser at 65 ℃ for 1.5 h. Water (200 μ L) was added to the reaction, and the resulting mixture was concentrated on silica gel and purified by chromatography (silica gel, 0 to 30% EtOAc/hexanes) to provide tert-butyl 2- (6-fluoropyridin-3-yl) acetate as a yellow oil (2.43g, 11.50mmol, 40.5% yield). ¹H NMR(400MHz，CDCl₃) δ 8.09(s, 1H), 7.74(td, J ═ 8.0, 2.5Hz, 1H), 6.90(dd, J ═ 8.4, 2.9Hz, 1H), 3.52(s, 2H), 1.44(s, 9H). M/z (ESI, cation) 212.1(M + H)⁺。

Step 2: 2- (6-Fluoropyridin-3-yl) -2-methylpropionic acid tert-butyl ester

Potassium tert-butoxide (2.71g, 24.16mmol) was added to a mixture of tert-butyl 2- (6-fluoropyridin-3-yl) acetate (2.43g, 11.50mmol) and methyl iodide (1.511mL, 24.16mmol) in THF (100mL) at-78 deg.C and the resulting yellow-orange mixture was stirred at-78 deg.C for 7h, then allowed to warm to 25 deg.C and stirred for 20 h. The resulting off-white suspension was then concentrated on silica gel and purified by chromatography (silica gel, 0 to 20% EtOAc/hexanes) to provide tert-butyl 2- (6-fluoropyridin-3-yl) -2-methylpropionate as a colorless oil (2.07g, 8.65mmol, 75% yield).¹H NMR(400MHz，CDCl₃)δ8.20(d，J＝2.3Hz，1H)，7.73-7.79(m，1H)，6.88(dd，J＝8.6，3.1Hz，1H)，1.56(s，6H)，1.38(s，9H)。¹⁹F NMR(377MHz，CDCl₃) Delta-71.44 (d, J ═ 4.8Hz, 1F). M/z (ESI, cation) 240.2(M + H)⁺。

And step 3: 2- (6-Fluoropyridin-3-yl) -2-methylpropan-1-ol

Lithium aluminum hydride (1.0M in THF) (Aldrich, St. Louis, MO; 12.98mL, 12.98mmol) was added (gas evolution) to a solution of tert-butyl 2- (6-fluoropyridin-3-yl) -2-methylpropionate (2.07g, 8.65mmol) in THF (34mL) at 0 deg.C and the resulting solution was stirred for 5min at 0 deg.C. EtOAc (15mL) was then added at 0 ℃ to quench excess lithium aluminum hydride, followed by 10% aqueous sodium potassium tartrate (150 mL). The resulting mixture was stirred for 10min at 25 ℃ and then partitioned between EtOAc (200mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were washed with brine (150mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2- (6-fluoropyridin-3-yl) -2-methylpropan-1-ol as a colorless oil (1.46g, 8.63mmol, 100% yield). ¹H NMR(400MHz，CDCl₃)δ8.22(br.s.，1H)，7.78-7.84(m，1H)，6.89(dd，J＝8.6，3.1Hz，1H)，3.63(s，2H)，1.36(s，6H)。¹⁹F NMR(377MHz，CDCl₃) Delta-72.21 (br.s., 1F). M/z (ESI, cation) 170.2(M + H)⁺。

And 4, step 4: 5- (1- (tert-Butyldimethylsilanyloxy) -2-methylpropan-2-yl) -2-fluoropyridine

Tert-butyldimethylsilyl trifluoromethanesulfonate (2.180mL, 9.49mmol) was added to a solution of 2- (6-fluoropyridin-3-yl) -2-methylpropan-1-ol (1.46g, 8.63mmol) and N, N-diisopropylethylamine (3.31mL, 18.98mmol) in CH2Cl2(43.1mL) at 0 deg.C, and the resulting mixture was stirred at 0 deg.C for 30 min. Subsequently, the reaction mixture was concentrated on silica gel and chromatographed (silica gel, 0 to 15% EtOAc/hexanes) to provide 5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridine as a colorless oil (2.22g, 7.83mmol, 91% yield).¹H NMR(400MHz，CDCl₃)δ8.20(d，J＝2.0Hz，1H)，7.79(td，J＝8.2，2.7Hz，1H)，6.85(dd，J＝8.6，2.9Hz，1H)，3.51(s，2H)，1.31(s，6H)，0.83(s，9H)，-0.06(s，6H)。¹⁹F NMR(377MHz，CDCl₃) Delta-73.08 (d, J ═ 6.0Hz, 1F). M/z (ESI, cation) 284.3(M + H)⁺。

And 5: 5- (1- (tert-Butyldimethylsilanyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-ylboronic acid

N-butyllithium (1.66M in hexane) (Aldrich, St. Louis, MO; 0.429mL, 0.712mmol) was added (dropwise, over 1 min) to a solution of 5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridine (183.5mg, 0.647mmol) in THF (3.3mL) at-78 deg.C and the resulting yellow solution was stirred for 1h at-78 deg.C. Triisopropyl borate (Aldrich, St. Louis, MO, 0.179mL, 0.777mmol) was then added and the resulting mixture stirred at-78 ℃ for 1 h. Subsequently, the reaction mixture was partitioned between EtOAc (50mL) and water (30mL) (1N HCl (about 200 μ L) was added to bring the pH of the aqueous layer to 6.5). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-ylboronic acid (228.0mg, 0.697mmol, 108% yield) as a colorless oil. M/z (ESI, cation) 328.3(M + H) ⁺。

Step 6: 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-ylboronic acid (177mg, 0.541mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9; 78mg, 0.541mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO; 19.15mg, 0.027mmol) and potassium acetate (159mg, 1.622mmol) in bis (tert-butyl-4-dimethylaminophenyl) phosphine, under argon at 100 deg.CA yellow solution in a mixture of alkane (4.0mL) and water (1.0mL) was stirred for 2 h. Subsequently, the yellow reaction mixture is reacted in CH₂Cl₂(80mL) and water (50 mL). The organic layer was separated and washed with CH₂Cl₂The aqueous layer was extracted (2X 30 mL). The combined organic extracts were then dried over sodium sulfate and concentrated with silica gel. Chromatographic purification (silica gel, 0 to 60% EtOAc/hexanes) afforded 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (73.0mg, 0.186mmol, 34.5% yield) as a white solid.¹H NMR(400MHz，CDCl₃)δ8.56(dd，J＝9.2，2.5Hz，1H)，8.33(d，J＝1.4Hz，1H)，5.65(br.s.，2H)，3.57(s，2H)，2.54(s，3H)，1.37(s，6H)，0.84(s，9 H)，-0.03(s，6H)。¹⁹F NMR(377MHz，CDCl₃) Delta-70.17 (d, J ═ 9.2Hz, 1F). M/z (ESI, cation) 392.3(M + H)⁺。

And 7: 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Sodium bis (trimethylsilyl) amide (1.0M in THF) (Aldrich, St. Louis, MO; 0.447mL, 0.447mmol) was added to 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-fluoropyridin-3-yl) -one at 0 deg.C6-methyl-1, 3, 5-triazin-2-amine (73.0mg, 0.186mmol) and 5-fluoro-6-methoxypyridin-3-amine (Andhem, North Brunswick, NJ; 31.8mg, 0.224mmol) in THF (2.0mL) in an orange-brown solution and the resulting brown solution was stirred at 0 deg.C for 1 h. Carefully using NH₄Saturated aqueous Cl (5mL) quenched excess sodium bis (trimethylsilyl) amide and the resulting mixture was in CH₂Cl₂(50mL) with NH₄The solution was partitioned between half-saturated aqueous Cl (30 mL). The aqueous layer is replaced by CH₂Cl₂(30mL) extracted, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) afforded 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (88.8mg, 0.173mmol, 93% yield) as a yellow-orange solid. M/z (ESI, cation) 514.0(M + H)⁺. And 8: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropan-1-ol

Tetra (n-butyl) ammonium fluoride (1.0M in THF) (Fluka, St. Louis, Mo; 0.432mL, 0.432mmol) was added to a solution of 4- (5- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (88.8mg, 0.173mmol) in orange brown THF (2.0mL) at 0 deg.C and the resulting brown solution was stirred for 10min at 0 deg.C followed by 3h at 25 deg.C. Subsequently, the reaction mixture was concentrated on silica gel and purified by chromatography (silica gel, 0 to 100% EtOAc/hexanes) to provide 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropan-1-ol as a yellow solid (44.0mg, 0.110mmol, 63.7% yield).¹H NMR(400MHz，d₆-DMSO)δ11.87(s，1H)，8.81(d，J＝2.7Hz，1H)，8.37-8.43(m，3H)，7.86(br.s.，1H)，7.72(br. s.，1H)，4.75(br.s.，1H)，3.93(s，3H)，3.43(s，2H)，2.44(s，3H)，1.27(s，6H)。¹⁹F NMR(377MHz，d₆-DMSO) δ -139.89to-139.79(m, 1F). m/z (ESI, cation) 400.3(M+H)⁺。

Example 312: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol

Step 1: 2-fluoro-5- (prop-1-en-2-yl) pyridine

5-bromo-2-fluoropyridine (Acros, Morris Plains, NJ; 1.737mL, 16.88mmol), potassium trifluoro (prop-1-en-2-yl) borate (Aldrich, St. Louis, MO; 3.75g, 25.3mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St. Louis, MO; 0.239g, 0.338mmol) and potassium carbonate (7.00g, 50.6mmol) were dissolved in di-tert-butyl (4-dimethylaminophenyl) phosphine at 80 deg.C A dark wine red solution in a mixture of alkane (40mL) and water (10.00mL) was stirred for 2.5 h. Subsequently, the reaction mixture was cooled to 25 ℃ and in CH₂Cl₂(300mL) and water (100 mL). The aqueous layer is replaced by CH₂Cl₂(2 × 100mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated with silica gel. Chromatographic purification (silica gel, 0 to 20% EtOAc/hexanes) afforded 2-fluoro-5- (prop-1-en-2-yl) pyridine as a colorless oil (2.06g, 15.02mmol, 89% yield).¹H NMR(400MHz，CDCl3)δppm 8.29(d，J＝2.5Hz，1H)，7.81-7.89(m，1H)，6.89(dd，J＝8.5，3.0Hz，1H)，5.36(s，1H)，5.16(s，1H)，2.15(s，3H)。¹⁹F NMR (377MHz, CDCl3) delta-70.28 (br.s., 1F). M/z (ESI, cation) 138.1(M + H)⁺。

Step 2: 2- (6-Fluoropyridin-3-yl) propan-1-ol

Borane tetrahydrofuran complex (1.0M in THF) (Aldrich, St. Louis, MO; 15.75mL, 15.75mmol) was added to 2-fluoro-5- (prop-1-en-2-yl) at 0 deg.CPyridine (1.44g, 10.50mmol) in THF (70mL) and the resulting mixture stirred under argon at 25 ℃ for 1.5 h. Subsequently, the resulting mixture was cooled to 0 ℃ and sodium hydroxide (2.5N aqueous solution; 5.25mL, 13.12mmol) and hydrogen peroxide (30% aqueous solution) (Columbus Chemical Industries, Columbus, Wis; 1.877mL, 18.37mmol) were added successively (gas evolution) and the resulting pale yellow solution was stirred at 60 ℃ for 1.25 h. The reaction mixture was then partially concentrated in vacuo (to remove THF) and washed with EtOAc (300mL) and NaHCO ₃Half-saturated aqueous solution (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 100 mL). The combined organic extracts were washed with brine (200mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc in hexanes) afforded 2- (6-fluoropyridin-3-yl) propan-1-ol as a colorless oil (0.951g, 6.13mmol, 58.4% yield).¹H NMR(400MHz，CDCl₃)δ8.10(d，J＝2.0Hz，1H)，7.68(td，J＝8.0，2.5Hz，1H)，6.90(dd，J＝8.4，2.9Hz，1H)，3.67-3.79(m，2H)，3.00(sxt，J＝6.8Hz，1H)，1.31(d，J＝7.0Hz，3H)。¹⁹F NMR (377MHz, CDCl3) delta ppm-71.31(br.s., 1F). M/z (ESI, cation) 156.2(M + H)⁺。

And step 3: 5- (1- (tert-Butyldimethylsilanyloxy) propan-2-yl) -2-fluoropyridine

Tert-butyldimethylsilyl trifluoromethanesulfonate (2.160mL, 9.41mmol) was added to 2- (6-fluoropyridin-3-yl) propan-1-ol (1.39g, 8.96mmol) and N, N-diisopropylethylamine (3.35mL, 19.26mmol) in CH at 0 deg.C₂Cl₂(45mL) and the resulting mixture was stirred at 0 ℃ for 2.5 h. Subsequently, the reaction mixture was concentrated on silica gel and chromatographed (silica gel, 0 to 20% EtOAc/hexanes) to provide 5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridine (1.89g, 7.01mmol, 78% yield) as a colorless oil.¹H NMR(400MHz，CDCl₃)δ8.06(d，J＝2.2Hz，1H)，7.65(td，J＝8.1，2.5Hz，1H)，6.86(dd，J＝8.4，2.9Hz，1H)，3.58-3.69(m，2H)，2.93(sxt，J＝6.7Hz，1H)，1.28(d，J＝7.0Hz，3H)，0.84(s，9H)，-0.04(s，3H)，-0.05(s，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-72.06 (d, J ═ 6.0Hz, 1F). M/z (ESI, cation) 270.3(M + H) ⁺。

And 4, step 4: 5- (1- (tert-Butyldimethylsilanyloxy) propan-2-yl) -2-fluoropyridin-3-ylboronic acid

N-butyllithium (1.55M in hexane) (Aldrich, St. Louis, MO; 4.98mL, 7.72mmol) was added (dropwise, over 5 min) to a solution of 5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridine (1.89g, 7.01mmol) in THF (35mL) at-78 deg.C, and the resulting yellow solution was stirred for 1h at-78 deg.C. Subsequently, triisopropyl borate (Aldrich, St. Louis, MO; 1.935mL, 8.42mmol) was added and the resulting mixture was stirred at-78 ℃ for 1 h. Subsequently, the reaction mixture was partitioned between EtOAc (250mL) and water (90mL) (1N aqueous HCl (12.0mL) was added to bring the pH to about 6.5). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridin-3-ylboronic acid (2.25g, 7.18mmol, 102% yield) as a colorless oil, which was used directly in the next step. M/z (ESI, cation) 314.2(M + H)⁺。

And 5: 4- (5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

5- (1- (tert-Butyldimethylsilanyloxy) propan-2-yl) -2-fluoropyridin-3-ylboronic acid (1.79g, 5.71mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9; 0.826g, 5.71mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich, St.Louis, MO; 0.202g, 0.mmol) and potassium acetate (1.286 g, 17.14mmol) dissolved in bis (tert-butyl) phosphine) at 100 ℃ under argonYellow solution in a mixture of alkane (50mL) and water (12.50mL)Stirring for 2 h. Subsequently, the yellow reaction mixture is reacted in CH₂Cl₂(200mL) and half-saturated saline (100 mL). The organic layer was separated and washed with CH₂Cl₂The aqueous layer was extracted (2X 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated with silica gel. Chromatographic purification (silica gel, 0 to 70% EtOAc/hexanes) afforded 4- (5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (1.11g, 2.94mmol, 51.5% yield) as a colorless oil.¹HNMR(400MHz，CDCl₃)δ8.44(dd，J＝9.3，2.4Hz，1H)，8.19(d，J＝1.4Hz，1H)，5.49(br.s.，2H)，3.63-3.76(m，2H)，2.96-3.07(m，1H)，2.55(s，3H)，1.34(d，J＝7.0Hz，3H)，0.85(s，9H)，-0.02(s，3H)，-0.03(s，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-68.99 (d, J ═ 6.0Hz, 1F). M/z (ESI, cation) 378.3(M + H)⁺. Step 6: 4- (5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Sodium bis (trimethylsilyl) amide (1.0M in THF) (Aldrich, St. Louis, MO; 1.279mL, 1.279mmol) was added to a brown solution of 4- (5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (201.2mg, 0.533mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, NJ; 91mg, 0.640mmol) in THF (5.0mL) at 0 deg.C and the resulting brown solution was stirred at 0 deg.C for 1.5 h. Additional sodium bis (trimethylsilyl) amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.300mL, 0.300mmol) was then added and the resulting mixture was stirred at 0 deg.C for 30 min. Carefully using NH₄Saturated aqueous Cl (5mL) quenched excess sodium bis (trimethylsilyl) amide and the resulting mixture was in CH₂Cl₂(50mL) with NH₄The solution was partitioned between half-saturated aqueous Cl (30 mL). The aqueous layer is replaced by CH₂Cl₂(30mL) extracted, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc in hexanes) afforded4- (5- (1- (tert-Butyldimethylsilanyloxy) propan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (241.0mg, 0.482mmol, 91% yield) as a yellow-orange solid. ¹H NMR(400MHz，CDCl₃)δ11.82(s，1H)，8.73(d，J＝2.5Hz，1H)，8.26(dd，J＝12.3，2.2Hz，1H)，8.22(d，J＝2.3Hz，1H)，8.04(d，J＝2.3Hz，1H)，5.40(br.s.，2H)，4.02(s，3H)，3.67(dd，J＝6.2，2.8Hz，2H)，2.91(q，J＝6.5Hz，1H)，2.57(s，3H)，1.32(d，J＝7.0Hz，3H)，0.87(s，9H)，0.00(s，3H)，-0.01(s，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-139.42 (s, 1F). M/z (ESI, cation) 500.3(M + H)⁺。

And 7: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol

Tetra (n-butyl) ammonium fluoride (1.0M in THF) (Fluka, St. Louis, Mo; 1.206mL, 1.206mmol) was added to an orange-brown solution of 4- (5- (1- (tert-butyldimethylsilyloxy) propan-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (241.0mg, 0.482mmol) in THF (5.0mL) at 25 deg.C and the resulting mixture was stirred for 2h at 25 deg.C. Subsequently, the reaction mixture was concentrated on silica gel and purified by chromatography (silica gel, 0 to 100% EtOAc/hexanes) to provide 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol as a yellow solid (139.0mg, 0.361mmol, 74.8% yield).¹H NMR(400MHz，d₆-DMSO)δ11.88(s，1H)，8.66(d，J＝2.5Hz，1H)， 8.41(d，J＝2.2Hz，1H)，8.35-8.40(m，1H)，8.25(d，J＝2.5Hz，1H)，7.88(br.s.，1H)，7.74(br.s.，1H)，4.70(br.s.，1H)，3.93(s，3H)，3.49(d，J＝6.5Hz，2H)，2.83(sxt，J＝6.9Hz，1H)，2.44(s，3H)，1.22(d，J＝7.0Hz，3H)。¹⁹F NMR(376MHz，d₆-DMSO) δ -139.83(d, J ═ 13.0Hz, 1F). M/z (ESI, cation) 386.2(M + H)⁺。

And 8: (R) -2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol and (S) -2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol

The isomeric mixture of 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-1-ol was separated into its constituent enantiomers by Supercritical Fluid Chromatography (SFC) using the following conditions:

column: chiralpakIC(21×250mm，5μm)

Mobile phase: 78: 22 (A: B)

A: liquid CO₂

B: methanol (0.2% diethylamine)

Flow rate: 50mL/min

Oven/column temperature: 40 deg.C

1.1 mg/injection (repeat injection)

Two separate peaks containing both enantiomers were collected, concentrated in vacuo and dried under high vacuum to give both enantiomers. Absolute stereochemistry was not determined.

First elution peak:

¹H NMR(400MHz，CDCl₃)δ11.84(s，1H)，8.72(d，J＝2.2Hz，1H)，8.22-8.30(m，2H)，8.03(d，J＝2.0Hz，1H)，5.38(br.s.，2H)，4.02(s，3H)，3.75(d，J＝6.8Hz，2H)，2.93-3.01(m，1H)，2.57(s，3H)，1.33(d，J＝6.8Hz，3H)。¹⁹F NMR(377MHz，CDCl₃) Delta-138.86 (d, J ═ 12.6Hz, 1F). M/z (ESI, cation) 386.2(M + H)⁺。

Second elution peak:

¹H NMR(400MHz，CDCl₃) δ 11.85(br.s., 1H), 8.81(d, J ═ 1.2Hz, 1H), 8.27(d, J ═ 1.8Hz, 1H), 8.13(dd, J ═ 13.1, 2.2Hz, 1H), 8.03(d, J ═ 2.0Hz, 1H), 5.61(br.s., 2H), 4.03(s, 3H), 3.69-3.82(m, 2H), 2.95-3.03(m, 1H), 2.59(s, 3H), 1.33(d, J ═ 7.0Hz, 3H). M/z (ESI, cation) 386.2(M + H)⁺。

Chiral SFC analysis showed that the two separated enantiomers had ee > 98%.

Example 313: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi Block, Inc., 2.507g, 14.30mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 51; 5.24g, 13.62mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich; 0.482g, 0.681mmol) and potassium acetate (4.10g, 41.8mmol) in ethanol (100mL) and water (10mL) was degassed at 100 ℃ in N (2-fluoro-2-yl) boronic acid₂Stirring for 16 h. The reaction mixture was cooled, concentrated, and the residue partitioned between water (50mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2X 20mL) and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate and filteredAnd concentrated. Chromatographic purification of the residue (silica gel, 15% to 50% EtOAc/hexanes) afforded 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.62g, 7.54mmol, 55.4% yield). M/z (ESI, cation) 480(M + H)⁺。

Step 2: 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A stirred solution of 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, NJ; 0.834g, 5.87mmol) and 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.8776g, 3.91mmol) in THF (50.0mL, 610mmol) was treated dropwise with LiHMDS (1.0M in THF, 16.74mL, 16.74mmol) at-15 deg.C (ice-salt bath) and stirred for 40 min. Subsequently, the reaction was washed with water and saturated NH₄Cl (aq) (25mL each) was quenched and diluted with EtOAc (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2X 50 mL). Subsequently, the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. Chromatographic purification of the residue (silica gel, 0% to 1% MeOH/DCM) followed by washing of the purified product with isopropanol gave 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.07g, 3.44mmol, 88% yield).¹H NMR(400MHz，CDCl₃)δ8.77(d，J＝2.54Hz，1H)；8.23(d，J＝2.54Hz，1H)；7.95(d，J＝1.96Hz，1H)；7.90(d，J＝12.13Hz，1H)；7.18(dd，J＝17.41，8.41Hz，4H)；6.86(t，J＝8.12Hz，4H)；4.86(s，2H)；4.82(s，2H)；4.01(s，3H)；3.81(s，3H)；3.79(s，3H)；2.60(s，3H)。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((4- (methylsulfonyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

From 4- (5-chloro-2- (5) by a procedure similar to that described previously in example 270, step 1 and steps 4 through 5 -fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine and tert-butyl 3- (trifluoromethyl) piperazine-1-carboxylate (Anichem, Inc.) the title compound was prepared and isolated as a yellow solid. M/z (ESI, cation) 572(M + H)⁺。¹H NMR(400MHz，CDCl₃)δ11.93(s，1H)8.74(d，J＝2.35Hz，1H)8.28(d，J＝2.35Hz，1H)8.25(dd，J＝12.23，2.25Hz，1H)8.04(d，J＝2.15Hz，1H)5.45(br.s.，2H)4.03(s，3H)3.85-3.97(m，2H)3.80(dd，J＝12.42，2.25Hz，1H)3.44-3.54(m，1H)3.33-3.40(m，1 H)3.27(dd，J＝12.32，1.76Hz，1H)2.97-3.16(m，2H)2.83(s，3H)2.63-2.73(m，1H)2.58(s，3H)。

Example 314: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol

The title compound was prepared from 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2, 2, 2-trifluoroethanol following a procedure analogous to example 269 and was isolated as a yellow solid. M/z (ESI, cation) 426(M + H)⁺。 ¹H NMR(400MHz，d₆-DMSO)δ12.06(s，1H)8.95(s，1H)8.41(d，J＝1.76Hz，2H)8.35(d，J＝12.52Hz，1H)7.97(br.s.，1H)7.81(br.s.，1H)6.97(d，J＝5.48Hz，1H)4.97-5.51(m，1H)3.94(s，3H)2.45(s，3H)。

Example 315: (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

(S) -3-methylmorpholine (Aldrich, 0.105g, 1.041mmol) and 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (example 143, step 2; 0.310g, 0.520mmol) were suspended in THF (3mL) and titanium (IV) ethoxide (0.60mL, 2.90mmol) was added. The mixture was sealed and heated at 70 ℃ overnight. The light brown solution was cooled to 0 ℃ and excess sodium cyanoborohydride (0.327g, 5.20mmol) was added and the mixture was stirred at 0 ℃ for 2 h. The resulting solution was quenched with a few drops of MeOH followed by water. DCM was added to the whole mass and stirred vigorously for 10 min. The mixture was filtered and passed through Celite (diatomaceous earth) short tubular column. The filter cake was washed with DCM (3X 10 mL). The combined organic phases were concentrated to give a crude residue. Flash column chromatography purification (short column, SiO)₂100% DCM to 5% MeOH in DCM) afforded (S) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methylmorpholino) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (375mg) as a yellow solid, which was deprotected under similar conditions according to the procedure reported hereinbefore (example 178, step 4) to give the title compound as a yellow solid (199mg, 82%). M/z (ESI, cation) 441(M + H)⁺。¹H NMR(400MHz，CDCl₃) δ (rotamer mixture) 12.09(br.s., 1H)9.01(br.s., 1H)8.15-8.56(m, 2H)8.05(br.s., 1H)7.26(br.s., 1H)4.88-6.53(m, 1H)4.32(br.s., 1H)4.03(br.s., 3H)3.84(br.s., 4H)3.57(br.s., 2H)2.91(br.s., 2H)2.55(br.s., 3H)1.21(d, J ═ 5.28Hz, 3H).

Example 316: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester

In a 5mL microwave tube, 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.00g, 2.084 mmol; example 313, step 1), 2- (dicyclohexylphosphino) -2, 4, 6, -triisopropyl-1, 1' -biphenyl (0.099g, 0.208mmol), cesium carbonate (2.037g, 6.25mmol), (R) - ((4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) methyl) potassium trifluoroborate (obtained from (R) -4-N-boc-2-methyl-piperazine (Sigma Adrich, inc.), 0.701g, 2.188mmol, prepared similarly), palladium acetate (0.023g, 0.104mmol), followed by purging with argon. Subsequently, the solid was treated with THF (10.00mL), water (1.0mL) and heated at 85 ℃ overnight under microwave irradiation. Passing the mixture through CeliteShort column filtration (celite), washing with ethyl acetate (3 ×) and concentration. The crude product was adsorbed onto a silica gel packed column and chromatographed via silica gel column (100% DCM to 5% MeOH in DCM) to give the desired product 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester as a yellow foam (1.01g, 1.535mmol, 73.7% yield). M/z (ESI, cation) 658(M + H) ⁺. Step 2: (R) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a slightly cooled stirred solution of 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) methyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester (1.01g, 1.535mmol) in DCM (5.0mL, 78mmol) was slowly added TFA (4.00mL, 51.9mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the viscous residue was taken up in DCMTo this solution (10.0mL) was then added TEA (2.140mL, 15.35mmol) and methanesulfonyl chloride (0.598mL, 7.68mmol) slowly at 0 ℃. At the same temperature, the mixture was stirred for 1h, concentrated and the crude product was partitioned between 1n naoh (aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2X 20mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetate dissolved in hexanes) to afford the desired product (R) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.4779g, 0.752mmol, 49.0% yield) as a pale yellow foam. M/z (ESI, cation) 636(M + H) ⁺。

And step 3: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (0.118g, 0.827mmol) and (R) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.4779g, 0.752mmol) in THF (10.00mL) at-10 ℃ was added dropwise 1.0MLiHMDS (Aldrich; 2.255mL, 2.255mmol) dissolved in THF and the mixture was stirred at the same temperature for 30 min. The reaction was washed with water and saturated NH₄Cl (aq) (25mL each) was quenched and diluted with EtOAc (25 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 50mL), and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 0% to 1% DCM in MeOH) followed by washing with IPA to obtain the desired product (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.377g, 0.497 mmo) l, yield 66.2%).

And 4, step 4: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared from (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine by a similar deprotection step as described previously in example 178 step 4 using trifluoroacetic acid and trifluoromethanesulfonic acid and was isolated as a yellow solid. M/z (ESI, cation) 518(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.95(s，1H)8.71(d，J＝2.35Hz，1H)8.41(d，J＝2.15Hz，1H)8.33-8.40(m，1H)8.27(d，J＝2.15Hz，1H)7.90(br.s.，1H)7.76(br.s.，1H)3.93(s，3H)3.91(s，1H)3.13-3.30(m，3H)2.87-2.95(m，1H)2.85(s，3H)2.53-2.79(m，3H)2.44(s，3H)2.14-2.28(m，1H)1.16(d，J＝6.26Hz，3H)。

Example 317: (S) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared by a procedure similar to that described in example 316 above from 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc.) and (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (prepared similarly from (S) -tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.) as reported in examples 316, steps 1 to 2) and isolated as a yellow solid. M/z (ESI, cation) 534(M + H) ⁺.¹H NMR(400MHz， d₆-DMSO)δ11.99-12.52(m，1H)8.76-9.96(m，1H)8.15-8.63(m，3H)6.57-8.07(m，2H)4.09-5.06(m，2H)3.94(s，3H)3.59-3.86(m，2H)2.86-3.35(m，7H)2.46(s，3H)0.96-1.58(m，4H)。

Example 318: (S) -4- (2- (6-chloropyridin-3-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared by a procedure similar to that described in example 316 above from 6-chloropyridin-3-amine (sigmaldrich, Inc.) and (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (prepared similarly to 3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (Sigma Aldrich, Inc.) as reported in examples 316 steps 1 to 2) and isolated as a yellow solid. M/z (ESI, cation) 504(M + H)⁺。¹H NMR(400MHz，d-DMSO)δ12.16(s，1H)8.88(d，J＝2.74Hz，1H)8.73(d，J＝2.35Hz，1H)8.47(dd，J＝8.71，2.84Hz，1H)8.31(d，J＝2.35Hz，1H)7.93(br.s.，1H)7.78(br.s.，1H)7.45(d，J＝8.61Hz，1H)3.94(d，J＝13.11Hz，1H)3.07-3.29(m，3H)2.86-2.97(m，1H)2.85(s，3H)2.64-2.79(m，2H)2.54-2.64(m，1H)2.45(s，3H)2.14-2.29(m，1H)1.16(d，J＝6.06Hz，3H)。

Example 319: (S) -4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

By a procedure similar to that described in example 316, starting from 2-methoxypyrimidin-5-amine (Aces Pharma, Inc.) andthe title compound was prepared (S) -4- (2-fluoro-5- ((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (prepared similarly from 3-methylpiperazine-1-carboxylic acid (S) -tert-butyl ester (Sigma Aldrich, Inc.) as reported in example 316, steps 1 to 2) and isolated as a yellow solid. M/z (ESI, cation) 501(M + H) ⁺。¹H NMR(400MHz，d₆-DMSO)δ11.77(s，1H)9.03(s，2H)8.71(d，J＝1.96Hz，1H)8.24(d，J＝2.15Hz，1H)7.90(br.s.，1H)7.74(br.s.，1H)3.91(s，3H)3.24(d，J＝13.50Hz，2H)2.86-2.96(m，1H)2.85(s，3H)2.55-2.79(m，4H)2.44(s，3H)2.11-2.37(m，2H)1.16(d，J＝6.26Hz，3H)。

Example 320: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -1, 1, 1-trifluoropropan-2-ol

Step 1: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroacetone

To 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol (prepared as described in example 269 above) (104mg, 0.161mmol) and 1- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -2, 2, 2-trifluoroethanol at room temperatureA stirred solution of molecular sieves in dichloromethane (3.00mL) was added TPAP (Sigma Aldrich, inc., 5.64mg, 0.016mmol), NMO (Sigma Aldrich, inc., 24.45mg, 0.209mmol) and the mixture was stirred at the same temperature for 1h and then concentrated. The dark residue was diluted again with ethyl acetate and passed through Celite(diatomaceous earth)/SiO₂And (5) filtering by using a short pipe column. The filtered solid was washed with ethyl acetate (3X 10 mL). The combined organic phases were concentrated to give a yellow crude residue 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroacetone, which was used directly in the next step without further purification.

Step 2: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -1, 1, 1-trifluoropropan-2-ol

To a stirred mixture of crude 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroacetone (71mg, 0.110mmol) in TFA (1.5mL, 19.47mmol) was added trifluoromethanesulfonic acid (0.15mL, 1.689mmol) and the dark brown solution was stirred at 70 ℃ for 2 h. After cooling, the dark reddish brown solution obtained is treated with SiO₂Concentrated and the residue was purified by flash column chromatography (ISCO Combiflash System, DCM to 5% MeOH/NH in DCM₃) Purification to give the semi-pure ketone, which was dried in vacuo and used directly in the next step.

The semi-pure ketone isolated above was dissolved in THF (2.00mL, 24.41mmol), cooled to 0 deg.C and an excess of 3.0M methylmagnesium bromide in diethyl ether (2.00mL, 6.00mmol) was slowly added. The mixture was stirred for an additional 1h at 0 ℃ and carefully quenched with 1N HCl, water, and ethyl acetate (0.5, 2.0, 5.0mL each). The separated aqueous layer was extracted with ethyl acetate (2 × 10mL), and the combined organic layers were washed with brine, over Na ₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (DCM to 5% MeOH/NH in DCM₃) Purification followed by washing with a minimal amount of iPrOH gave 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -1, 1, 1-trifluoropropan-2-ol as a yellow solid (8.4mg, 0.020mmol, 18% yield). M/z (ESI, cation) 422(M + H)⁺。¹H NMR(400MHz，d₆-DMSO)δ11.84(m，1H)9.01(br.s.，1H)8.52(br.s.，1H)8.43(br.s.，1H)8.16(d，J＝8.41Hz，1H)7.89(br.s.，1H)7.72(br.s.，1H)6.83(d，J＝8.02Hz，1H)6.71(s，1H)3.85(s，3H)2.44(s，3H)1.72(br.s.，3H)。

Example 321: 4- (2- (6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared analogously as described in example 325 from 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2, 2, 2-trifluoroethanol and 6-methoxypyridin-3-amine and was isolated as a yellow solid. M/z (ESI, cation) 554(M + H)⁺。¹H NMR(400MHz，CD₃OD) δ 9.09(d, J ═ 1.96Hz, 1H)8.92(d, J ═ 2.54Hz, 1H)8.29-8.43(m, 2H)7.39(d, J ═ 9.19Hz, 1H)4.64(q, J ═ 9.00Hz, 1H)4.15(s, 3H)3.25(t, J ═ 4.79Hz, 4H)2.84-2.90(m, 2H)2.83(s, 3H)2.72-2.81(m, 2H)2.59(s, 3H), and no 3 exchangeable protons were observed.

Examples 322 and 323: (R) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol and (S) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol

The preparation of the isomer mixture has been described above (example 269). By chiral column chromatography (preparation of SFC, ODH column (21X 250mm, 5 um)) Supercritical CO₂20% methanol with 0.2% DEA) and provides the individual enantiomers (R) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol and (S) -1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol as yellow solids.

Example 324: 4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a solution of 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol (0.172g, 0.266mmol) in dichloromethane (3.00mL, 0.266mmol) was added triethylamine (0.093mL, 0.664mmol) and methanesulfonyl chloride (0.042mL, 0.531mmol) at 0 ℃ and the mixture was stirred at the same temperature for 1.5 h. The reaction was saturated with NH at 0 deg.C₄Cl and water were quenched, and the separated aqueous layer was extracted with DCM (2X 10mL) and the combined organic layers were extracted with Na₂SO₄Dried, and concentrated and dried in vacuo to give crude 4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.177g, 0.0266mmol), which was used directly in the next step without further purification.

Step 2: 4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.177g, 0.266mmol) was dissolved in MeCN (6.00mL) and a saturated aqueous solution of ammonium hydroxide (0.6mL, 4.31mmol) was added at room temperature and the mixture was stirred at the same temperature for 5 h. The reaction mixture was concentrated and the crude product was adsorbed onto silica gel and passed through a silica gel column (100% DCM to 5% MeOH in DCM (w/NH) ₃) Chromatography to obtain 4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine 4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.165g, 96%).

And step 3: 4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Trifluoroacetic acid and trifluoromethanesulfonic acid were used as described previously in example 178, step 4; the title compound was similarly prepared by deprotection of 4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.165g, 0.255mmol) and isolated as a yellow solid (69mg, 66%). M/z (ESI, cation) 407(M + H)⁺。¹H NMR(400MHz， CD₃OD) δ 9.22(br.s., 1H)8.89(br.s., 1H)8.47(br.s., 1H)8.40(d, J ═ 7.83Hz, 1H)7.27(d, J ═ 9.39Hz, 1H)5.47(q, J ═ 7.37Hz, 1H)4.10(s, 3H)2.54(s, 3H); no 5 exchangeable protons were observed.

Supercritical CO chromatography (preparative SFC, OJH column (21X250mm, 5um), supercritical CO₂15% methanol with 0.2% DEA) and provided the individual enantiomers (R) -4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and (S) -one as yellow solids4- (5- (1-amino-2, 2, 2-trifluoroethyl) -2- (6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine. Example 325: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazine-2-amine compound

Step 1: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2, 2, 2-trifluoroethanol

To a stirred solution of 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoronicotinaldehyde (3.7810g, 7.99 mmol; example 143, step 1-2) in THF (50.00mL) at 0 ℃, trimethyl (trifluoromethyl) silane (TCI America, inc.; 1.703g, 11.98mmol) was added followed by CsF (0.243g, 1.597mmol) and the mixture was stirred at the same temperature for 10min, after which it was warmed to room temperature and stirred for 3.5 h. The reaction was quenched with 1N HCl and stirred for another 30min, and then EtOAc (10mL) was added. The separated aqueous layer was extracted with ethyl acetate (2 × 20mL), and the combined organic layers were washed with brine, over Na ₂SO₄Dried and concentrated to give 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2, 2, 2-trifluoroethanol (4.69g, 8.63mmol, 108% yield) as a brown foam residue of the desired product which was used directly in the next step.

Step 2: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol

To a mixture of 5-fluoro-6-methoxypyridin-3-amine (2.427g, 17.07mmol) and 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2, 2, 2-trifluoroethanol (4.64g,8.54mmol) of THF (50.00mL, 610mmol) was added dropwise to a stirred mixture of LiHMDS (1.0M in THF, Aldrich; 42.7mL, 42.7mmol), and the mixture was stirred at the same temperature for 30 min. The reaction was washed with water and saturated NH₄Cl (aq) (25mL each) was quenched and diluted with EtOAc (25 mL). The separated aqueous layer was extracted with ethyl acetate (2X 50mL) and the combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 0% to 50% ethyl acetate in hexanes) to afford the desired product 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol (5.1428g, 7.73mmol, 91% yield) as a brown foam.

And step 3: 4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a solution of (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethanol (1.03g, 1.547mmol) in dichloromethane (20mL, 1.547mmol) was added triethylamine (0.539mL, 3.87mmol) and methanesulfonyl chloride (0.244mL, 3.09mmol) at 0 ℃ and the mixture was stirred at the same temperature for 3h and warmed to room temperature and stirred for an additional 2 h. Reacting with NH at room temperature₄Saturated aqueous Cl and water were quenched, and the separated aqueous layer was extracted with DCM (2X 50mL) and the combined organic layers were Na₂SO₄Dried, and concentrated and dried in vacuo to give the crude product. M/z (ESI, cation) 684(M + H)⁺. The material was used without further purification.

And 4, step 4: 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethyl) piperazine-1-carboxylic acid tert-butyl ester.

4- (5- (1-chloro-2, 2, 2-trifluoroethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.059g, 1.548mmol) in CH ₃CN (10.00mL) solution was treated with 1-N-Boc-piperazine (Aldrich, 0.577g, 3.10mmol) and triethylamine (1.079mL, 7.74mmol) and the mixture was heated at 100 ℃ for 3 h. The reaction mixture was concentrated and the crude product was adsorbed onto a silica gel packed column and passed through a silica gel column (100% DCM to 5% MeOH in DCM (w/NH)₃) Chromatography to give tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethyl) piperazine-1-carboxylate (1.24g, 1.487mmol, 96% yield) as a brown foam. M/z (ESI, cation) 834(M + H)⁺。

And 5: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound was prepared from tert-butyl 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2, 2, 2-trifluoroethyl) piperazine-1-carboxylate by a similar deprotection step as described in step 4 of example 178 above using trifluoroacetic acid and trifluoromethanesulfonic acid and was isolated (quantitative) as a yellow solid. M/z (ESI, cation) 572(M + H) ⁺。1H NMR(400MHz，d₆-DMSO)δ11.96(s，1H)8.84(d，J＝2.15Hz，1H)8.40(d，J＝2.35Hz，1H)8.29-8.39(m，2H)8.03(br.s.，1H)7.88(br.s.，1H)4.86(q，J＝9.45Hz，1H)3.95(s，3H)3.13(t，J＝4.60Hz，4H)2.86(s，3H)2.69-2.78(m，2H)2.58-2.69(m，2H)2.45(s，3H)。

By chiral column chromatography (preparation of SFC, AD column (21X250mm, 10um), eluent: supercritical CO₂To 30% iPOH with 0.2% DEA as additive) and provided the individual enantiomer (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pir-zine as a yellow solidPyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine and (S) - (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

Example 326: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine

Step 1: n- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine

Will dissolve in II4- (2-fluoro-5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (400mg, 0.643mmol) and isoquinolin-7-amine (139mg, 0.965mmol) (Ark Pharm, Inc, IL) in an alkane (2mL) were charged to a glass microwave reaction vessel and the reaction mixture was cooled at 0 ℃. To this solution was mixed sodium bis (trimethylsilyl) amide (1.0N in THF, 2mL, 2 mmol). The red solution was stirred at 0 ℃ for 1h and at 25 ℃ for 16 h. The reaction mixture was washed with saturated NH ₄Dilute Cl and extract with EtOAc (3 ×). The organic extracts were washed with saturated NaCl and over MgSO₄And (5) drying. The solution was filtered and concentrated in vacuo. The crude material was adsorbed onto a silica gel packed column and purified by chromatography through a silica gel column (40g) in 0% to 5% 2M NH in DCM₃MeOH to afford N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine as a yellow solid (150mg, 31.3% yield). m/z (ESI, cation): 746(M + H)⁺。¹H NMR(400MHz，DMSO-d₆)：δppm 2.63(s，3H)2.82(s，3H)3.06-3.10(m，4H)3.57(s，2H)3.70(s，3H)3.75(s，3H)4.86(s，4H)6.84-6.97(m，4H)7.30(t，J＝6.85Hz，4H)7.72(d，J＝5.48Hz，1H)7.74-7.79(m，1H)7.82-7.88(m，1H)8.35(d，J＝5.67Hz，1H)8.39(d，J＝2.35Hz，1H)8.58(d，J＝1.76Hz，1H)8.75(d，J＝2.35Hz，1H)9.13(s，1H)12.19(s，1H)。

Step 2: n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine

To a 25mL round bottom flask were added N- (3- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine (150mg, 0.201mmol) and 5% TfOH-TFA (5 mL). The reaction mixture was stirred at 70 ℃ for 30 minutes and cooled to room temperature. After TFA removal in high vacuum, the residue was taken up with saturated NaHCO₃The resulting suspension was filtered to provide the crude product as a yellow solid. After air drying, the solid was treated with MeOH-DCM-ether and filtered to provide N- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-yl) isoquinolin-7-amine as a yellow solid (100mg, 98% yield). m/z (ESI cation): 506(M + H) ⁺。¹H NMR(400MHz，DMSO-d₆)：δppm2.88(s，3H)3.09-3.16(m，4H)3.29-3.36(m，7H)3.56(s，2H)7.74(d，J＝5.67Hz，1H)7.83(br s，1H)7.93(d，J＝8.80Hz，2H)8.07(dd，J＝8.90，2.05Hz，1H)8.36(d，J＝5.67Hz，1H)8.40(d，J＝2.15Hz，1H)8.79(d，J＝2.35Hz，1H)8.87(d，J＝1.56Hz，1H)9.21(s，1H)12.42(s，1H)。

Example 327, the following: 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

To a 150mL round bottom flask were added 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (1g, 1.640mmol) and sodium borohydride (0.06g, 1.640mmol) dissolved in DCM (10mL) -MeOH (10 mL). The suspension was stirred at room temperature for 16 h. The solution was passed through saturated NH₄Quench Cl, extract aqueous with DCM (3 ×), combine organics over MgSO₄Dried and concentrated in vacuo to afford 1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (0.9g, 90% yield) as a yellow solid. m/z (ESI cation) m/z: 612(M + H)⁺。 ¹H NMR(400MHz，DMSO-d₆)：δppm 1.36(d，J＝6.46Hz，3H)2.57(s，3H)3.74(s，3H)3.91(s，3H)4.75(dd，J＝6.26，4.50Hz，1H)4.83(d，J＝12.32Hz，4H)5.25(d，J＝4.30Hz，1H)6.82-6.97(m，4H)7.19-7.35(m，4H)7.98-8.14(m，2H)8.30(d，J＝2.35Hz，1H)8.78(d，J＝2.35Hz，1H)11.68(s，1H)。

Step 2: 4- (5- (1-azidoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol (0.9g, 1.635mmol) in toluene (15mL) was charged to a glass microwave reaction vessel. The tube was sealed under an inert atmosphere. To this suspension, diphenyl phosphorazidate (0.9mL, 4.2mmol) and 1, 8-diazabicyclo [5.4.0 ] were mixed ]Undec-7-ene (0.64mL, 4.3mmol) and the solution was stirred for 16 h. The mixture was diluted with EtOAc and passed through saturated NH₄Washed with Cl and brine, and concentrated in vacuo to provide 4- (5- (1-azidoethyl) -2- (5-fluoro-6-methoxy) as a yellow solidPyrid-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.1g, 92% purity, 100% yield) was used in the next step without further purification. MS (ESI cation) m/z: 637(M + 1).

And step 3: 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A50 mL round bottom flask was charged with 4- (5- (1-azidoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1g, 1.571mmol) dissolved in THF (10 mL). 10% Pd-C (0.5g) was admixed under nitrogen and the suspension was stirred under a hydrogen balloon for 16 h. Passing the mixture through CeliteThe pad was filtered and the pad layer was washed with EtOAc and the filtrate was concentrated in vacuo to afford 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine as a black solid (0.8g, 83% yield). m/z (ESI cation) m/z: 611(M + H) ⁺。

And 4, step 4: 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 25mL round bottom flask was added 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (150mg, 0.246mmol) and 7% TfOH-TFA (5 mL). The solution was heated at 70 ℃ for 20 minutes. The mixture was cooled to 0 ℃ and neutralized with 10N NaOH. The resulting suspension was filtered to provide 4- (5- (1-aminoethyl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow solid (80mg, 88% yield). m/z (ESI cation): 371(M + H)⁺。¹H NMR 400MHz，DMSO-d₆)：δppm1H NMR(400MHz，DMSO-d₆)δppm 1.07(d，J＝6.26Hz，3H)1.75(br s，2H)2.23(s，3H)3.81-3.86(m，1H)7.60(d，J＝61.62Hz，2H)8.09-8.25(m，3H)8.61(s，1H)11.68(s，1H)。

Example 328: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (tetrahydro-2H-pyran-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 1: 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Di (320mg, 1.523mmol) of 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane (320mg, 1.523mmol) (Frontier Scientific), 4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (600mg, 1.250mmol), potassium carbonate (400mg, 2.89mmol) and Amphos-PdCl2(50mg, 0.071mmol) were combined together in the presence of a suitable solvent The mixture of alkanes (8mL) was sparged with argon for 5 min. The mixture was heated at 110 ℃ under nitrogen. After 14h, x-phos and Pd were added₂dba₃(40 mg each). After 3h, more x-phos, Pd was added₂dba₃And borate esters. After 16h, the mixture was cooled to room temperature and partitioned between EtOAc (40mL) and water (20 mL). The aqueous phase was extracted once with EtOAc. The combined organic phases were washed with water (3X) and Na₂SO₄Dried and concentrated. The residue was purified on silica gel (5 to 30% EtOAc). The dechlorinated fraction appears as a first main front, followed by the product appearing as the next main front. The product was collected as a pink solid (130 mg). m/z (ESI, cation): 528.2(M + H)⁺。¹H NMR(400MHz，CDCl₃-d)δppm 2.49-2.58(m，5H)3.79(s，3H)3.91(s，3H)3.95(t，J＝5.38Hz，2H)4.31-4.36(m，2H)4.82(d，J＝8.61Hz，4H)6.20(br.s.，1H)6.86(dd， J＝11.15，8.61Hz，4H)7.22(d，J＝6.85Hz，4H)8.31(d，J＝1.96Hz，1H)8.50(dd，J＝9.00，2.54Hz，1H)。

Step 2: 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Solid 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (130mg, 0.246mmol) from step 1 was dissolved in THF (30mL) and combined with palladium hydroxide on carbon (20%, 80 mg). The mixture was purged/backfilled with hydrogen gas under vacuum (3 ×) and stirred under a hydrogen balloon. After 15h, the mixture was heated to about 50 ℃ for 2 h. The mixture was cooled to room temperature and passed through Celite (diatomaceous earth) pad filtration. The filtrate was concentrated to a yellow film. m/z (ESI, cation): 530.2(M + H)⁺。

And step 3: 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The crude product from step 2 was dissolved in TFA (2500. mu.L, 32.4 mmol). TfOH (50. mu.L, 0.563mmol) was added. The mixture was heated at 66 ℃. After 16h, the residue was transferred to Na₂CO₃The solution was cooled on ice (saturated) and extracted with DCM. Passing the organic phase over Na₂SO₄Dried and concentrated. The residue silica (1 to 5% MeOH in EtOAc) was purified to give the product as a yellow solid (55mg, 77%). This material was mixed with toluene and concentrated to dryness before use. m/z (ESI, cation): 290.1(M + H)⁺。¹H NMR(400MHz，CDCl₃)δppm 1.77-1.95(m，4H)2.55(s，3H)2.83-2.96(m，1H)3.56(td，J＝11.40，2.84Hz，2H)4.07-4.18(m，2H)5.82(br.s.，2H，NH2)8.20(s，1H)8.39(dd，J＝9.00，2.54Hz，1H)。

And 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (tetrahydro-2H-pyran-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

To a solution of N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (60mg, 0.271mmol) and 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (55mg, 0.190mmol) in anhydrous DMF (1mL) cooled in an ice bath was added solid NaHMDS (210mg, 1.088mmol) under nitrogen. The resulting orange mixture was stirred and cooled. After 1.5h, HCl (5N, 0.25mL, 1.25mmol) was added to the mixture. The resulting mixture was diluted with water (5mL) and acidified to about pH 5 with 5N HCl. The resulting slurry was filtered and washed with water (3X 3 mL). The solid was washed with EtOAc to give the product as a brown solid. The mother liquor was chromatographed on silica gel (0-5% MeOH in EtOAc) to give additional product. The combined product was about 30mg (32%). m/z (ESI, cation): 491.1(M + H) ⁺。¹H NMR(400MHz，DMSO-d₆)δppm1.60-1.82(m，4H)2.46(s，3H)2.84(t，J＝11.35Hz，1H)3.12(s，3H)3.46(t，J＝10.76Hz，2H)3.97(d，J＝12.13Hz，2H)7.78(br.s.，1H)7.92(br.s.，1H)8.33(s，1H)8.64(d，J＝3.33Hz，2H)8.72(s，1H)9.64(b r.s.，1H)12.17(s，1H)。

Example 329: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide

Step 1: 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 20mL microwave reaction tube were added 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9, 1.00g, 6.94mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi-Blocks, 1.62g, 9.22mmol), potassium acetate (Aldrich, 2.07g, 21.1mmol) and Am-Phos (Aldrich, 0.247g, 0.349mmol) dissolved in EtOH (12mL) and water (1.2 mL). The mixture was degassed by bubbling argon for 5 min. At 100 DEG CNext, the tube was heated in a microwave reactor (Biotage) for 20 min. The reaction mixture was dissolved in water (100mL) with 1% NH₄OH was partitioned between 25% IPA in chloroform (60 mL). Dissolving the aqueous phase in a solution containing 1% NH₄OH was extracted with 25% IPA (2X 50mL) in chloroform. The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. DCM was added to the residue, causing a precipitate to form. The solid was collected via filtration and washed with MeOH to give 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.937g) as a pale yellow powder. The filtrate and washings were combined and concentrated, followed by column chromatography (eluent: dissolved in CHCl) ₃0.25% to 6.25% iPrOH (w/10% NH)₄OH)) followed by MeOH to give additional product as a white solid (0.149 g). Total yield 1.08g (65%).¹H NMR(400MHz，DMSO-d₆) δ ppm 8.54(dd, J ═ 8.02, 2.74Hz, 1H)8.46-8.51(m, 1H)7.73(s, 2H)2.37(s, 3H). m/z (ESI, cation) m/z: 240.1(M + H)⁺。

Step 2: n- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide

In a 20mL scintillation vial, 5-bromo-3-iodo-2-methoxypyridine (Alfa Aesar, 2.02g, 6.43mmol), methanesulfonamide (Fluka, 0.645g, 6.78mmol), copper (I) iodide (Strem, 0.122g, 0.643mmol), cesium carbonate (Aldrich, 5.27g, 16.1mmol), and water (0.60mL, 33.3mmol) were mixed into DMF (6 mL). The reaction mixture was stirred at 105 ℃ overnight. Subsequently, the mixture was heated in a microwave reactor (Biotage) for 30min at 120 ℃. The reaction mixture was partitioned between Tris-HCl buffer (1M, pH 7.0) (20mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (100g, eluent: 0% to 50% EtOAc in hexanes) to give N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide as a white solid (1.06g, 59% yield). ¹H NMR(300MHz，CDCl₃) δ ppm7.97(d, J ═ 2.19Hz, 1H)7.90(d, J ═ 2.19Hz, 1H)6.72(br.s., 1H)4.00(s, 3H)3.04(s, 3H). m/z (ESI, cation): 280.8, 282.8[ M +1, M +3 ]]。

And step 3: n- (5- (diphenylmethyleneamino) -2-methoxypyridin-3-yl) methanesulfonamide

To a 5mL microwave reaction tube was added N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide (0.208g, 0.739mmol), xantphos (Acros, 0.044g, 0.077mmol), Pd in DMF (3mL)₂dba₃(Aldrich, 0.034g, 0.037mmol), NaOtBu (Aldrich, 0.178g, 1.85mmol), and benzophenone imine (Aldrich, 0.130mL, 0.776 mmol). The mixture was degassed by bubbling argon for 5 min. The tubes were heated at 120 ℃ for 30min in a microwave reactor (Biotage). The reaction mixture was partitioned between Tris-HCl buffer (1M, pH 7.0) (20mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50g, eluent: 20% to 80% EtOAc in hexane) to give N- (5- (diphenylmethyleneamino) -2-methoxypyridin-3-yl) methanesulfonamide as a pale yellow solid (0.109g, 39% yield). ¹H NMR(400MHz，CDCl₃)δppm 7.69-7.74(m，2H)7.53(d，J＝2.35Hz，1H)7.46-7.51(m，1H)7.38-7.44(m，2H)7.30-7.36(m，3H)7.12-7.18(m，3H)6.60(s，1H)3.94(s，3H)2.69(s，3H)。

And 4, step 4: n- (5-amino-2-methoxypyridin-3-yl) methanesulfonamide

In a 150mL round-bottom flask, N- (5- (diphenylmethyleneamino) -2-methoxypyridin-3-yl) methanesulfonamide (0.100g, 0.262mmol) and 1N hydrochloric acid (0.30mL, 0.30mmol) were mixed into THF (2 mL). The yellow mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between tris-HCl buffer (1M, pH 7.0) (10mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (10 mL). The aqueous phase was acidified to about pH 5 and extracted with EtOAc (10 mL). The combined organic phases are dried over sodium sulfate,filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25g, eluent: 50% to 100% EtOAc in hexane) to give N- (5-amino-2-methoxypyridin-3-yl) methanesulfonamide as a yellow solid (0.028g, 49% yield).¹H NMR(400MHz，CDCl₃) δ ppm 7.43(d, J ═ 2.54Hz, 1H)7.27(d, J ═ 2.74Hz, 1H)6.66(br.s., 1H)3.93(s, 3H)3.46(br.s., 2H)2.99(s, 3H). M/z (ESI, cation) 218.0(M + H)⁺。

And 5: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide.

To a stirred solution of N- (5-amino-2-methoxypyridin-3-yl) methanesulfonamide (step 4, 0.028g, 0.13mmol) and 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (step 1, 0.0364g, 0.152mmol) in DMF (1mL) in a 5mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 0.52mL, 0.52mmol) dropwise at 0 ℃. The solution was stirred at 0 ℃ for 1.5 h. The reaction mixture was poured into saturated NH ₄Cl (15mL) and stirred. The resulting solid was collected via filtration. The crude product was purified by preparative HPLC (column: Phenomenex, Gemni 5 μm C18100X 30mm, 10% -90% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The corresponding fractions were combined and concentrated. Saturated NaHCO₃Added to the residue and sonicated. The resulting yellow solid was collected and washed with water and MeOH to give 5N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide as a bright yellow solid (12.9mg, 23% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 11.76(s, 1H)9.27(s, 1H)8.72(d, J ═ 2.54Hz, 1H)8.32(dd, J ═ 10.47, 2.45Hz, 2H)8.09(d, J ═ 2.15Hz, 1H)7.77-8.01(m, 2H)3.91(s, 3H)3.05(s, 3H)2.44(s, 3H). m/z (ESI, cation): 436.9(M + H)⁺。

Example 330: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 0: n- (5-bromo-2-chloropyridin-3-yl) -N- (methylsulfonyl) methanesulfonamide

To a stirred solution of 5-bromo-2-chloropyridin-3-amine (3.04g, 14.7mmol) in pyridine (20mL) in a 150mL round bottom flask was added methanesulfonyl chloride (2.83mL, 36.6mmol) dropwise at 0 ℃. The ice bath was removed and the light brown solution was stirred at room temperature overnight. Water (100mL) was added and a precipitate formed. The mixture was stirred at room temperature to break up the agglomerates. The cream-colored solid was collected via filtration and washed several times with water, followed by air drying to give N- (5-bromo-2-chloropyridin-3-yl) -N- (methylsulfonyl) methanesulfonamide as a cream powder (5.16g, 96.9% yield). ¹H NMR(300MHz，DMSO-d₆) δ ppm 3.65(s, 6H), 8.69(d, J ═ 2.3Hz, 1H), 8.75(d, J ═ 2.3Hz, 1H). m/z (ESI, cation): 362.8[ M + H]⁺。

Step 1: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) methanesulfonamide

To a 20mL microwave reaction tube, N- (5-bromo-2-chloropyridin-3-yl) -N- (methylsulfonyl) methanesulfonamide (step 0, 1.11g, 3.04mmol), xantphos (0.179g, 0.308mmol), NaOtBu (1.18g, 12.3mmol), Pd, dissolved in DMF (10mL) was added₂dba₃(0.139g, 0.152mmol) and benzophenone imine (0.62mL, 3.7 mmol). The mixture was degassed by bubbling argon for 10 min. The tubes were heated at 120 ℃ for 30min in an Initiator microwave reactor (Biotage). The reaction mixture was partitioned between tris-HCl buffer (1M, pH 7.0) (80mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2X 60 mL). The combined organic phases were washed with water (200mL) and saturated aqueous sodium chloride (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100g, eluent: 0% to 50% EtOAc in hexane) to affordTo N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) methanesulfonamide as a light brown solid (0.90g, 77% yield). ¹H NMR(400MHz，CDCl₃)δppm 7.72-7.77(m，3H)7.50-7.56(m，1H)7.43(t，J＝7.53Hz，2H)7.32-7.37(m，3H)7.28-7.31(m，1H)7.11-7.16(m，2H)6.66(s，1H)2.78(s，3H)。

Step 2: n- (5-amino-2-chloropyridin-3-yl) methanesulfonamide

In a 1L round-bottom flask, N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) methanesulfonamide (0.90g, 2.3mmol) and 1N hydrochloric acid (2.5mL, 2.5mmol) were mixed into THF (10 mL). The mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.586g of a brown residue. This material was purified by silica gel column chromatography (25g, eluent: 30% to 100% EtOAc in hexane) to give 0.144g of a pale yellow solid. The pH of the original aqueous phase was adjusted to about pH 5 and extracted with EtOAc to give 0.34g of additional crude product, which was purified by silica gel column chromatography (25g, eluent: 40% to 100% EtOAc in hexanes) to give 0.275g of a white crystalline solid, yielding a total of 0.419g of N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (81% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 9.34(s, 1H)7.56(d, J ═ 2.54Hz, 1H)7.08(d, J ═ 2.54Hz, 1H)5.64(s, 2H)3.04(s, 3H). m/z (ESI, cation): 221.9(M + H) ⁺。

And step 3: 2-fluoro-5-methoxypyridine

In a 20mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04g, 9.18mmol), potassium carbonate (1.90g, 13.8mmol) and methyl iodide (Aldrich, 0.689mL, 11.0mmol) were mixed into DMF (6 mL). The brown mixture was stirred at 45 ℃ for 2.5 h. The mixture was diluted with water and the aqueous phase was extracted with EtOAc (3X 20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give2-fluoro-5-methoxypyridine (1.08g, 92% yield) was obtained as a light brown oil. This material was used for the next reaction without further purification.¹H NMR(400MHz，CDCl₃) δ ppm 7.79-7.85(m, 1H)7.33(td, J ═ 6.02, 3.23Hz, 1H)6.86(dd, J ═ 8.90, 3.42Hz, 1H)3.85(s, 3H). m/z (ESI, cation): 128.1(M + H)⁺。

And 4, step 4: 2-fluoro-5-methoxypyridin-3-ylboronic acid

In a 100mL round bottom flask, diisopropylamine (Aldrich, 1.40mL, 9.99mmol) was dissolved in THF (6 mL). nBuLi (Aldrich, 2.5M in hexane, 3.60mL, 8.99mmol) was added slowly at 0 ℃. The mixture was stirred at 0 ℃ for 30min, then cooled to-78 ℃. 2-fluoro-5-methoxypyridine (0.520g, 4.09mmol) dissolved in 4mL THF was slowly added and the mixture was stirred at this temperature for 40 min. Triisopropyl borate (Aldrich, 2.07mL, 8.99mmol) dissolved in a total of 4mL of THF was added slowly and the mixture was stirred at-78 deg.C for 5 min. The cold bath was removed and the reaction mixture was stirred at room temperature for 1 h. 1N NaOH (20mL) was added to the mixture to quench the reaction. The layers were separated and the aqueous phase was treated with 5N HCl to adjust the pH to about 5. The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.593g of a tan solid. This material was used in the next step without further purification.

And 5: 4- (2-fluoro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 20mL microwave reaction tube were added 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9, 1.02g, 7.05mmol), 2-fluoro-5-methoxypyridin-3-ylboronic acid (1.67g, 9.77mmol), Am-Phos (Aldrich, 0.255g, 0.360mmol) and potassium acetate (Aldrich, 2.11g, 21.5mmol) dissolved in EtOH (10mL) and water (1 mL). The mixture was degassed by bubbling argon for 5 min. The tubes were heated in a microwave reactor (Biotage) for 20min at 100 ℃. The reaction mixture was partitioned between water (200mL) and EtOAc (200 mL). The layers were separated and the insoluble material (precipitate 1) was collected. Feeding the aqueous phase intoStep (ii) was extracted with 10% isopropanol (3 × 100mL) dissolved in chloroform. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. After DCM was added to the crude product, a precipitate appeared and the solid was collected via filtration. The first precipitate (precipitate 1) and the solids from the extraction were all of the desired product (1.17g, 70.3%).¹H NMR(400MHz，CDCl₃) δ ppm8.08(dd, J ═ 7.53, 3.23Hz, 1H)7.97(dd, J ═ 3.03, 1.86Hz, 1H)5.47(br.s., 2H)3.92(s, 3H)2.54(s, 3H). m/z (ESI, cation): 236.0(M + H)⁺。

Step 6: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

In a 5mL microwave vial, 4- (2-fluoro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.0550g, 0.234mmol) and N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (step 2, 0.0579g, 0.261mmol) were dissolved in DMF (1 mL). NaHMDS (Aldrich, 1M in THF, 0.935mL, 0.935mmol) was added slowly at 0 ℃ and the dark red mixture was stirred at this temperature for 40 min. The mixture was poured into saturated NH₄Cl (20mL) and stirred for 5 min. The resulting solid was collected via filtration, washed with water and prepared by preparative HPLC using Phenomenex Gemni 5 micron C18100 × 30mm column (1% -90% CH)₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). Fractions were combined and concentrated. The residue was taken up in saturated NaHCO₃In (1). The aqueous solution was pH-adjusted to pH 4-5, and the resulting solid was collected to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide as a yellow solid (0.0146g, 14% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 11.97(br.s., 1H)9.62(br.s., 1H)8.61(d, J ═ 14.08Hz, 2H)8.41(br.s., 1H)8.20(br.s, 1H)7.68-8.09(m, 2H)3.86(br.s., 3H)3.13(br.s, 3H)2.45(br.s, 3H). m/z (ESI, cation) m/z: 436.9(M + H) ⁺。

Example 331: n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxy-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide

To a stirred solution of N' - (5-amino-2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide (example 384, step 2, 0.0697g, 0.278mmol) and 4- (2-fluoro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 330, step 5, 0.0595g, 0.253mmol) in DMF (1mL) in a 5mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 1.02mL, 1.02mmol) dropwise at 0 ℃. At this temperature, the dark red solution was stirred for 45 min. Adding saturated NH₄Cl (0.2mL) to quench the reaction. The reaction mixture was poured into saturated NH₄Cl (20mL) and the mixture was stirred for 5 min. The resulting brown precipitate was collected and the crude product was passed through preparative HPLC using a phenomenex gemni 5 micron C18100 x 30mm column (1% to 90% CH)₃CN w/0.1％TFA/H₂Ow/0.1% TFA, within 10 min). The corresponding fractions were collected and concentrated in vacuo. The residue was collected and washed with water and a small amount of MeOH to give N' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxy-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide (0.0240g, 20% yield) as a yellow solid. ¹H NMR(400MHz，DMSO-d₆) δ ppm 12.00(br.s., 1H)9.53(br.s., 1H)8.77(br.s., 1H)8.52(br.s., 1H)8.35-8.46(m, 1H)8.19(br.s., 1H)7.71-8.03(m, 2H)3.86(br.s., 3H)2.79(br.s., 6H)2.46(b r.s., 3H). m/z (ESI, cation) m/z: 466.0(M + H)⁺。

Example 332: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 1: 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 20mL microwave reaction tube were added 2-fluoro-5- (morpholinomethyl) pyridin-3-ylboronic acid (example 129, step 3) (2.00g, 8.33mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9, 0.501g, 3.47mmol), Am-Phos (Aldrich, 0.124g, 0.175mmol) and potassium acetate (Aldrich, 1.14g, 11.6mmol) dissolved in EtOH (10mL) and water (1 mL). The mixture was degassed by bubbling argon for 10 min. The tubes were heated in a microwave reactor (Biotage) for 20min at 100 ℃. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration. The filtrate was partitioned between saturated aqueous sodium chloride (60mL) and 10% isopropanol in chloroform (60 mL). The aqueous phase was extracted with 10% isopropanol (2 × 60mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (100g, eluent: dissolved in CHCl) ₃0% to 25% iPrOH) to give 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a white foam (0.27g, 26% yield).¹H NMR(400MHz，CDCl₃) δ ppm 8.46(dd, J ═ 9.00, 2.35Hz, 1H)8.27(s, 1H)5.83(br.s., 2H)3.70-3.75(m, 4H)3.56(s, 2H)2.54(s, 3H)2.44-2.50(m, 4H). m/z (ESI, cation): 305.0(M + H)⁺。

Step 2: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

To a stirred solution of 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.0602g, 0.198mmol) and N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (example 330, step 2, 0.0494g, 0.223mmol) in DMF (1mL) in a 5mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 0.80mL, 0.80mmol) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 45 min. The reaction mixture was combined with a saturated aqueous solution of ammonium chloride (30mL) and 25% iso-chloroformPartitioned between propanol (20 mL). The aqueous phase was acidified to a pH of about 3 to 4 and then extracted with 25% isopropanol (2 × 30mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue. After addition of MeOH to the residue, a tan precipitate appeared. The solid was collected via filtration and washed with MeOH to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide as a tan solid (0.0774g, 77% yield). ¹H NMR(400MHz，DMSO-d₆) δ ppm 12.26(s, 1H)9.66(b r.s., 1H)8.76(s, 1H)8.67(t, J ═ 2.45Hz, 2H)8.31(d, J ═ 1.56Hz, 1H)7.74-8.01(m, 2H)3.43-3.66(m, 6H)3.14(s, 3H)2.38-2.48(m, 7H). m/z (ESI, cation): 505.9(M + H)⁺。

Example 333: n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (4-morpholinylmethyl) -2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide

To a stirred solution of 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 384, step 2, 0.0614g, 0.202mmol) and N' - (5-amino-2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide (KY, 0.050g, 0.199mmol) in DMF (1mL) in a 5mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 0.80mL, 0.80mmol) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to a pH of about 3 to 4 and then extracted with 25% isopropanol (2 × 30mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl) ₃0% -25% of iPrOH) to give N' - (5- ((3- (4-amino-6-methyl-1, 3, 5-tris) as a yellow solidOxazin-2-yl) -5- (4-morpholinylmethyl) -2-pyridyl) amino) -2-chloro-3-pyridyl) -N, N-dimethylsulfonamide (0.0437g, 44% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 12.28(s, 1H)9.57(s, 1H)8.82(s, 1H)8.76(d, J ═ 2.35Hz, 1H)8.53(d, J ═ 2.35Hz, 1H)8.29(d, J ═ 2.35Hz, 1H)7.74-7.98(m, 2H)3.57(t, J ═ 4.21Hz, 4H)3.48(s, 2H)2.79(s, 6H)2.46(s, 3H)2.35-2.43(m, 4H). m/z (ESI, cation): 535.0(M + H)⁺。

Example 334: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide

Step 1: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) morpholine-4-sulfonamide

To a 20mL microwave reaction tube was added N- (5-bromo-2-chloropyridin-3-yl) morpholine-4-sulfonamide (example 366, step 3, 0.510g, 1.43mmol), xanthphos (0.0839g, 0.145mmol), Pd2dba3(0.0646g, 0.071mmol), NaOtBu (Aldrich, 0.418g, 4.35mmol) and benzophenone imine (Aldrich, 0.264mL, 1.57mmol) dissolved in DMF (6 mL). The mixture was degassed by bubbling argon for 5 min. The tubes were heated at 120 ℃ for 30min in a microwave reactor (Biotage). The reaction mixture was partitioned between saturated aqueous ammonium chloride (40mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2X 40 mL). The combined organic phases were washed with water (80mL) and saturated aqueous sodium chloride (80 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (100g, eluent: 0% to 70% EtOAc in hexane) to give 2N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) morpholine-4-sulfonamide fractions (total 0.42g, 72% yield), a yellow solid (0.26g) and a light brown solid (0.21 g). ¹H NMR(400MHz，CDCl₃)δppm 7.73(d，J＝7.43Hz，2H)7.62(d，J＝2.35Hz，1H)7.49-7.55(m，1H)7.43(t，J＝7.53Hz，2H)7.31-7.37(m，4H)7.11-7.16(m，2H)6.63(br.s.，1H)3.60-3.65(m，4H)3.03-3.09(m，4H)。

Step 2: n- (5-amino-2-chloropyridin-3-yl) morpholine-4-sulfonamide

Two batches of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) morpholine-4-sulfonamide (0.47 g total, 1.0mmol) were placed in two 150mL round bottom flasks. To each flask were added 1N hydrochloric acid (0.6 mL each, 1.2mL total) and 3mL THF (3 mL each, 6mL total). After stirring at room temperature for 10min, the two reaction mixtures were combined and most of the THF was removed in vacuo and the residue was partitioned between saturated aqueous ammonium chloride (30mL) and 25% isopropanol in chloroform (30 mL). The aqueous phase was extracted with 25% isopropanol (2X 20mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (25g, eluent: dissolved in CHCl)₃0% to 10% iPrOH) to give N- (5-amino-2-chloropyridin-3-yl) morpholine-4-sulfonamide as a light brown solid (0.233g, 77% yield).¹H NMR(400MHz，CDCl₃) δ ppm 7.64(d, J ═ 2.74Hz, 1H)7.30(d, J ═ 2.74Hz, 1H)6.68(br.s., 1H)3.83(br.s., 2H)3.66-3.71(m, 4H)3.22-3.27(m, 4H). m/z (ESI, cation): 293.0(M + H)⁺。

And step 3: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide

To a stirred solution of N- (5-amino-2-chloropyridin-3-yl) morpholine-4-sulfonamide (0.0819g, 0.280mmol) and 4- (2-fluoro-5-methoxypyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 330, step 5, 0.0621g, 0.264mmol) in DMF (1mL) in a 5mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 1.06mL, 1.06mmol) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30mL) and 25% isopropanol in chloroform (20 mL). Acidifying the aqueous phase topH 3 to 4, followed by extraction with 25% isopropanol (2X 30mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18100X 30mm column (1% to 90% CH)₃CN w/0.1％TFA/H₂Ow/0.1% TFA, within 10 min). Fractions were collected and the solvent was evaporated to give a red solid. The solid was dissolved in tris-HCl buffer (1M, pH 7.0) with CHCl₃Medium 25% IPA. The aqueous phase was acidified to pH about 3 and subsequently dissolved in CHCl₃25% IPA in (b). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in about 1mL DMSO and about 2mL water was added. The resulting solid was collected via filtration and washed with copious amounts of water and dried to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide as a dark yellow solid (0.015g, 11% yield). ¹H NMR(400MHz，DMSO-d₆) δ ppm 12.01(br.s., 1H)9.73(br.s., 1H)8.79(br.s., 1H)8.52(br.s., 1H)8.38-8.47(m, 1H)8.18(br.s., 1H)7.76-7.99(m, 2H)3.86(br.s., 3H)3.57-3.66(m, 4H)3.09-3.21(m, 4H)2.45(br.s., 3H). m/z (ESI, cation): 508.0(M + H)⁺。

Example 335: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 1: 2-fluoro-5- (2-methoxyethoxy) pyridine

In a 20mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04g, 9.24mmol), 2-bromomethyl ether (Aldrich, 1.04mL, 11.1mmol), and potassium carbonate (1.97g, 14.2mmol) were mixed into DMF (8 mL). The suspension was stirred at 45 ℃ for 1 h. The temperature was raised to 55 ℃ for 45 min. 2-bromomethyl methyl ether (0.50mL) was added,and the mixture was stirred at 40 ℃ overnight. The reaction mixture was poured into about 50mL of water, and the aqueous phase was extracted with diethyl ether (2X 40 mL). The aqueous phase was saturated with solid NaCl and extracted with ether (2X 40 mL). The combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate (2X 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Under a stream of air, the light brown oil was allowed to stand for 30min to remove the residual ether to give 2-fluoro-5- (2-methoxyethoxy) pyridine (1.64g, 100% yield) as an amber oil. ¹H NMR(400MHz，CDCl₃) δ ppm 7.84-7.87(m, 1H)7.37(ddd, J ═ 9.05, 6.21, 3.13Hz, 1H)6.85(dd, J ═ 8.80, 3.52Hz, 1H)4.13-4.17(m, 2H)3.74-3.78(m, 2H)3.45(s, 3H). m/z (ESI, cation): 172.1(M + H)⁺。

Step 2: 2-fluoro-5- (2-methoxyethoxy) pyridin-3-ylboronic acid

To a stirred solution of diisopropylamine (Aldrich, 3.03mL, 21.2mmol) in THF (30mL) in a 250mL round bottom flask was slowly added nBuLi (Aldrich, 2.5M in hexanes, 8.12mL, 20.3mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min. The mixture was cooled to-78 ℃ and 2-fluoro-5- (2-methoxyethoxy) pyridine (1.58g, 9.23mmol) dissolved in a total of 5mL THF was slowly added. At this temperature, the orange mixture was stirred for 30min, followed by the slow addition of triisopropyl borate (Aldrich, 4.72mL, 20.3mmol) dissolved in a total of 5mL THF. The mixture was stirred at-78 ℃ for 10min, after which the cold bath was removed and the mixture was stirred at room temperature for 1 h. 1N NaOH (about 70mL) was added and the layers were separated. The aqueous phase was washed with EtOAc (50mL) and acidified to about pH 5 with 5N HCl. The aqueous phase was extracted with EtOAc (4X 50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 2-fluoro-5- (2-methoxyethoxy) pyridin-3-ylboronic acid as a pale yellow residue (1.76g, 89% yield). This material was used without further purification.

And step 3: 4- (2-fluoro-5- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 20mL microwave reaction tube, 2-fluoro-5- (2-methoxyethoxy) pyridin-3-ylboronic acid (1.06g, 4.95mmol), 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (example 9, 0.508g, 3.51mmol), Am-Phos (Aldrich, 0.125g, 0.176mmol), and potassium acetate (Aldrich, 1.04g, 10.6mmol) in EtOH (10mL) and water (mL) were added. The mixture was degassed by bubbling argon for 5 min. The tubes were heated in a microwave reactor (Biotage) for 20min at 100 ℃. The reaction mixture was partitioned between water (50mL) and EtOAc (50 mL). The aqueous phase was dissolved in CHCl with EtOAc (2X 50mL)₃10% IPA (3X 50mL) in (C) was extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with DCM and the resulting solid was collected to give 4- (2-fluoro-5- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as an off-white solid (0.234 g). The filtrate was concentrated and purified by column chromatography on silica gel (100g, eluent: dissolved in CHCl)₃Medium 0% to 12.5% iPrOH) to give additional material (0.399g) as a pale yellow solid. The total yield was 0.632g, 64%. ¹H NMR(400MHz，CDCl₃)δppm 8.14(dd，J＝7.63，3.13Hz，1H)8.01(dd，J＝2.93，1.76Hz，1H)5.56(br.s.，2H)4.19-4.27(m，2H)3.75-3.81(m，2H)3.46(s，3H)2.53(s，3H)。

And 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

To a stirred mixture of 4- (2-fluoro-5- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.105g, 0.376mmol) and N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (example 330, step 2, 0.0977g, 0.441mmol) in DMF (1mL) in a 5mL microwave vial was slowly added NaHMDS (Aldrich, 1M in THF, 1.20mL, 1.20mmol) at 0 ℃. The dark brown mixture was stirred for 30min at 0 ℃. Additional NaHMDS (0.5mL) was added at 0 deg.C and stirring was continued at 0 deg.C for 30 min. The reaction mixture was poured into 30mL of saturated NH₄Cl and stirred for 30 min. The resulting yellow solid was collected via filtration and washed with copious amounts of waterAnd air-dried to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide as a yellow solid (0.120g, 66% yield).¹HNMR(400MHz，DMSO-d₆) δ ppm 11.96(s, 1H)9.62(s, 1H)8.61(d, J ═ 19.95Hz, 2H)8.44(d, J ═ 2.74Hz, 1H)8.21(d, J ═ 2.54Hz, 1H)7.75-8.01(m, 2H)4.12-4.27(m, 2H)3.69(d, J ═ 4.30Hz, 2H)3.33(br.s., 3H)3.13(s, 3H)2.45(s, 3H). m/z (ESI, cation): 481.0(M + H) ⁺。

Example 336: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide

In a 5mL microwave vial, 4- (2-fluoro-5- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 335 step 3, 0.0647g, 0.232mmol) and N- (5-amino-2-methoxypyridin-3-yl) methanesulfonamide (example 329 step 4, 0.0636g, 0.293mmol) were mixed into DMF (1 mL). NaHMDS (Aldrich, 1M in THF, 0.95mL, 0.95mmol) was added dropwise at 0 deg.C. The dark red mixture was stirred for 30min at 0 ℃. Buffer (pH 5.0, citric acid/NaOH) (10mL) was added and the mixture was stirred for 30 min. The resulting solid was collected via filtration and washed with MeOH to give 0.0414g of a brown solid. The filtrate was concentrated and purified by silica gel column chromatography (25g, eluent: dissolved in CHCl)₃2.5% to 12.5% iPrOH) to yield 0.0122g of dark orange solid. The aforementioned brown solids and this material were combined and taken up in methanol and sonicated. Evaporation of MeOH gave N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide as a brown solid (0.0366g, 33% yield). ¹H NMR(400MHz，DMSO-d₆)δppm 11.53(s，1H)9.18(s，1H)8.41(d, J ═ 3.13Hz, 1H)8.32(d, J ═ 2.35Hz, 1H)8.17(d, J ═ 2.54Hz, 1H)8.13(d, J ═ 3.13Hz, 1H)7.66-7.92(m, 2H)4.15(dd, J ═ 5.28, 3.72Hz, 2H)3.90(s, 3H)3.67(dd, J ═ 5.18, 3.81Hz, 2H)3.31-3.32(m, 3H)3.05(s, 3H)2.44(s, 3H). m/z (ESI, cation): 476.9(M + H)⁺。

Example 337: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-methoxypyridin-3-yl) methanesulfonamide

In a 5mL microwave vial, 4- (2-fluoro-5- (morpholinomethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 332, step 1, 0.0684g, 0.225mmol) and N- (5-amino-2-methoxypyridin-3-yl) methanesulfonamide (example 330 step 4, 0.0584g, 0.269mmol) were mixed into DMF (1 mL). NaHMDS (Aldrich, 1M in THF, 0.90mL, 0.90mmol) was added dropwise at 0 deg.C. The dark red mixture was stirred for 30min at 0 ℃. Buffer (pH 5.0, citric acid/NaOH) (10mL) was added and the mixture was stirred at 0 ℃ for 30 min. The resulting solid was collected via filtration and washed with water. The filtrate was extracted with 10% isopropanol (2X 20mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.0902g of a yellow solid. This material and the previously collected solid were combined and washed with DCM and MeOH, followed by preparative HPLC using Phenomenex, Gemni 5 micron C18100 × 30mm column (1% to 90% CH) ₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 20 min). Fractions were collected and concentrated. To the residue was added buffer (pH 5.0, citric acid/NaOH) (about 2 to 3mL), followed by pH 7 buffer to bring the pH close to 6. The resulting solid was collected via filtration and washed with copious amounts of water, then dried in a vacuum oven overnight to give N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (morpholinomethyl) pyridin-2-ylamino) -2-methoxyi as a yellow solidPyridinol-3-yl) methanesulfonamide (0.0734g, 65% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 11.90(s, 1H)9.26(s, 1H)8.89(s, 1H)8.43(br.s., 1H)8.32(d, J ═ 2.35Hz, 1H)8.23(d, J ═ 2.35Hz, 1H)7.91(br.s., 1H)7.81(br.s., 1H)4.36(br.s., 2H)3.94-4.01(m, 2H)3.93(s, 3H)3.67(br.s., 2H)3.26-3.30(m, 2H)3.11(br.s., 2H)3.05(s, 3H)2.44(s, 3H). m/z (ESI, cation): 502.0(M + H)⁺。

Example 338: n- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide

LiHMDS (1.14mL, 1.14mmol) was added dropwise to a stirred solution of 6- (2-fluoropyridin-3-yl) -2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (example 4, 0.0895g, 0.286mmol) and N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (example 330, step 2, 0.0772g, 0.348mmol) in THF (1mL) in a 5mL microwave vial at 0 ℃. The dark red mixture was stirred for 30min at 0 ℃. The reaction was quenched by the addition of saturated aqueous sodium chloride (0.2 mL). The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water (40mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in THF (5mL) and 5N HCl (1mL) was added. The yellow mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the crude product was passed through preparative HPLC using Phenomenex, Gemni 5 micron C18100 x 30mm column (1% to 90% CH) ₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The pure fractions were collected and lyophilized to give N- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide (TFA salt, 0.0185g, 11% yield) as an orange solid.¹H NMR(400MHz，DMSO-d₆)δppm 13.12(b r.s., 1H)9.79(d, J ═ 7.63Hz, 1H)9.67(s, 1H)8.74(d, J ═ 2.54Hz, 1H)8.63(s, 1H)8.50(d, J ═ 2.54Hz, 1H)8.41(dd, J ═ 4.69, 1.96Hz, 1H)7.14(dd, J ═ 7.92, 4.79Hz, 1H)3.13-3.18(m, 3H)2.86-2.90(m, 3H). Note that: one proton is missing from the NMR spectrum. m/z (ESI, cation): 430.9(M + H)⁺Is the parent ion.

Example 339: n- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide

Step 1: 1- (6-Fluoropyridin-3-yl) ethanol

Methyl magnesium bromide (Aldrich, 3M in ether, 9.21mL, 27.6mmol) was added dropwise to a stirred mixture of 6-fluoronicotinaldehyde (Frontierscience, 3.14g, 25.1mmol) in THF (40mL) in a 250mL round bottom flask at about 5 to 10 ℃. The mixture was stirred at about 5 ℃ for 30 min. A mixture of water (30mL) and saturated aqueous ammonium chloride (30mL) was added slowly, and EtOAc (20mL) was added. The layers were separated. The aqueous phase was extracted with EtOAc (2X 60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100g, eluent: 20% to 70% EtOAc in hexanes) to afford a clear oil (2.30g, 65% yield). ¹H NMR(400MHz，CDCl₃) δ ppm 8.19(d, J ═ 1.76Hz, 1H)7.85(td, J ═ 8.07, 2.45Hz, 1H)6.92(dd, J ═ 8.41, 2.93Hz, 1H)4.94-5.02(m, 1H)2.00(d, J ═ 3.72Hz, 1H)1.53(d, J ═ 6.46Hz, 3H). m/z (ESI, cation): 142.1(M + H)⁺。

Step 2: 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine

To a stirred solution of 1- (6-fluoropyridin-3-yl) ethanol (2.30g, 16.3mmol) and Et3N (4.52mL, 32.6mmol) in DCM (50mL) in a 500mL round-bottomed flask at 0 deg.C was added dropwiseMethanesulfonyl chloride (Aldrich, 1.30mL, 16.8mmol) was added. The mixture was stirred at 0 ℃ for 30 min. Water (50mL) was added and the layers were separated. The aqueous phase was extracted with DCM (2X 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give a cloudy, viscous, pale yellow oil. To this intermediate, DCM (40mL), Et was added₃N (9mL) and morpholine (5.68mL, 65.2mmol), and the mixture was stirred at room temperature overnight. THF (5mL) was added and stirring was continued. After stirring overnight, water (60mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2X 60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (100g, eluent: dissolved in CHCl) ₃0% to 5% iPrOH) to give 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine as a pale yellow oil (2.92g, 85% yield).¹H NMR (400MHz, chloroform-d) δ ppm 8.12(s, 1H)7.79(td, J ═ 8.12, 2.35Hz, 1H)6.90(dd, J ═ 8.41, 2.93Hz, 1H)3.68(t, J ═ 4.60Hz, 4H)3.36-3.44(m, 1H)2.44-2.56(m, 2H)2.30-2.40(m, 2H)1.35(d, J ═ 6.65Hz, 3H). m/z (ESI, cation): 211.1(M + H)⁺。

And step 3: 4- (1- (6-fluoro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) ethyl) morpholine

To a stirred solution of diisopropylamine (Aldrich, redistilled, 99.95%, 0.813mL, 5.80mmol) in THF (10mL) in a 150mL round bottom flask was added dropwise nBuLi (Aldrich, 2.5M in hexane, 2.32mL, 5.80mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min. The mixture was cooled to-78 ℃ and 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine (1.02g, 4.84mmol) dissolved in a total of 3mL THF was added dropwise. The mixture was stirred at-78 ℃ for 45 min. At this temperature, triisopropyl borate (Aldrich, 1.39mL, 6.04mmol) dissolved in a total of 3mL of THF was added dropwise, followed by removal of the cold bath. The mixture was stirred at room temperature for 1 hour 20 minutes. Pinacol (0.773g, 6.54mmol) dissolved in a total of 5mL THF was added in one portion and the mixture was stirred at room temperature for 10 min. Acetic acid (0.291mL, 5) dissolved in a total of 3mL THF was added in one portion 08mmol) and the mixture was stirred at room temperature for 2 h. Passing the mixture through CeliteThe pad was filtered and extracted with 1N NaOH (2X 50 mL). The aqueous phase was treated with 4N HCl until pH about 6 to 7 while applying an ice-water bath, followed by extraction with EtOAc (3 × 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give crude 4- (1- (6-fluoro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) ethyl) morpholine as a light brown viscous oil (1.22g, 75% yield). This material was used for the next reaction without further purification.

And 4, step 4: 4- (1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) morpholine

Adding the solution dissolved in 1, 4-bis (tert-butyl acetate) into a 5mL microwave reaction tube4- (1- (6-fluoro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) ethyl) morpholine (0.523g, 1.55mmol), 6-chloro-2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (example 3, 0.322g, 1.28mmol), Am-Phos (Aldrich, 0.0531g, 0.075mmol) and potassium acetate (Aldrich, 0.379g, 3.87mmol) in an alkane (4mL) and water (0.4 mL). The mixture was degassed by bubbling argon for 5 min. The tubes were heated in a microwave reactor (Biotage) for 15min at 100 ℃. The reaction mixture was partitioned between water (40mL) and EtOAc (40 mL). The layers were separated and saturated NH was ₄Cl (30mL) was added to the aqueous phase. The aqueous phase was extracted with EtOAc (2X 40 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (50g, eluent: 20% to 70% EtOAc in hexane, then 0% to 12.5% IPA/CHCl₃) Purification to give 4- (1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) morpholine as an off-white solid (0.30g, 55% yield).¹H NMR(400MHz，CDCl₃) δ ppm8.27-8.37(m, 3H)5.86(d, J ═ 10.37Hz, 1H)4.15-4.24(m, 1H)3.78-3.88(m, 1H)3.64-3.75(m, 4H)3.53(q, J ═ 6.72Hz, 1H)2.89(s, 3H)2.50-2.60(m, 2H)2.38-2.48(m, 2H)2.01-2.22(m, 3H)1.69-1.91(m, 3H)1.43(d, J ═ 6.65Hz, 3H). m/z (ESI, cation): 427.1(M + H)⁺。

And 5: n- (2-chloro-5- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide

To a stirred solution of 4- (1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) morpholine (0.157g, 0.368mmol) and N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (example 330 step 2, 0.103g, 0.462mmol) in THF (2mL) in a 20mL microwave vial was added NaHMDS (Aldrich, 1M in THF, 1.47mL, 1.47mmol) dropwise at 0 ℃. The dark red mixture was stirred for 30min at 0 ℃. The mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (50g, eluent: dissolved in CHCl) ₃0% to 10% iPrOH) to give N- (2-chloro-5- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide as a yellow solid (0.169g, 73% yield).¹H NMR(400MHz，CDCl₃) δ ppm 13.18(s, 1H)9.78(d, J ═ 1.96Hz, 1H)8.83(d, J ═ 2.54Hz, 1H)8.63(d, J ═ 2.54Hz, 1H)8.36(d, J ═ 2.35Hz, 1H)8.31(s, 1H)6.76(br.s., 1H)5.85-5.90(m, 1H)4.17-4.24(m, 1H)3.79-3.88(m, 1H)3.73(t, J ═ 4.50Hz, 4H)3.51-3.59(m, 1H)3.14(s, 3H)2.94(s, 3H)2.45-2.62(m, 4H)2.01-2.22(m, 3H)1.66 (m, 1H) 3.93 (d, 6H) 3.93 (d, 3H). m/z (ESI, cation): 628.0(M + H)⁺。

Step 6: n- (2-chloro-5- (3- (2-methyl-9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide

In a 20mL scintillation vial, N- (2-chloro-5- (3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide (0.165g, 0.263mmol) and 5N hydrochloric acid (0.5mL, 2.5mmol) were mixed into THF (3 mL). The solution was stirred at room temperature for 30 min. 10mL of buffer (pH 5, citric acid/NaOH) was added, and the pH was further adjusted to about 5 by adding a few drops of 6N NaOH. The aqueous phase was extracted with 10% isopropanol (3X 20mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was passed through preparative HPLC using a Phenomenex, Gemni 5 micron C18100X 30mm column (1% to 90% CH) ₃CN w/0.1％TFA/H₂O w/0.1% TFA, within 10 min). The corresponding fractions were collected and concentrated to reduce volume to dryness. The residue was treated with about 5mL of pH 5 buffer and pH 7 buffer was added to adjust the pH to about 6. The aqueous phase was extracted with 10% isopropanol (3X 20mL) dissolved in chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.101g of a yellow solid.¹H NMR(400MHz，DMSO-d₆) δ ppm 13.65(br.s., 1H)13.11(br.s., 1H)9.82(br.s., 1H)9.68(br.s., 1H)8.71(d, J ═ 1.96Hz, 1H)8.66(s, 1H)8.53(s, 1H)8.34(d, J ═ 1.17Hz, 1H)3.50-3.67(m, 5H)3.15(s, 3H)2.88(s, 3H)2.35-2.46(m, 2H) 1.42(d, J ═ 6.65Hz, 3H). Note that: 2 protons are hidden under the DMSO peak and cannot be integrated. m/z (ESI, cation): 544.0(M + H)⁺。

Example 340: n' - (2-chloro-5- ((3- (2-methyl-9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide

Step 1: n' - (2-chloro-5- ((3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide

To a 20mL scintillation vial of 4- (1- (6-fluoro-5- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) pyridin-3-yl) ethyl) morpholine (example 339 step 4, 0.0475g, 0.111mmol) and N' - (5-amino-2-chloro-3-pyridyl) -N, N-dimethylsulfonamide (example 384, step 2, 0.0380g, 0.152mmol) in THF (1mL) stirred solution at 0 deg.C was added NaHMDS (Aldrich, 1M in THF, 0.445mL, 0.445mmol) dropwise. The dark red mixture was stirred for 30min at 0 ℃. The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (20mL) and EtOAc (20mL) to yield an insoluble material. The biphasic mixture was filtered and the solid collected and washed with water to give N' - (2-chloro-5- ((3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide (0.0472g, 65% yield) as a yellow solid. ¹H NMR (400MHz, chloroform-d) δ ppm 13.12(s, 1H)9.76(s, 1H)8.86(d, J ═ 2.35Hz, 1H)8.50(d, J ═ 1.96Hz, 1H)8.32(s, 2H)6.79(br.s., 1H)5.87(d, J ═ 8.22Hz, 1H)4.16-4.26(m, 1H)3.79-3.90(m, 1H)3.73(br.s., 4H)3.55 (b.s., 1H)2.87-3.04(m, 9H)2.50 (b.s., 4H)1.98-2.21(m, 3H)1.69-1.92(m, 3H)1.48(d, J ═ 6.46H). m/z (ESI, cation): 657.0(M + H)⁺。

Step 2: n' - (2-chloro-5- ((3- (2-methyl-9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide

In a 20mL scintillation vial, N' - (2-chloro-5- ((3- (2-methyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide (0.047g, 0.072mmol) and 5N hydrochloric acid (0.5mL, 2.5mmol) were mixed into THF (2 mL). The solution was stirred at room temperature for 30 min. Buffer (pH 5, citric acid/NaOH) (10mL) was added and the pH was further adjusted to about 5 using a few drops of 6N NaOH. The aqueous phase was extracted with 10% isopropanol (2X 20mL) dissolved in chloroform. The combined organic phases are dried over sodium sulfateDry, filter and concentrate in vacuo to afford N' - (2-chloro-5- ((3- (2-methyl-9H-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide (0.0237g, 58% yield) as a yellow powder. ¹H NMR (400MHz, chloroform-d) δ ppm 13.10(s, 1H)11.17(br.s., 1H)9.81(br.s., 1H)8.86(d, J ═ 2.15Hz, 1H)8.51(d, J ═ 2.35Hz, 1H)8.34(d, J ═ 1.37Hz, 1H)8.22(s, 1H)6.81(br.s., 1H)3.74(br.s., 4H)3.56(d, J ═ 6.65Hz, 1H)2.96(s, 9H)2.44-2.66(m, 4H)1.50(d, J ═ 6.65Hz, 3H). m/z (ESI, cation): 573.0(M + H)⁺

Example 341: (R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: (R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of (R) -4- (2-fluoro-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (example 146, step 6) (155mg, 0.244mmol) and 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc) (77mg, 0.488mmol) in 1mL THF was treated with sodium bis (trimethylsilyl) amide (0.853mL of a 1.0M solution in THF, 0.853mmol) at 0 ℃ and the dark red solution was stirred at this temperature for 1 h. It was quenched with 4mL of saturated aqueous ammonium chloride solution and extracted with EtOAc (2X 20 mL). The combined organic phases were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated. The residue was loaded onto a silica gel column and eluted with 50-100% EtOAc in DCM to give the title compound as an orange amorphous solid (140mg, 74% yield). ¹H NMR(400MHz，DMSO-d6)δppm 12.11(s, 1H), 8.70(d, J ═ 2.40Hz, 1H), 8.37(d, J ═ 2.30Hz, 1H), 8.18(dd, J ═ 8.8, 2.40Hz, 2H), 7.28(m, 4H), 6.90(m, 4H), 4.85-4.81(m, 4H), 3.87(s, 3H), 3.74(s, 3H), 3.70(s, 3H), 3.60(m, 1H), 3.04(m, 4H), 2.78(s, 3H), 2.59(s, 3H), 2.47(m, 4H), 1.34(m, 3H). M/z (ESI, cation) 774.9(M + H)⁺。

Step 2: (R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of (R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (130mg, 0.168mmol) in 3mL TFA was treated with 0.1mL trifluoromethanesulfonic acid. It was heated in an oil bath for 3h at 80 ℃. The dark solution was concentrated and the residue was treated with ice cubes followed by 0.5N NaOH until the pH was about 8. The mixture was extracted with 2X 30mL of EtOAc followed by 2X 15mL of DCM. The combined organic solutions were dried and concentrated. The residue was loaded onto a silica gel column and eluted with 1 to 10% MeOH in DCM to give (R) -4- (2- (6-chloro-5-methoxypyridin-3-ylamino) -5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (70mg, 78% yield) as a yellow crystalline solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 12.22(s, 1H), 8.74(d, J ═ 2.4Hz, 1H), 8.44(d, J ═ 2.2Hz, 1H), 8.36(dd, J ═ 10.4, 2.2Hz, 2H), 7.95(br., 1H), 7.83(br., 1H), 3.94(s, 3H), 3.60(m, 1H), 3.09(m, 4H), 2.86(s, 3H), 2.46(s, 3H), 2.44(m, 4H), 1.36(d, J ═ 6.7Hz, 3H). M/z (ESI, cation) 534.2(M + H)⁺。

Example 342: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Step 1: 4- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (273mg, 1.14mmol), X-Phos (50mg, 0.11mmol), diacetoxypalladium (24mg, 0.11mmol), cesium fluoride (519mg, 3.42mmol) and tributyl (1-ethoxyvinyl) stannane (0.54mL, 1.60mmol) were combined at 120 deg.C in 1, 4-bis-p-A mixture of alkane (4mL) and DMF (1mL) was heated in a microwave for 1 h. The reaction mixture was passed through a short packed neutral alumina column eluting with 50mL of DCM followed by 150mL of EtOAc. Will contain the desired substance [ M/z (ESI, cation) 276.0(M + H) +]The fractions were collected and concentrated to give the title compound as an off-white crystalline solid (203mg, 64.7% yield). ¹H NMR(400MHz，DMSO-d₆) δ ppm 8.60(2H, m), 7.67(2H, m), 4.93(1H, d, J ═ 3.1Hz), 4.67(1H, d, J ═ 3.1Hz), 3.95(2H, m), 2.38(3H, s), 1.11(3H, m). M/z (ESI, cation) 276.0(M + H)⁺。

Step 2: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone

To a mixture of 4- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (100mg, 0.363mmol) and 6-chloro-5-methoxypyridin-3-amine (Small cMolecules, Inc) (86mg, 0.545mmol) in 1mL THF and 0.3mL DMF was added dropwise sodium bis (trimethylsilyl) amide (1.09mL of a 1.0M solution in THF, 1.09mmol) at 0 ℃ and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4mL of 0.5N HCl and stirred at room temperature for 10 min. The mixture was treated with 1N NaOH to a pH of about 8. It was extracted twice with EtOAc (30 mL). The combined organic phases were washed with brine and over Na₂SO₄And (5) drying. Concentrating to half of its volume, precipitatingThe tan solid was filtered through a sintered funnel, washed with 2mL of diethyl ether, collected and dried to give 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (90mg, 64% yield). ¹H NMR (400MHz, DMSO-d6) delta ppm 12.63(s, 1H), 9.29(s, 1H), 9.03(s, 1H), 8.47(s, 1H), 8.30(s, 1H), 8.06(br., 1H), 7.90(br., 1H), 3.96(s, 3H), 2.60(s, 3H), 2.47(s, 3H). M/z (ESI, cation) 386.0(M + H)⁺。

And step 3: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

A solution of 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-chloro-5-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (85mg, 0.220mmol) in 2mL THF was treated with methylmagnesium bromide (0.73mL of a 3.0M solution in ether, 2.20mmol) at 0 deg.C and stirred at this temperature for 15 min. Subjecting to cooling with NH₄The Cl saturated solution was quenched and extracted twice with EtOAc. The combined organic solutions were concentrated and the residue was purified on a silica gel column and eluted with 50 to 100% EtOAc in DCM to give the title compound as a yellow crystalline solid (23mg, 26% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 12.19(br., 1H), 8.97(d, J ═ 2.6Hz, 1H), 8.50(d, J ═ 2.6Hz, 1H), 8.44(d, J ═ 2.3Hz, 1H), 8.37(d, J ═ 2.4Hz, 1H), 7.95(s, 1H), 7.80(s, 1H), 5.21(s, 1H), 3.94(s, 3H), 2.47(s, 3H), 1.49(s, 6H). M/z (ESI, cation) 402.0(M + H) ⁺。

Example 343: 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (2.0g, 4.17mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (Frontier Scientific) (1.051g, 5.00mmol), Pd at 130 deg.C₂(dba)₃(0.191g, 0.208mmol), dicyclohexyl (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) phosphine (0.199g, 0.417mmol) and 2N Na₂CO₃(5.21mL, 10.42mmol) of 10mL ErbBThe alkane mixture was heated by microwave for 30 min. The reaction mixture was partitioned between 10mL of 0.5N NaOH and 50mL EtOAc. The organic layer was separated and washed with brine, dried and concentrated. The residue was purified on a silica gel column and eluted with 25 to 75% EtOAc in hexanes to give the title compound as an off-white crystalline solid (1.19g, 54% yield).¹H NMR (400MHz, DMSO-d6) δ ppm8.51-8.47(m, 2H), 7.24(t, J ═ 9.2Hz, 4H), 6.90(m, 4H), 6.38(m, 1H), 4.78(s, 2H), 4.76(s, 2H), 4.24(d, J ═ 2.7Hz, 2H), 3.84(m, 2H), 3.74(s, 3H), 3.72(s, 3H), 2.51(m, 2H), 2.47(s, 3H). M/z (ESI, cation) 528.0(M + H) ⁺。

Step 2: 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (191mg, 0.362mmol) and 6-fluoro-5-methoxypyridin-3-amine (77mg, 0.543mmol) in 1.5mL of THF was treated with sodium bis (trimethylsilyl) amide (0.90mL of a 1.0M solution in tetrahydrofuran, 0.90mmol) at 0 deg.C and stirred at this temperature for 15 min. It was quenched with 4mL of saturated aqueous ammonium chloride solution and extracted with EtOAc (2X 20mL). The combined organic phases were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated. The residue was loaded onto a silica gel column and eluted with 50-100% EtOAc in DCM to give the title compound as an orange amorphous solid (167mg, 71.0% yield).¹H NMR (400MHz, DMSO-d6) δ ppm 11.73(s, 1H), 8.70(d, J ═ 2.5Hz, 1H), 8.46(d, J ═ 2.3Hz, 1H), 8.10(m, 2H), 7.30(d, J ═ 8.6Hz, 2H), 7.21(d, J ═ 8.4Hz, 2H), 6.91(d, J ═ 8.6Hz, 2H), 6.85(d, J ═ 8.6Hz, 2H), 6.18(s, 1H), 4.87(s, 2H), 4.80(s, 2H), 4.21(m, 2H), 3.92(s, 3H), 3.82(m, 2H), 3.74(s, 3H), 3.69(s, 3H), 2.57(s, 2H), 2.40(m, 2H). M/z (ESI, cation) 650.3(M + H) ⁺。

And step 3: 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (140mg, 0.215mmol) in 3mL TFA was treated with 0.15mL trifluoromethanesulfonic acid and heated in an oil bath at 80 ℃ for 3H. It was concentrated and the dark residue was stirred in 15mL EtOAc and subsequently treated with 5mL 1N NaOH. The aqueous layer was extracted with 2X 10mL of DCM. The combined EtOAc and DCM extracts were concentrated. The residue was purified on silica gel column and eluted with 35-100% EtOAc in DCM to give 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine as a yellow crystalline solid (70mg, 79% yield).¹H NMR (400MHz, DMSO-d6) δ ppm 11.95(s, 1H), 8.85(d, J ═ 2.6Hz, 1H), 8.49(d, J ═ 2.5Hz, 1H), 8.41-8.35(m, 2H), 7.91(br., 1H), 7.76(br., 1H), 6.24(m, 1H), 4.24(m, 2H), 3.94(s, 3H), 3.84(m, 2H), 2.45(s, 5H). M/z (ESI, cation) 410.0(M + H) ⁺。

Example 344: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

Palladium hydroxide (20% wt) (80mg, 0.114mmol) was placed in a solution of 4- (5- (3, 6-dihydro-2H-pyran-4-yl) -2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (300mg, 0.569mmol) in 5mL EtOH and 5mL EtOAc and hydrogenated in a hydrogen-filled balloon. After 18h, the mixture was passed through CeliteThe pad was filtered and washed with 2 × 10mL of EtOAc. The filtrate was concentrated and the residue was purified on a silica gel column and eluted with 20-65% EtOAc in hexanes to provide 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (230mg, 76% yield) as an off-white amorphous solid.¹H NMR (400MHz, DMSO-d6) δ ppm 8.36(dd, J ═ 9.4, 1.6Hz, 1H), 8.30(d, J ═ 1.9Hz, 1H), 7.24(m, 4H), 6.90(m, 4H), 4.79(s, 2H), 4.75(s, 2H), 3.94(m, 2H), 3.74(s, 3H), 3.72(s, 3H), 3.45(m, 2H), 2.95(m, 1H), 2.47(s, 3H), 1.70(m, 4H). M/z (ESI, cation) 530.3(M + H) ⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A mixture of 4- (2-fluoro-5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (210mg, 0.397mmol) and 5-fluoro-6-methoxypyridin-3-amine (85mg, 0.595mmol) in 1.5mL THF at 0 deg.CTreated with sodium bis (trimethylsilyl) amide (0.99mL of a 1.0M solution in tetrahydrofuran, 0.99 mmol). It is stirred at this temperature for 15min and then saturated NH₄Cl (5mL) was quenched and extracted with 2X 10mL EtOAc. The combined organic solutions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column and eluted with 10-30% EtOAc in DCM to give the title compound as a brown amorphous solid (220mg, 85% yield).¹H NMR (400MHz, DMSO-d6) δ ppm 11.65(s, 1H), 8.56(d, J ═ 2.6Hz, 1H), 8.26(d, J ═ 2.4Hz, 1H), 8.07(m, 2H), 7.29(d, J ═ 8.6Hz, 2H), 7.22(d, J ═ 8.4Hz, 2H), 6.91(d, J ═ 8.6Hz, 2H), 6.85(d, J ═ 8.6Hz, 2H), 4.87(s, 2H), 4.80(s, 2H), 3.96(m, 2H), 3.91(s, 3H), 3.74(s, 3H), 3.69(s, 3H), 3.45(m, 2H), 2.78(m, 1H), 2.57(s, 3H), 4.67 (m, 1H). M/z (ESI, cation) 652.0(M + H) ⁺。

And step 3: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (210mg, 0.322mmol) in 3mL TFA was treated with 0.15mL trifluoromethanesulfonic acid and heated in an oil bath at 80 ℃ for 3H. It was concentrated and the residue was cooled with an ice bath and treated with 5mL of 1N NaOH. The precipitated brown solid was filtered and washed with 3X 3mL of water followed by 3X 10mL of EtOAc. The brown solid was collected and dried in a vacuum oven at 50 ℃ for 24h to give the title compound (120mg, 91% yield).¹H NMR (400MHz, DMSO-d6) Δ ppm 11.86(s, 1H), 8.70(s, 1H), 8.45-8.30(m, 3H), 7.88(br., 1H), 7.74(br., 1H), 3.95(m, 2H), 3.93(s, 3H), 3.47(m, 2H), 2.81(m, 1H), 2.46(s, 3H), 1.72(m, 4H). M/z (ESI, cation) 412.1(M + H)⁺。

Example 345: 2- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Step 1: 6- (5-chloro-2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine

6-chloro-2-methylpyrimidin-4-amine (1.03g, 7.17mmol) (Synchem Inc.), 5-chloro-2-fluoropyridin-3-ylboronic acid (1.572g, 8.97mmol) (Combi-Blocks Inc.), PdCl in sealed glass tubes at 105 deg.C₂8mL of Amphos (0.254g, 0.359mmol) and potassium acetate (2.11g, 21.52mmol)A mixture of alkane, 1mL EtOH and 4mL water was microwaved for 45 min. Liquid chromatography/mass spectrometry of the crude material indicated that the reaction was incomplete. 83mg of Pd (PPh) was added to the reaction mixture₃)₄300mg of 5-chloro-2-fluoropyridin-3-ylboronic acid and 0.3mL of 2N Na₂CO₃. It was heated by microwave for 20min at 115 ℃. The precipitated yellow solid was filtered and washed with 3mL of 1N NaOH, followed by 3mL of water and 5mL of EtOAc. The yellow crystalline solid was dried in a vacuum oven at 45 ℃ for 18h to afford 6- (5-chloro-2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine (1.18g, 68% yield).¹H NMR (400MHz, DMSO-d6) δ ppm 8.59(dd, J ═ 8.4, 2.7Hz, 1H), 8.40(m, 1H), 7.08(br, 2H), 6.82(d, J ═ 1.8Hz, 1H), 2.40(s, 3H). M/z (ESI, cation) 238.9(M + H)⁺。

Step 2: 6- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine to a 5mL microwave reaction tube Alkane (4mL) and 6- (5-chloro-2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine (227mg, 0.95mmol), palladium acetate (10mg, 0.048mmol), X-phos (40mg, 0.09mmol), cesium fluoride (433mg, 2.85mmol) and tributyl in DMF (1mL)The radical (1-ethoxyvinyl) stannane (0.45mL, 1.33 mmol). The glass tube was sealed and heated with a microwave at 120 ℃ for 1 h. The reaction mixture was passed through a short packed column of neutral alumina column and eluted with 50mL of DCM followed by 150mL of EtOAc and 50mL of 5% MeOH in EtOAc. The desired fractions were collected and concentrated to give 6- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine as an off-white crystalline solid (208mg yield 80%). M/z (ESI, cation) 275.1(M + H)⁺。

And step 3: 1- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone

To a mixture of 6- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine (208mg, 0.76mmol) and 5-fluoro-6-methoxypyridin-3-amine (162mg, 1.14mmol) in 1.5mL THF at 0 ℃ was added dropwise sodium bis (trimethylsilyl) amide (1M in THF) (2.28mL, 2.28mmol) and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4mL of 0.5N HCl and stirred for 10 min. The mixture was basified to pH 8 with 1N NaOH and stirred with 10mL of EtOAc for 5 min. The precipitated brown solid was filtered and washed with 2X 2mL of water followed by 2X 2mL of EtOAc. The brown solid was dried in a vacuum oven at 45 ℃ for 18h to afford 1- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (90mg, 32% yield). ¹H NMR (400MHz, DMSO-d6) delta ppm12.93(s, 1H), 8.90(s, 1H), 8.50(s, 1H), 8.37(s, 1H), 8.24(s, 1H), 7.10(br., 2H), 6.93(s, 1H), 3.95(s, 3H), 2.60(s, 3H), 1.58(s, 3H). M/z (ESI, cation) 369.0(M + H)⁺。

And 4, step 4: 2- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

A suspension of 1- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (88mg, 0.24mmol) in 2mL THF at 0 deg.C was treated with methylmagnesium bromide (0.55mL of a 3.0M solution in ether1.67 mmol). It was stirred at 0 ℃ for 15min and saturated with 5mL NH₄And (4) quenching by Cl. The mixture was extracted with 2X 15mL EtOAc. The organic extract was dried and concentrated. The crude material was purified on silica gel column and eluted with 20-70% EtOAc in DCM to give 2- (5- (6-amino-2-methylpyrimidin-4-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol as a yellow crystalline solid (58mg, 63% yield).¹H NMR(400MHz，DMSO-d₆) δ ppm 12.23(s, 1H), 8.35(m, 1H), 8.32(d, J ═ 2.2Hz, 1H), 8.17(m, 2H), 7.02(br, 2H), 6.03(s, 1H), 5.18(s, 1H), 3.92(s, 3H), 2.47(s, 3H), 1.48(s, 6H). M/z (ESI, cation) 385.2(M + H) ⁺。

Example 346: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropionic acid

Step 1: 2- (5-bromo-2-fluoropyridin-3-yl) -6-methyl-1, 3, 6, 2-boronic acid diethanolamine ester-4, 8-dione

After dissolving 5-bromo-2-fluoropyridin-3-ylboronic acid (14.87g, 67.7mmol) (Frontier scientific) and 2, 2' - (methyluretdiyl) succinic acid (10.95g, 74.4mmol) (Aldrich) in toluene (242mL) and DMSO ((97mL) and heating the resulting mixture under reflux under a dean Stark trap for 2H, collecting water (> 2.5mL) in the trap, vacuum concentrating the reaction mixture to remove toluene and slowly adding water to the resulting solution until a white solid precipitates to give the desired product this solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven to give the title compound as a white fluffy solid (yield 82%). M/z (ESI, cation) 330.8/332.9(M + H)⁺。

Step 2: 2- (6-fluoro-5- (6-methyl-4, 8-dioxo-1, 3, 6, 2-boronic acid diethanolamin ester-2-yl) pyridin-3-yl) acetic acid tert-butyl ester

To 2- (5-bromo-2-fluoropyridin-3-yl) -6-methyl-1, 3, 6, 2-boronic acid diethanolamide ester-4, 8-dione (2.79g, 8.43mmol) was added diethanol (25.3mL, 12.65mmol) (RiekeMetals) in diethyl ether (25.3mL, 12.65mmol) Alkane (84mL), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.299g, 0.422mmol) and (2-tert-butoxy-2-oxoethyl) zinc (II) chloride, and the resulting mixture was sparged with nitrogen for 5min at ambient temperature. Subsequently, the reaction mixture was heated to 80 ℃ for 2 h. Subsequently, the reaction mixture was cooled to ambient temperature, adsorbed onto silica gel and purified via flash chromatography (silica gel) with 100% DCM to 5% MeOH/DCM to give the title compound as a beige solid (62% yield). M/z (ESI, cation) 367.2(M + H)⁺。

And step 3: 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) acetic acid tert-butyl ester

To 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.783g, 2.035mmol) (example 51), tert-butyl 2- (6-fluoro-5- (6-methyl-4, 8-dioxo-1, 3, 6, 2-boronic acid diethanolamin-2-yl) pyridin-3-yl) acetate (1.49g, 4.07mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.072g, 0.102mmol) was added bis (tert-butyl) phosphine)An alkane (20mL) and potassium carbonate in water (3.05mL, 6.10mmol), and the resulting mixture was heated at 80 ℃ for 1 h. Subsequently, the reaction mixture was added to a separatory funnel and partitioned between EtOAc (100mL) and sodium bicarbonate (saturated aqueous solution). The organic layer was separated, washed 2 times with 75mL of sodium bicarbonate (saturated aqueous solution), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica; 0% to 40% EtOAc/hexanes) afforded the title compound (37% yield). M/z (ESI, cation) 560.4(M + H) ⁺。

And 4, step 4: 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2-methylpropionic acid tert-butyl ester

A solution of tert-butyl 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) acetate (430mg, 0.768mmol) in tetrahydrofuran (7.6mL) was cooled to-78 deg.C and LiHMDS (845. mu.L, 0.845mmol) in THF was added. After stirring the resulting solution at-78 ℃ for 30min, the reaction mixture was allowed to warm to ambient temperature. Subsequently, the reaction solution was cooled again to-78 ℃ and iodomethane (1.0M; 768 μ L, 0.768mmol) dissolved in THF was added. The resulting mixture was stirred at-78 ℃ for 6h to achieve the first methyl addition (confirmed by LCMS monitoring). The reaction mixture was diluted with 100mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 50mL sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate and concentrated in vacuo to afford the monomethyl addition product. This material was then dissolved in tetrahydrofuran (7.6mL) and cooled to-78 ℃. LiHMDS (1.0M, Aldrich; 845. mu.L, 0.845mmol) in THF was added, and the resulting mixture was stirred for 30min before methyl iodide (1.0M; 768. mu.L, 0.768mmol) in THF was added. The resulting mixture was stirred at-78 ℃ for 6h, and then the reaction mixture was diluted with 150mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed using 100% hexanes to 50% EtOAc/hexanes (silica gel) to give the title compound (41% yield). M/z (ESI, cation) 588.4(M + H) ⁺。

And 5: 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropionic acid tert-butyl ester

Tert-butyl 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) -2-methylpropionate (185mg, 0.315mmol) and5-fluoro-6-methoxypyridin-3-amine (Aldrich; 67.1mg, 0.472mmol) was dissolved in tetrahydrofuran (3.1mL) and the resulting mixture was cooled to-60 deg.C and 1M sodium bis (trimethylsilyl) amide (Aldrich; 944. mu.L, 0.944mmol) in THF was added. The resulting mixture was stirred at-60 ℃ for 1h, and then the reaction mixture was diluted with 100mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate, and concentrated in vacuo. Chromatography of the residue with 100% hexanes to 50% EtOAc/hexanes (silica gel) afforded the title compound as a yellow oil (11% yield). M/z (ESI, cation) 709.8(M + H)⁺。

Step 6: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropionic acid

Tert-butyl 2- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropionate (25mg, 0.035mmol) was dissolved in TFA (344 μ L) and trifluoromethanesulfonic acid (15.48mg, 0.103mmol) was added and the resulting mixture was stirred at 80 ℃ for 4 h. Subsequently, the reaction mixture was concentrated in vacuo and the residue was taken up in 100mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica; 0% to 100% EtOAc/hexane) gave an impure product which was further purified by preparative TLC (2 plates; silica gel). The TLC plate was loaded with impure material and eluted in 10% MeOH in DCM to give the title compound (70% yield), followed by extraction of the product containing band with methanol, filtration and concentration in vacuo.¹H NMR(400MHz，d₄-MeOH) δ 9.00(d, J ═ 2.74Hz, 1H)8.58(s, 1H)8.39(d, J ═ 2.54Hz, 1H)8.16-8.24(m, 2H)4.01(s, 3H)2.52(s, 3H)1.59(s, 6H). M/z (ESI, cation) 414.0(M + H)⁺. M/z (ESI, cation) 414.0(M + H) ⁺。

Example 347: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropane-1, 2-diol

Step 1: 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.35g, 2.242mmol) (example 313, step 2) was dissolved in TFA (22mL), trifluoromethanesulfonic acid (0.587mL, 6.73mmol) was added, and the resulting mixture was stirred at 80 ℃ for 2 h. The reaction mixture was then concentrated and the residue was taken up in 400mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 4 times with 150mL of sodium bicarbonate (saturated aqueous solution), isolated and concentrated via rotary evaporator to give the title compound as an insoluble yellow solid which was used without further purification. M/z (ESI, cation) 362.0(M + H)⁺。

Step 2: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methylpropan-1-enyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To 4- (5-chloro-2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.85g, 2.350mmol) was added bis Alkane (23.50mL), potassium carbonate in water (3.52mL, 7.05mmol), 4, 5, 5-tetramethyl-2- (2-methylprop-1-enyl) -1, 3, 2-dioxolane (0.723mL, 3.52mmol) (Frontier Scientific) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (Aldrich; 0.083g, 0.117 mmol). The resulting mixture is sparged with nitrogen and then subsequently treated withStirred at 80 ℃ for 16 h. The reaction mixture was then diluted with 150mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated aqueous solution), washed 2 times with 150mL sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica; 0% to 100% EtOAc/hexanes) afforded the title compound as a yellow solid (88% yield). M/z (ESI, cation) 382.2(M + H)⁺。

And step 3: 4- (5- (3, 3-Dimethyloxiran-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

A solution of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (2-methylprop-1-enyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (380mg, 0.996) in DCM (9.9mL) was cooled to 0 deg.C and 3-chloroperoxybenzoic acid (268mg, 1.196mmol) was then added. The resulting mixture was stirred at 0 ℃ for 1.5h and then allowed to warm to ambient temperature and stirred for 2 h. Subsequently, the reaction mixture was diluted with 200mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated aqueous solution). The organic layer was washed 1 time with 150mL sodium bicarbonate (saturated aqueous solution), separated, dried over sodium sulfate and concentrated in vacuo to give the title compound. M/z (ESI, cation) 398.2(M + H) ⁺。

And 4, step 4: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-methylpropane-1, 2-diol

4- (5- (3, 3-Dimethyloxieth-2-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (5mg, 0.013mmol) was dissolved in concentrated hydrochloric acid (252. mu.L, 1.258mmol) and stirred at 25 ℃ for 30 min. Subsequently, the reaction mixture was added to a separatory funnel and partitioned between DCM (100mL) and 1N NaOH (aq). The organic layer was separated, washed 2 times with 50mL of 1N NaOH (aq), dried over sodium sulfate and concentrated in vacuo. The combined aqueous layers were then extracted with EtOAc (3 × 80mL) and the combined extracts were concentrated in vacuo. Subsequently, the combined crude product was dissolved in methanol (about 20mg/mL)And by preparative HPLC (Phenomenex Luna 5. mu. M C18, 30X 150mm, 10-100% MeCN/H with 0.1% TFA modifier₂O) purification to give the title compound.¹H NMR(400MHz，d₄-MeOH) δ 9.25(d, J ═ 1.96Hz, 1H)8.17(d, J ═ 2.15Hz, 1H)8.09(d, J ═ 2.15Hz, 1H)7.92(dd, J ═ 11.35, 1.96Hz, 1H)4.49(s, 1H)4.04(s, 3H)2.50(s, 3H)1.23(s, 3H)1.15(s, 3H). M/z (ESI, cation) 416.0(M + H) ⁺。

Example 348: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxy-5- (trifluoromethyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Step 1: 6-methoxy-5- (trifluoromethyl) pyridin-3-amine

To 5-iodo-2-methoxy-3- (trifluoromethyl) pyridine (0.97g, 3.20mmol) (ECAInternational Product List) were added DMF (8.0mL), (9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis (diphenylphosphine) (0.093g, 0.160mmol), Pd₂(dba)₃(0.147g, 0.160mmol), benzophenone imine (0.806mL, 4.80mmol) and sodium 2-methylpropan-2-olate (1.231g, 12.80mmol), and the resulting mixture was heated at 120 ℃ for 30 min. Subsequently, the reaction mixture was diluted with 100mL of EtOAc, added to a separatory funnel, partitioned with 1N HCl (aq), and washed 2 times with 50mL of sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 5% (2M aqueous ammonia in MeOH)/DCM) afforded the title compound (34% yield). M/z (ESI, cation) 193.2(M + H)⁺。

Step 2: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxy-5- (trifluoromethyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol

The procedure is as described in example 356, step 1,2. 4 and 5 analogously, 6-methoxy-5- (trifluoromethyl) pyridin-3-amine (145mg, 0.755mmol) was used instead in step 4 to synthesize the title compound as a yellow solid.¹H NMR(400MHz，d₄-MeOH) δ 9.04(d, J ═ 2.54Hz, 1H)8.59(d, J ═ 2.35Hz, 1H)8.54(d, J ═ 2.35Hz, 1H)8.43(d, J ═ 2.54Hz, 1H)4.02(s, 3H)2.51(s, 3H)1.60(s, 6H). M/z (ESI, cation) 436.0(M + H)⁺。

Example 349: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

The title compound was synthesized following a procedure analogous to example 356, steps 1, 2 and 4, substituting 5-fluoro-6-methoxypyridin-3-amine (247mg, 1.738mmol) (AniChem) in step 4. M/z (ESI, cation) 370.0(M + H)⁺。

Step 2: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanol

1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethanone (250mg, 0.677mmol) was dissolved in THF (1.35mL), sodium borohydride (128mg, 3.38mmol) was added and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was then quenched with water and added to a separatory funnel. Subsequently, the reaction mixture was partitioned between EtOAc (100mL) and ammonium chloride (saturated aqueous solution). The organic layer was separated, washed 2 times with 75mL of ammonium chloride (saturated aqueous solution), dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 5% (2M aqueous ammonia in MeOH)/DCM) gave a yellow solid The title compound of (yield 40%).¹H NMR(400MHz，CDCl₃) δ 11.90(s, 1H)8.87(s, 1H)8.34(d, J ═ 2.15Hz, 1H)8.20-8.30(m, 1H)8.05(d, J ═ 1.76Hz, 1H)5.41(br.s., 2H)4.95(q, J ═ 6.52Hz, 1H)4.03(s, 3H)2.57(s, 3H)1.83(br.s., 1H)1.58(br.s., 3H). M/z (ESI, cation) 372.0(M + H)⁺。

Example 350: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5, 6-dimethoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

The title compound was synthesized as a yellow solid by following a procedure analogous to example 356, steps 1, 2, 4 and 5, substituting 5, 6-dimethoxypyridin-3-amine (92mg, 0.597mmol) (WO2008124083) in step 4.¹HNMR(400MHz，CDCl₃) δ 11.72(s, 1H)8.95(d, J ═ 2.54Hz, 1H)8.46(d, J ═ 2.74Hz, 1H)7.97(s, 1H)7.79(d, J ═ 2.15Hz, 1H)5.49(s, 2H)4.02(s, 3H)3.93(s, 3H)2.56(s, 3H)1.87(br.s., 1H)1.64(s, 6H). M/z (ESI, cation) 398.0(M + H)⁺。

Example 351: 3-chlorobenzoic acid 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -2-hydroxy-2-methylpropyl ester

After purification via flash chromatography (silica gel, 0% to 4% (2M aqueous ammonia in MeOH)/DCM), the title compound was isolated from example 347, step 3.¹H NMR(400MHz，d₄-MeOH)δ11.82(s，1H)8.96(d，J＝2.15Hz，1H)8.36(d，J＝1.96Hz，1H)8.16(s，1H)8.03-8.12(m，4H)7.57-7.66(m，1H)7.43-7.53(m，1H)5.81(s, 1H)3.91(s, 3H)2.41(s, 3H)1.34(s, 3H)1.28(s, 3H). M/z (ESI, cation) 554.2(M + H)⁺。

Example 352: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoropyridin-3-ylamino) pyridin-3-yl) propan-2-ol

The title compound was synthesized as a yellow solid by following a procedure analogous to example 356, steps 1, 2, 4 and 5, substituting 3-amino-5-fluoropyridine (73.9mg, 0.659mmol) (Matrix Scientific) in step 4.¹H NMR(400MHz，d₆-DMSO) δ 12.31(s, 1H)9.00(d, J ═ 2.54Hz, 1H)8.80(s, 1H)8.58(d, J ═ 12.32Hz, 1H)8.52(d, J ═ 2.54Hz, 1H)8.14(d, J ═ 2.54Hz, 1H)7.95(br.s., 1H)7.78(br.s., 1H)5.20(s, 1H)2.47(s, 3H)1.49(s, 6H). M/z (ESI, cation) 356.0(M + H)⁺。

Example 353: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-methoxypyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Following a procedure analogous to example 356, steps 1, 2, 4 and 5, using 5-methoxy-pyridin-3-ylamine (94mg, 0.757mmol) (J) in step 4&W PharmLab) was substituted to synthesize the title compound as a yellow solid.¹H NMR(400MHz，d₄-MeOH)9.06(d, J ═ 2.54Hz, 1H)8.53(s, 1H)8.43(s, 1H)8.20-8.28(m, 1H)7.86(d, J ═ 2.74Hz, 1H)3.93(s, 3H)2.53(s, 3H)1.62(s, 6H). M/z (ESI, cation) 368.0(M + H) ⁺。

Example 354: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxy-5-methylpyridin-3-ylamino) pyridin-3-yl) propan-2-ol

The title compound was synthesized as a yellow solid by following a procedure analogous to example 356, steps 1, 2, 4 and 5, substituting 6-methoxy-5-methylpyridin-3-amine hydrochloride (126mg, 0.719mmol) (Asymchem) in step 4.¹H NMR(400MHz，CDCl₃) δ 11.51(s, 1H)8.93(d, J ═ 2.54Hz, 1H)8.43(d, J ═ 2.54Hz, 1H)8.15(d, J ═ 2.54Hz, 1H)7.91(d, J ═ 1.96Hz, 1H)5.57(s, 2H)3.96(s, 3H)2.54(s, 3H)2.22(s, 3H)1.98(br.s., 1H)1.63(s, 6H). M/z (ESI, cation) 382.1(M + H)⁺。

Example 355: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (methylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol

The title compound was synthesized as a yellow solid by a procedure similar to example 356, substituting methanesulfinic acid sodium salt (0.743g, 7.28mmol) (Acros Organics) in step 3.¹H NMR(400MHz，d₆-DMSO) δ 9.14-9.16(m, 1H)9.11-9.14(m, 1H)9.01(d, J ═ 2.54Hz, 1H)8.64(d, J ═ 1.96Hz, 1H)8.53(d, J ═ 2.54Hz, 1H)5.22(s, 1H)3.33(s, 3H)2.48(s, 3H)1.50(s, 6H). M/z (ESI, cation) 416.1(M + H) ⁺。

Example 356: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (phenylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol

Step 1: 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

4- (5-chloro-2-fluoropyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (3.87g, 8.06mmol) (example 313, step 1) was dissolved in TFA (81mL), trifluoromethanesulfonic acid (2.1mL, 24mmol) was added and the resulting mixture was stirred at 80 ℃ for 2 h. The reaction mixture was then concentrated in vacuo. The residue was partitioned between EtOAc (150mL) and sodium bicarbonate (saturated aqueous solution). The organic layer was separated, washed 2 times with 100mL sodium bicarbonate (saturated aqueous solution), dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 40% EtOAc/hexanes) afforded the title compound (51% yield). M/z (ESI, cation) 240.1(M + H)⁺。

Step 2: 4- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (1.34g, 5.59mmol) was added DMF (8mL), bisAlkane (48mL), cesium fluoride (2.55g, 16.78mmol), X-Phos (0.258g, 0.559mmol), palladium (II) acetate (0.126g, 0.559mmol), and tributyl (1-ethoxyvinyl) stannane (2.64mL, 7.83mmol) (Aldrich), and the resulting mixture was stirred at 110 ℃ for 1.5 h. The reaction mixture was cooled to ambient temperature and purified via flash chromatography (neutral alumina) with 100% DCM (to remove stannane) followed by 100% EtOAc to give the title compound (> 99% yield). M/z (ESI, cation) 276.0(M + H) ⁺。

And step 3: 5- (phenylsulfonyl) pyridin-3-amines

To 5-bromopyridin-3-amine (1.59g, 9.19mmol) (Aldrich) was added benzenesulfinic acid sodium salt (1.810g, 11.03mmol) (Sigma-Aldrich), copper (I) iodide (0.175g, 0.919mmol), (S) -pyrrolidine-2-carboxylic acid (0.212g, 1.919 mmol)838mmol), sodium hydroxide (0.074g, 1.838mmol) and DMSO (18mL), and the resulting mixture was stirred at 100 ℃ for 3 days. Subsequently, the reaction mixture was diluted with 200mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated aqueous solution). The organic layer was separated, washed 4 times with 150mL sodium bicarbonate (saturated aqueous solution), dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2M aqueous ammonia in MeOH)/DCM) gave the title compound (yield 11%). M/z (ESI, cation) 235.3(M + H)⁺。

And 4, step 4: 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (phenylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) ethanone

4- (5- (1-ethoxyvinyl) -2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (255mg, 1.110mmol) was dissolved in THF (9.2mL) and the resulting mixture was cooled to 0 deg.C and NaHMDS (1.0M, Aldrich; 2775. mu.l, 2.77mmol) in THF was added. The reaction mixture was stirred at 0 ℃ for 1.5 h. Subsequently, the reaction mixture was diluted with 100mL of EtOAc, added to a separatory funnel and partitioned with ammonium chloride (saturated aqueous solution). The organic layer was separated, washed 2 times with 50mL of ammonium chloride (saturated aqueous solution), dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2M aqueous ammonia in MeOH)/DCM) gave the title compound as a yellow amorphous solid (44% yield). M/z (ESI, cation) 462.2(M + H) ⁺。

And 5: 2- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (phenylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) propan-2-ol

To cerium (III) chloride (304mg, 1.235mmol) was added THF (4.1mL) and the resulting mixture was heated to 40 ℃ for 1 h. Subsequently, the reaction mixture was cooled to-78 ℃ and methylmagnesium bromide (3.0M, Aldrich; 1372. mu.L, 4.12mmol) in ether was added. The resulting mixture was stirred at-78 ℃ for 15 min. Followed by addition of 1- (5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5- (phenylsulfonyl) pyridin-3-ylamino) pyridin-3-yl) ethan-yl) in THF (4.1mL)Ketone (190mg, 0.412mmol) and the resulting mixture was stirred at-78 ℃ for 4 h. Subsequently, the reaction mixture was diluted with 100mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated aqueous solution). The organic layer was separated, washed 2 times with 50mL of sodium bicarbonate (saturated aqueous solution), dried over sodium sulfate and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2M aqueous ammonia in MeOH)/DCM) afforded the title compound as a pale yellow solid (36% yield).¹H NMR(400MHz，d₆-DMSO) δ 12.38(s, 1H)9.18-9.23(m, 1H)9.06(d, J ═ 2.35Hz, 1H)9.00(d, J ═ 2.35Hz, 1H)8.67(d, J ═ 2.15Hz, 1H)8.53(d, J ═ 2.54Hz, 1H)8.02-8.08(m, 2H)7.98(br.s., 1H)7.79(br.s., 1H)7.71-7.77(m, 1H)7.64-7.71(m, 2H)5.22-5.26(m, 1H)2.46(s, 3H)1.51(s, 6H). M/z (ESI, cation) 478.1(M + H) ⁺。

Example 357: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-isopropyl-N-methylpiperazine-1-carboxamide

Step 1: N-isopropyl-N-methyl-1H-imidazole-1-carboxamide

A50 mL round bottom flask was charged with 1, 1' -carbonyldiimidazole (1.663g, 10.25mmol), (Fluka Chemie) DCM (25 mL). The solution was stirred at 0 ℃ using a water bath solution and treated once with n-isopropylmethylamine (0.5mL, 6.84mmol) (Aldrich). The water bath was removed and the solution was stirred at room temperature. After 2 hours, all starting materials were consumed. The reaction mixture was diluted with DCM (10mL) and quenched with water. The organic layer was separated, dried over sodium sulfate and concentrated to give N-isopropyl-N-methyl-1H-imidazole-1-carboxamide (0.920g, 5.50mmol, 80% yield).

Step 2: 1- (isopropyl (methyl) carbamoyl) 3-methyl-1H-imidazol-3-ium iodide

To a 50mL round bottom flask was added N-isopropyl-N-methyl-1H-imidazole-1-carboxamide (0.550g, 3.29mmol), acetonitrile (29mL, 3.29mmol), methyl iodide (0.817mL, 13.16 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo to give 1- (isopropyl (methyl) carbamoyl) 3-methyl-1H-imidazol-3-ium iodide.

And step 3: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-isopropyl-N-methylpiperazine-1-carboxamide

To a 50mL round bottom flask was added 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- (piperazin-1-ylmethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.350g, 0.526mmol), 1- (isopropyl (methyl) carbamoyl) -3-methyl-1H-imidazol-3-ium (0.479g, 2.63mmol), DCM (25mL, 0.526mmol), triethylamine (0.366mL, 2.63mmo 1). After 1h, the mixture was washed with 1.0N HCl (2 × 5mL) and brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-isopropyl-N-methylpiperazine-1-carboxamide, which was treated with trifluoroacetic acid (5mL, 67.3mmol), trifluoromethanesulfonic acid (0.2mL, 0.278 mmol). The solution was stirred at 80 ℃ for 1 hour. The dark solution was cooled to room temperature and concentrated to a slurry. The slurry is treated with NaHCO₃Neutralized to pH 8. The precipitate was dissolved in DCM/MeOH and adsorbed onto a silica gel packed column and passed through a silica gel column (40g) with 5 to 10% 2M NH dissolved in DCM ₃MeOH gradient elution to afford 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-isopropyl-N-methylpiperazine-1-carboxamide (0.033g, 0.063mmol, 26.7% yield). M/z (ESI, cation) 525.2(M + H)⁺。¹H NMR(400MHz，DMSO-d₆)δppm 1.07(d，J＝6.85Hz，6H)2.44(s，3H)2.64(s，3H)2.97(dd，J＝5.38，4.60Hz，4H)3.09(d，J＝7.24Hz，1H)3.25(d，J＝4.89Hz，4H)3.95(s，3H)4.12(s，2H)7.83(br.s.，1H)7.96(br.s.，1H)8.33-8.37(d，1H)8.40(s，1H)8.44(s，1H)8.87(dd，J＝2.15，0.39Hz，1H)12.01(s，1H)。

Example 358: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-methyl-N- (2, 2, 2-trifluoroethyl) piperazine-1-carboxamide

The title compound was synthesized following a procedure similar to example 357 substituting 2, 2, 2-trifluoro-N-methylethylamine (AccelaChemBio Inc.) for N-isopropylamine (0.035g, 0.064mmol, 50.4% yield). m/z (ESI, cation): 547.2(M + H)⁺。¹H NMR(400 MHz，CDCl₃)δppm 2.48(b，3H)2.56(s，3H)2.99(s，3H)3.36(b，4H)3.53(b，3H)3.91(d，J＝9.19Hz，2H)3.94(s，3H)6.78(d，J＝9.00Hz，1H)8.12(dd，J＝9.00，2.74Hz，1H)8.23(dd，J＝2.15，0.39Hz，1H)8.35(s，2H)8.35(d，J＝0.39Hz，1H)8.75(s，1H)11.68(s，1H)。

Example 359: 4- ((5- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -6- (6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -N-cyclopropyl-N-methylpiperazine-1-carboxamide

The title compound was synthesized according to a procedure similar to example 357, substituting N-methylcyclopropylamine (Accela ChemBio Inc.) for N-isopropylmethylamine (0.152g, 0.301mmol, 82% yield). m/z (ESI, cation): 505.2(M + H)⁺。¹H NMR(400MHz，CDCl₃)δppm 0.56-0.65(m，2H)0.65-0.76(m，2H)2.55(s，4H)2.55(s，3H)2.82(s，3H)3.53(br.s.，4H)3.68(br.s.，3H)3.94(s，3H)5.72(br.s.，2H)6.78(d，J＝8.80Hz，1H)8.11-8.16(d，1H)8.26(s，1H)8.35(s，1H)8.85(s，1H)11.76(br.s.，1H)。

Example 360: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

Step 1: 5- (1-bromoethyl) -2-fluoropyridine

To a 250mL round bottom flask was added 2-fluoro-5-formylpyridine (5.10mL, 40.8mmol) (Frontier Scientific) and tetrahydrofuran (100mL, 1233 mmol). The solution was stirred at-10 ℃ using an ice bath and treated dropwise with methylmagnesium bromide (14.27mL, 42.8mmol) via addition funnel (Aldrich). After addition, the ice bath was removed and the mixture was stirred at ambient temperature. After 30 minutes, the reaction was complete. The mixture was stirred at-10 ℃ and treated dropwise with methanesulfonyl chloride (3.41mL, 44.0mmol) (Aldrich) via syringe. After addition, the water bath was removed and the mixture was stirred at ambient temperature and LC/MS was continued. The reaction mixture was quenched with water (50mL) and diluted with DCM (150 mL). The aqueous layer was extracted with DCM (3 × 50mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 5- (1-bromoethyl) -2-fluoropyridine (7.16g, 35.1mmol, 86% yield).

Step 2: 4- (1- (6-Fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester

To a 100mL round bottom flask was added 5- (1-bromoethyl) -2-fluoropyridine (3.9g, 19.11mmol), acetonitrile (75mL, 1435mmol), (R) -4-N-boc-2-methyl-piperazine (4.02g, 20.07mmol) (Aldrich), potassium carbonate (1.384mL, 22.94mmol) (Aldrich), potassium iodide (0.205mL, 3.82mmol) (Fluka). The reaction mixture was stirred at 70 ℃ overnight. The reaction mixture was diluted with water (50mL) and DCM (50mL) and extracted with DCM (3 × 50mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 4- (1- (6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester (3.05g, 9.43mmol, 49.3% yield). The crude product was adsorbed onto a silica gel packed column and chromatographed via a silica gel column (80g) eluting with a gradient of 0% to 50% EtOAc in hexanes to provide 4- (1- (6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester (3.05g, 9.43mmol, 49.3% yield).

And step 3: 5- (1- ((R) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid

To a 150mL round bottom flask was added 4- (1- (6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester (3.0g, 9.28mmol) and tetrahydrofuran (100mL, 9.28 mmol). The solution was stirred at-78 ℃ and treated dropwise with a 2.5m solution of butyllithium in hexane via syringe (4.08mL, 10.20mmol) (Aldrich). The solution was stirred at-78 deg.C for 1hr and treated with triisopropyl borate (2.55mL, 11.13mmol) (Aldrich) in one portion. The mixture was stirred at-78 ℃ for 1 hour. NaOH (1.0N, 30mL) was added and the solution was stirred at room temperature for 30 min. The aqueous layer was separated and the organic layer was extracted with additional NaOH (1.0N, 30 mL). The combined aqueous layers were carefully acidified with 5N HCl (12mL) to about 4 to 5 about final pH. The reaction mixture was extracted with EtOAc (3 × 100 mL), and the organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo to give 5- (1- ((R) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (2.5g, 6.81mmol, 73.4% yield).

And 4, step 4: 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester

A mixture of 5- (1- ((R) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) ethyl) -2-fluoropyridin-3-ylboronic acid (1.4g, 3.81mmol), 4-chloro-N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (1.467g, 3.81mmol), 1, 4-bis (4-methoxybenzyl) anda glass microwave reaction vessel was charged with alkane (10mL, 3.81mmol), potassium acetate (1.122g, 11.44mmol), water (1mL, 3.81mmol) and amphos (0.270g, 0.381 mmol). The reaction mixture was stirred and heated in a microwave reactor (Personal Chemistry, Biotage AB, inc., Upssala, Sweden) for 20min at 120 ℃ (watt, Powermax characteristics, time to temperature rise in minutes). LC/MS showed the desired product, the starting triazine and the deboronated product. The reaction mixture was diluted with water (20mL) and DCM (25mL), and the aqueous layer was extracted with DCM (3 × 50mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto a silica gel packed column and chromatographed via a silica gel column (40g) eluting with a gradient of 0% to 50% EtOAc in hexanes to provide 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester (1.26g, 1.876mmol, 49.2% yield).

And 5: 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester and 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester -formic acid (R) -tert-butyl ester

To a 250mL round bottom flask was added 4- (1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6-fluoropyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (3R) -tert-butyl ester (1.0g, 1.489mmol), 5-fluoro-6-methoxypyridin-3-amine (0.317g, 2.233mmol) (Anichem), tetrahydrofuran (20mL, 247 mmol). The solution was stirred at-40 ℃ and treated dropwise with lithium bis (trimethylsilyl) amide (Aldrich) (4.47mL, 4.47mmol) via addition funnel. The solution was stirred at-40 ℃ for 30 minutes and water and NH were added₄Cl (20mL each) was quenched and diluted with EtOAc (20mL) and the aqueous layer was extracted with EtOAc (2X 20 mL). The organic extracts were washed with saturated NaCl (20mL) and dried over sodium sulfate, filtered and concentrated in vacuo. Will be coarseThe product was adsorbed onto a silica gel packed column and chromatographed via a silica gel column (40g) eluting with a gradient of 5% to 50% EtOAc in hexanes to provide (R) -tert-butyl 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylate (0.45g, 0.567mmol, 38.1% yield) and 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester (0.35g, 0.441mmol, 29.6% yield).

Step 6: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To a 100mL round bottom flask was added 4- ((R) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester (0.200g, 0.252mmol), dichloromethane (5mL, 78mmol), trifluoroacetic acid (5mL, 67.3 mmol). The solution was stirred for 1 hr. The solution was concentrated to reduce volume, and the residue was dissolved in DCM and washed with NaHCO₃Wash slowly to remove TFA. The DCM solution was dried over sodium sulfate, filtered and concentrated. The residue was dried under high vacuum overnight. The residue was dissolved in DCM, cooled to a reduced volume in a dry ice/IPA cooling bath, and treated with triethylamine (0.349mL, 2.52mmol) and methanesulfonyl chloride (0.098mL, 1.260 mmol). The solution was stirred at-50 ℃ for 30 minutes. The solvent was removed in vacuo and the crude product was washed with water (30mL), stirred and sonicated. The resulting suspension was collected, washed with water and dried in a vacuum oven overnight to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.150g, 0.194mmol, 77% yield).

And 7: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 50mL round bottom flask was added 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.130g, 0.168mmol), 2, 2, 2-trifluoroacetic acid (5mL, 0.842mmol), and trifluoromethanesulfonic acid (0.2mL, 0.168 mmol). The solution was stirred at 70 ℃ for 30 minutes. Volatiles were removed in vacuo and the residue was cooled in an ice bath and neutralized with 1N NaOH. The mixture was stirred at room temperature overnight and the precipitate was filtered and washed with water. The precipitate was purified by preparative TLC using 5% (MeOH in DCM). The sample was dried under high vacuum overnight to give 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.047g, 0.088mmol, 52.5% yield). M/z (ESI, cation) 532.2(M + H)⁺。¹H NMR(400MHz，DMSO-d₆)δppm 1.07(d，J＝6.26Hz，3H)1.38(d，J＝6.65Hz，3H)2.45(m，4H)-2.55(m，1H)2.84(s，5H)3.01-3.18(m，3H)3.94(s，3H)4.00(d，J＝6.85Hz，1H)7.74-7.78(m，1H)7.88-7.92(m，1H)8.31-8.34(m，1H)8.37-8.43(m，2H)8.70-8.74(m，1H)11.93(s，1H)。

Example 361: 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((S) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

In a similar manner as described in example 360, steps 6 and 7 above, 4- ((S) -1- (5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) ethyl) -3-methylpiperazine-1-carboxylic acid (R) -tert-butyl was usedThe title compound (0.031g, 0.058mmol, 47.4% yield) was prepared from butyl ester instead of 4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((R) -1- ((R) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine. m/z (ESI, cation): 532.2(M + H)⁺。¹H NMR(400MHz，DMSO-d₆)δppm 1.16(d，J＝6.46Hz，3H)1.27(br.s.，3H)2.45(s，4H)2.52(m，1H)2.85(s，5H)3.04(s，3H)3.94(s，3H)4.04(d，J＝6.85Hz，1H)7.76(m，1H)7.90(m，1H)8.37(m，1H)8.41(m，2H)8.75(br.s.，1H)11.95(s，1H)。

Example 362: 4- (2- (2-methoxypyrimidin-5-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound (0.023g, 0.045mmol, 33.7% yield) was prepared in a similar manner as described in example 360, steps 6 and 7 above using (S) -tert-butyl 3-methylpiperazine-1-carboxylate (Aldrich) (scheme 6) instead of (R) -4-N-boc-2-methyl-piperazine in step 1 and 2-methoxypyrimidin-5-amine instead of 5-fluoro-6-methoxypyridin-3-amine in step 5. m/z (ESI, cation): 515.2(M + H) ⁺。¹H NMR(400MHz，DMSO-d₆)δppm1.07(d，J＝6.26Hz，3H)1.38(d，J＝6.85Hz，3H)2.45(s，3H)2.53-2.57(m，1H)2.78-2.89(m，2H)2.84(s，4H)3.02-3.17(m，3H)3.32(s，1H)3.91-4.03(m，1H)3.94(s，4H)7.73-7.78(m，1H)7.87-7.92(m，1H)8.30-8.34(m，1H)8.37-8.43(m，2H)8.70-8.74(m，1H)11.93(s，1H)。

Example 363: 4- (2- (6-Chloropyridin-3-ylamino) -5- ((R) -1- ((S) -2-methyl-4- (methylsulfonyl) piperazin-1-yl) ethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound (0.041g, 0.079 mmol, 30.0% yield) was prepared in a similar manner to that described above for example 362 using 5-amino-2-chloropyridine instead of 2-methoxypyrimidin-5-amine in step 5. M/z 518.2(M + H)⁺。¹H NMR(400MHz，DMSO-d₆)δppm 1.06-1.07(d，J＝6.06Hz，3H)1.37-1.38(d，J＝6.65Hz，3H)2.46(br，3H)2.55(br.，2H)2.84(d，J＝9.78Hz，5H)3.04-3.06(t，J＝5.48Hz，1H)3.13(br.，2H)4.01(d，J＝6.85Hz，1H)7.46-7.46(d，J＝8.61Hz，1H)7.80(br.S.，1H)7.94(br.S.，1H)8.37(br.s.，1H)8.48-8.51(d，J＝8.61Hz，1H)8.75(br.s.，1H)8.86-8.89(br.，s，1H)12.15(s，1H)。

Example 364: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine.

Step 1: 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -2-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester

To a 15mL round bottom flask was added 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (0.438g, 0.735mmol), 2-methylpiperazine-1-carboxylic acid (R) -tert-butyl ester (0.368g, 1.838mmol), tetrahydrofuran (0.053g, 0.735mmol), titanium (iv) ethoxide (0.761mL, 3.68mmol) (Aldrich). The flask was sealed and the solution was stirred at 70 ℃ overnight. The solution was stirred at 0 ℃ and treated once with sodium cyanoborohydride (0.462g, 7.35mmol) (Aldrich). The suspension was stirred for two hours at 0 ℃. With a few drops of MeOH and water, The suspension was then quenched with DCM. The suspension was stirred vigorously for 10 minutes and passed through Celite(celite) filter and wash the filter cake with DCM. The organic phase was concentrated to give (R) -tert-butyl 4- ((5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) methyl) -2-methylpiperazine-1-carboxylate (0.425g, 0.545mmol, 74.1% yield).

Step 2: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound (0.164g, 0.216mmol, 46.9% yield) was prepared in a similar manner as described above for example 360, step 6.

And step 3: (R) -4- (2- (5-fluoro-6-methoxypyridin-3-ylamino) -5- ((3-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

The title compound (0.030g, 0.058mmol, 27.5% yield) was prepared in a similar manner as described above for example 360, step 7. M/z (ESI, cation) 518.2(M + H)⁺。 ¹H NMR(400MHz，DMSO-d₆)δppm 1.26(d，J＝6.65Hz，3H)2.10(d，J＝3.52Hz，1H)2.16-2.22(m，1H)2.44(s，3H)2.59-2.61(d，J＝9.59Hz，1H)2.77-2.81(d，1H)2.93(s，3H)3.15-3.23(m，1H)3.42(d，J＝12.91Hz，2H)3.51(s，1H)3.94(br，4H)7.77(br.s.，1H)7.88-7.93(br，1H)8.25-8.28(s，1H)8.35-8.36(s，1H)8.38-8.40(m，1H)8.43(d，J＝2.35Hz，1H)8.74-8.77(s，1H)11.93(s，1H)。

Example 365: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) cyclopropanesulfonamide

Step 1: n- (5-bromo-2-chloropyridin-3-yl) -N- (cyclopropylsulfonyl) cyclopropanesulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (1.000g, 4.82mmol) in pyridine (10mL) was added cyclopropanesulfonyl chloride (0.540mL, 5.30 mmol). In N₂Next, the resulting mixture was heated to 100 ℃ for 20 h. The reaction was cooled to room temperature and poured into a beaker and filled with EtOAc (50ml) and stirred by hand for 10 minutes. The organic layer was decanted into a round bottom flask. The original mixture (black paste) was dissolved in DCM (3ml), then EtOAc (20ml) was added and stirred by hand for 10min before decanting to the same round bottom flask mentioned earlier. The combined organic layers were concentrated in vacuo. The crude product was purified by column chromatography (80g, 10% to 20% EtOAc in hexanes) to afford the product as a light brown solid (880 mg). MS (ESI cation) m/z: 414.8.¹H NMR(300MHz，CDCl₃)δppm1.25(dd，J＝7.67，4.02Hz，4H)1.32(d，J＝3.95Hz，4H)3.14-3.32(m，2H)7.97(d，J＝1.90Hz，1H)8.53(d，J＝1.90Hz，1H)。

step 2: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) cyclopropanesulfonamides

To a 20mL microwave vial was added N- (5-bromo-2-chloropyridin-3-yl) -N- (cyclopropylsulfonyl) cyclopropanesulfonamide (0.880g, 2.117mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Acros) (0.122g, 0.212mmol), tris (dibenzylideneacetone) dipalladium (0) (Strem) (0.097g, 0.106mmol), sodium tert-butoxide (Fluka) (0.814g, 8.47mmol), DMF (10mL) and benzophenone imine (Aldrich) (0.426mL, 2.54 mmol). By adding N ₂The resulting mixture was degassed by bubbling for 5 min. It was sealed and microwave heated at 130 ℃ for 20 min. The resulting mixture was washed with EtOAc and saturated NH₄Partition between Cl (25 mL). The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g, 10% to 20% acetone in hexanes) to give a yellow colorDesired product as a foamy solid (300 mg). MS (ESI cation) m/z: 412.0.¹H NMR(300MHz，CDCl₃)δppm 0.89(d，J＝7.02Hz，2H)1.03(d，J＝3.07Hz，2H)6.60(br.s.，1H)7.14(d，J＝3.65Hz，2H)7.34(d，J＝6.28Hz，4H)7.39-7.48(m，2H)7.49-7.56(m，1H)7.68-7.80(m，3H)。

and step 3: n- (5-amino-2-chloropyridin-3-yl) cyclopropanesulfonamides

To a solution of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) cyclopropanesulfonamide (0.300g, 0.728mmol) in THF (5mL) was added 1N hydrochloric acid (1.092mL, 1.092 mmol). The reaction was stirred in a closed system at room temperature. After 30min, LC/MS showed no sign of starting material and the desired product mass was shown to be the main front. The reaction mixture was washed with EtOAc and saturated NaHCO₃Are distributed among the devices. The aqueous layer was extracted with more EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a yellow solid (170 mg). MS (ESI cation) m/z: 248.0: ¹H NMR(300MHz， CDCL₃)δppm 1.04(d，J＝6.58Hz，2H)1.13-1.32(m，2H)2.51(t，J＝4.60Hz，1H)3.85(b r.s.，2H)6.63(b r.s.，1H)7.35(s，1H)7.68(s，1H)。

And 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) cyclopropanesulfonamide

To a 15mL RB flask were added N- (5-amino-2-chloropyridin-3-yl) cyclopropanesulfonamide (0.050g, 0.202mmol), 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.050g, 0.242mmol), and DMF (2.0 mL). The mixture was cooled to 0 ℃ under N2. A1.0 m solution of sodium bis (trimethylsilyl) amide (Aldrich) (0.807mL, 0.807mmol) in THF was then added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature for 30 min. The reaction mixture was poured into a beaker, and the flask was filled with 15mL of saturated NH₄And (5) filling Cl. The resulting mixture was stirred at room temperature for 15h. The precipitate in the solution mixture was collected by filtration. The solid was washed with water and dried open to air for 4 h. This crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a yellow solid (60.0 mg). MS (ESI cation) m/z: 433.0.¹H NMR(300MHz，CDCl₃)δppm0.97-1.14(m，2H)1.33(dd，J＝4.60，1.83Hz，2H)2.51-2.69(m，4H)5.42(br.s.，2H)6.75(s，1H)6.92(dd，J＝7.82，4.90Hz，1H)8.32-8.45(m，1H)8.56(d，J＝2.34Hz，1H)8.76(d，J＝2.34Hz，1H)8.87(dd，J＝7.89，1.75Hz，1H)12.36(s，1H)。

example 366: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide

Step 1: n- (5-bromo-2-chloropyridin-3-yl) morpholine-4-sulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (Small Molecules, Inc.) (1.000g, 4.82mmol) in pyridine (8mL) was added 4-dimethylaminopyridine (Aldrich) (0.147g, 1.205mmol) and morpholine (Aldrich) (0.546mL, 6.27 mmol). The reaction mixture was cooled to-30 ℃ and the mixture was allowed to stir for 10 minutes. Sulfonyl chloride (Aldrich) (0.586mL, 7.23mmol) was then added dropwise to the reaction mixture. After the addition, the mixture was stirred in a cooling bath for a further 20min, then allowed to warm to room temperature and under N₂Stirring was continued for 20 h. The reaction mixture was poured into a beaker, which was filled with EtOAc (50ml) and stirred by hand for 10 minutes. The organic layer was decanted into a round bottom flask. The original mixture (black paste) was dissolved in DCM (3ml), then EtOAc (20ml) was added and stirred by hand for 10min before decanting to the same round bottom flask mentioned earlier. The combined organic layers were concentrated in vacuo. The crude product was purified by column chromatography (80g, 10% to 20% acetone in hexanes) to afford the desired product as a pale yellow solid (800 mg). MS (ESI cation) m/z:356.8。¹H NMR(300MHz，CDCl₃)δppm 3.15-3.41(m，4H)3.60-3.83(m，4H)6.79(br.s.，1H)8.08(s，1H)8.23(s，1H)。

step 2: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) morpholine-4-sulfonamide

To a 20mL microwave vial were added N- (5-bromo-2-chloropyridin-3-yl) morpholine-4-sulfonamide (0.500g, 1.40mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Acros) (0.048g, 0.084mmol), tris (dibenzylideneacetone) dipalladium (o) (Strem) (0.015g, 0.017mmol), sodium tert-butoxide (Fluka) (0.268g, 2.8mmol), toluene (10mL), and benzophenone imine (Aldrich) (0.260mL, 1.54 mmol). The resulting mixture was sealed and microwaved at 110 ℃ for 20 min. The reaction mixture was partitioned between EtOAc and Tris HCl 1M pH 7. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (24g, 10% to 20% EtOAc in hexanes) to give the desired product as a yellow foam (150.0 mg). MS (ESI cation) m/z: 457.0.¹H NMR(300MHz，CDCl₃)δppm 3.07(d，J＝4.38Hz，4H)3.63(d，J＝4.38Hz，4H)6.62(br.s.，1H)7.14(d，J＝3.95Hz，2H)7.35(d，J＝5.85Hz，4H)7.40-7.49(m，2H)7.49-7.58(m，1H)7.63(s，1H)7.74(d，J＝7.16Hz，2H)。

and step 3: n- (5-amino-2-chloropyridin-3-yl) morpholine-4-sulfonamide

To a solution of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) morpholine-4-sulfonamide (0.150g, 0.328mmol) in THF (3mL) was added 2N hydrochloric acid (JT Baker) (0.020mL, 0.657 mmol). The reaction was stirred in a closed system at room temperature for 20 min. The reaction mixture was washed with EtOAc and saturated NaHCO₃Are distributed among the devices. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO ₄Dried and concentrated. The crude product was purified by column chromatography (24g, 3% MeOH in DCM) to give the desired product as a white foamy solid (70.0 mg). MS (ESI cation) m/z: 293.0.¹H NMR(300MHz，CDCl₃)δppm 3.16-3.32(m，4H)3.61-3.74(m，4H)3.84(br.s.，2H)6.67(br.s.，1H)7.31(d，J＝2.34Hz，1H)7.64(d，J＝2.19Hz，1H)。

and 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) morpholine-4-sulfonamide

To a 15mL RB flask were added N- (5-amino-2-chloropyridin-3-yl) morpholine-4-sulfonamide (0.065g, 0.222mmol), 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.055g, 0.266mmol) and DMF (3.0 mL). The mixture was cooled to 0 ℃ under N2. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (0.888mL, 0.888mmol) in THF was added in one portion to the solution. The now dark brown mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH₄Quenched with Cl and CHCl₃(3X 10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24g, 3% MeOH in DCM) to give the desired product as a yellow solid (42.0 mg). MS (ESI cation) m/z: 478.0.¹H NMR(300MHz，DMSO-d₆)δppm 2.45(s，3H)3.15(br.s.，4H)3.61(br.s.，4H)7.03(dd，J＝7.53，4.60Hz，1H)7.79(br.s.，1H)7.91(br.s.，1H)8.38(d，J＝3.36Hz，1H)8.51(s，1H)8.82(d，J＝5.41Hz，2H)9.78(s，1H)12.26(s，1H)。

example 367: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide

Step 1: n- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (Small Molecules, Inc.) (1.000g, 4.82mmol) in pyridine (8mL) was added n-isopropylmethylamine (Aldrich) ((Aldrich))0.651mL, 6.27mmol) and 4-dimethylaminopyridine (Aldrich) (0.147g, 1.205 mmol). The reaction mixture was cooled to-30 ℃ and the mixture was allowed to stir for 10 minutes. Sulfonyl chloride (Aldrich) (0.586mL, 7.23mmol) was added dropwise to the mixture. After the addition, the mixture was stirred in a cooling bath for a further 20min, then allowed to warm to room temperature and under N₂Stirring was continued for 20 h. The reaction mixture was poured into a beaker, which was filled with EtOAc (30ml) and stirred by hand for 10 minutes. The organic layer was decanted into a round bottom flask. The original mixture (black paste) was dissolved in DCM (3ml), then EtOAc (20ml) was added and stirred by hand for 10min before decanting to the same round bottom flask mentioned earlier. The combined organic layers were concentrated in vacuo. The crude product was purified by column chromatography (120g, 10% to 20% EtOAc in hexanes) to afford the desired product as a light brown solid (660 mg). MS (ESI cation) m/z: 342.1.¹H NMR(300MHz，CDCl₃)δppm 1.00-1.26(m，6H)2.76(s，3H)4.19(dt，J＝13.37，6.61Hz，1H)6.85(br.s.，1H)7.94(d，J＝2.19Hz，1H)8.17(d，J＝2.19Hz，1H)。

step 2: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide

To pass through N₂A20 mL microwave vial degassed by bubbling was charged with N- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide (0.660g, 1.926mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.111g, 0.193mmol), tris (dibenzylideneacetone) dipalladium (o) (0.088g, 0.096mmol), sodium tert-butoxide (0.740g, 7.70mmol), DMF (12mL), and benzophenone imine (0.356mL, 2.119 mmol). The resulting mixture was sealed and microwaved at 140 ℃ for 20 min. The resulting mixture was washed with EtOAc and saturated NH₄Partition between Cl (25 mL). The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g, 10% to 20% EtOAc in hexanes) to give the desired product as a yellow foamy solid (270 mg). MS (ESI cation) m/z: 442.8.¹H NMR(300MHz，CDCl₃)δppm 1.04(d，J＝6.72Hz，6H)2.66(s，3H)3.99(dt，J＝13.52，6.69Hz，1H)6.70(br.s.，1H)7.13(d，J＝5.26Hz，2H)7.28-7.37(m，4H)7.39-7.47(m，2H)7.49-7.59(m，2H)7.74(d，J＝7.02Hz，2H)。

and step 3: n- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide

To a solution of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide (0.250g, 0.564mmol) in THF (3mL) was added 2N hydrochloric acid (0.423mL, 0.847 mmol). The reaction was stirred in a closed system at room temperature for 20 min. The reaction mixture was washed with EtOAc and saturated NaHCO ₃Are distributed among the devices. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (24g, 3% MeOH in DCM) to give the desired product as a white foamy solid (110.0 mg). MS (ESI cation) m/z: 279.0.¹H NMR(300MHz，CDCl₃)δppm 1.10(d，J＝6.72Hz，6H)2.75(s，3H)3.80(br.s.，2H)4.14(dt，J＝13.34，6.70Hz，1H)6.74(br.s.，1H)7.21(d，J＝2.63Hz，1H)7.59(d，J＝2.63Hz，1H)。

and 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide

A15 mL RB flask was charged with N- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl-N-methylaminosulfonamide (0.050g, 0.179mmol), 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.044g, 0.215mmol), and DMF (3.0 mL). In N₂The mixture was cooled down to 0 ℃. A1.0 m solution of sodium bis (trimethylsilyl) amide (Aldrich) (0.717mL, 0.717mmol) in THF was then added to the solution in one portion. The now dark brown mixture was stirred at 0 ℃ for 10min, then warmed to room temperature for 30 min. The reaction mixture was poured into a beaker, and the flask was filled with 15mL of saturated NH₄And (5) filling Cl. The resulting mixture was stirred for 1 h. Collecting the precipitate by filtration; washing the precipitate with water and drying in an open air oven for 20h to obtain To the product as a light brown solid (71 mg). MS (ESI cation) m/z: 464.0.¹H NMR(300MHz， DMSO-d₆)δppm 1.03(d，J＝6.58Hz，6H)2.45(s，3H)2.72(s，3H)4.07(dt，J＝13.23，6.54Hz，1H)7.03(dd，J＝7.82，4.75Hz，1H)7.79(br.s.，1H)7.91(br.s.，1H)8.30-8.41(m，1H)8.44(d，J＝2.19Hz，1H)8.77-8.85(m，1H)8.88(d，J＝2.19Hz，1H)9.46(s，1H)12.28(s，1H)。

example 368: n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-yl) -2-chloropyridine-3, 5-diamine

Step 1: 5-bromo-2-chloropyridin-3-ylcarbamic acid di-tert-butyl ester

To a solution of 5-bromo-2-chloropyridin-3-amine (1.000g, 4.82mmol) in DMF (8mL) at 0 deg.C was added portionwise a 60% sodium hydride dispersion (Lancaster) (0.272mL, 6.27mmol) in mineral oil. After stirring for 20min, di-tert-butyl dicarbonate (Fluka) (2.52g, 11.57mmol) was subsequently added. After addition, the ice bath was removed. The reaction mixture was allowed to warm and at room temperature under N₂Stirred for 3 h. The reaction mixture was poured into a beaker, which was saturated with NH₄Cl was charged and stirred for 2 hours. The precipitate in the solution mixture was collected by filtration. The solid was washed with water and dried open to the air for 20h to give the product as a light brown solid (1.6 g). MS (ESI cation) m/z: 407.0.¹H NMR(300MHz，CDCl₃)δppm 1.44(s，18H)7.73(d，J＝2.19Hz，1H)8.43(d，J＝2.19Hz，1H)。

step 2: 2-chloro-5- (diphenylmethyleneamino) pyridin-3-ylcarbamic acid tert-butyl ester

To a 20mL microwave vial was added di-tert-butyl 5-bromo-2-chloropyridin-3-ylcarbamate (0.500g, 1.226mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Acros) (0.071g, 0.123 m) mol), tris (dibenzylideneacetone) dipalladium (0) (Strem) (0.056g, 0.061mmol), sodium tert-butoxide (Fluka) (0.471g, 4.91mmol), DMF (12mL) and benzophenone imine (Aldrich) (0.226mL, 1.349 mmol). By adding N₂The resulting mixture was degassed by bubbling for 5 min. It was sealed and microwave heated at 130 ℃ for 20 min. The reaction mixture was washed with EtOAc and saturated NH₄Partition between Cl. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g, 10% to 20% EtOAc in hexanes) to give the desired product as a yellow film (280 mg). MS (ESI cation) m/z: 408.0.¹H NMR(300MHz，CDCl₃)δppm 1.52(s，9H)6.87(br.s.，1H)7.15(d，J＝3.36Hz，2H)7.29-7.35(m，3H)7.37-7.46(m，3H)7.47-7.54(m，1H)7.75(d，J＝7.16Hz，2H)8.05(d，J＝2.05Hz，1H)。

and step 3: 5-amino-2-chloropyridin-3-ylcarbamic acid tert-butyl ester

To a solution of tert-butyl 2-chloro-5- (diphenylmethyleneamino) pyridin-3-ylcarbamate (0.280g, 0.686mmol) in THF (5mL) was added 1n hydrochloric acid (JT Baker) (0.031mL, 1.030 mmol). The reaction was stirred in a closed system at room temperature for 20 min. The reaction mixture was washed with EtOAc/saturated NaHCO₃Are distributed among the devices. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (24g, 3% MeOH in DCM) to give the desired product as a white foamy solid (135.0 mg). MS (ESI cation) m/z: 244.1. ¹H NMR(300MHz，CDCl₃)δppm 1.54(s，9H)3.73(br.s.，2H)6.93(br.s.，1H)7.52(d，J＝2.63Hz，1H)7.94(d，J＝2.63Hz，1H)。

And 4, step 4: 5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-ylcarbamic acid tert-butyl ester

A15 mL RB flask was charged with tert-butyl 5-amino-2-chloropyridin-3-ylcarbamate (0.130g, 0.533mmol), 4- (2-fluoro-5-methoxypyridin-3-yl) -6-methyl-1, 35-triazin-2-amine (example 330 step 5) (0.151g, 0.640mmol) and DMF (2.0 mL). In N₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (2.134mL, 2.134mmol) in THF was then added to the solution in one portion. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 30 min. The reaction mixture was poured into a beaker, and the flask was filled with 15mL of saturated NH₄And (5) filling Cl. The resulting mixture was stirred at room temperature for 5 h. The precipitate in the solution mixture was collected by filtration. The solid was washed with water and dried open to air for 4 h. This crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a yellow solid (210 mg). MS (ESI cation) m/z: 459.0.¹H NMR(300MHz，DMSO-d₆)δppm 1.47(s，9H)2.45(s，3H)3.85(s，3H)7.80(br.s.，1 H)7.94(br.s.，1H)8.20(d，J＝3.07Hz，1H)8.42(d，J＝3.07Hz，1H)8.58(d，J＝2.34Hz，1H)8.63(d，J＝2.34Hz，1H)8.75(s，1H)11.91(s，1H)。

and 5: n5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-yl) -2-chloropyridine-3, 5-diamine

To a 20mL scintillation vial containing tert-butyl 5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-methoxypyridin-2-ylamino) -2-chloropyridin-3-ylcarbamate (0.210g, 0.458mmol) dissolved in DCM (5mL) was added trifluoroacetic acid (Aldrich) (0.170mL, 2.288 mmol). The resulting mixture was capped and stirred in a closed system at room temperature for 1 h. The reaction mixture was first washed with saturated NaHCO₃Neutralization followed by CHCl₃(3X 10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using column chromatography (40g, 3% to 5% MeOH in DCM) to give the desired product as a yellow solid (135 mg). MS (ESI cation) m/z: 359.0. c₁₅H₁₅Cl N₈Accurate calculated value of mass of O: 358.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.45(s，3H)3.84(s，3H)5.43(s，2H)7.78(br.s.，1H)7.86(br.s.，1H)7.89(d，J＝2.35Hz，1H)7.94(d，J＝2.15Hz，1H)8.16(d，J＝3.13Hz，1H)8.40(d，J＝3.13Hz，1H)11.75(s，1H)。

example 369: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 1: 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid

To a solution of diisopropylamine (Aldrich) (0.640mL, 4.57mmol) in THF (10mL) in a 100mL 3-necked round-bottomed flask at-40 deg.C was added dropwise via an addition funnel a solution of 1.6m butyllithium (Aldrich) (2.85mL, 4.57mmol) in hexane. After addition, it was stirred for a further 20min at-40 ℃ and subsequently cooled to-78 ℃. To this reaction mixture was added 4- (1- (6-fluoropyridin-3-yl) ethyl) morpholine (example 339 step 3) (0.800g, 3.81mmol) dissolved in THF (10mL) dropwise via addition funnel. After the addition, it was stirred further at-78 ℃. After 1h, triisopropyl borate (Aldrich) (1.309mL, 5.71mmol) was added dropwise to the reaction mixture via the addition funnel. After the addition, it was stirred at-78 ℃ for a further 20min, after which the cooling bath was removed and slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 1N NaOH (15 mL). The aqueous layer was extracted with EtOAc (2 × 15mL) -the organic layer was discarded; the aqueous layer was acidified to pH about 5 to 6 using 5N HCl. The resulting mixture was washed with EtOAc (2X 15mL) and CHCl ₃(2X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated to give the product as a light brown amorphous solid (780 mg). MS (ESI cation) m/z: 255.1.¹H NMR(400MHz，CDCl₃)δppm 1.38(dd，J＝11.44，6.75Hz，3H)2.36(d，J＝4.30Hz，2H)2.45-2.60(m，2H)3.35-3.47(m，1H)3.63-3.77(m，4H)8.15(dd，J＝9.00，2.35Hz，1H)8.19-8.27(m，2H)8.33(d，J＝9.00Hz，1H)。

step 2: 4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine

To a 20mL microwave vial was added 4-chloro-6-methyl-1, 3, 5-triazin-2-amine (0.300g, 2.075mmol), 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid (0.580g, 2.283mmol), Amphos (Aldrich) (0.073g, 0.104mmol), potassium acetate (Aldrich) (0.611g, 6.23mmol), EtOH (9mL), and water (0.9 mL). By adding N₂The resulting mixture was degassed by bubbling for 5min, then sealed and microwave heated at 100 ℃ for 20 min. Dissolving the reaction mixture in CHCl₃25% IPA (1% NH) in (C)₄OH) (30mL) and water (50 mL). More dissolved in CHCl₃The aqueous layer was extracted with 25% IPA (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a white solid (200 mg). MS (ESI cation) m/z: 319.1.¹H NMR(300MHz，CDCl₃)δppm 1.42(d，J＝6.58Hz，3H)2.32-2.47(m，2H)2.49-2.63(m，5H)3.50(q，J＝6.33Hz，1H)3.71(t，J＝4.38Hz，4H)5.49(br.s.，2H)8.29(s，1H)8.46(dd，J＝9.13，2.27Hz，1H)。

and step 3: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

To a 15mL round bottom flask was added 4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.100g, 0.314mmol), N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (0.084g, 0.377mmol), and DMF (2.0 mL). In N₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (0.254mL, 1.256mmol) in THF was then added to the solution in one portion. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with EtOAc (2X 10mL), CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a yellow solid (100 mg). MS (ESI cation) m/z: 520.1。¹H NMR(300MHz，DMSO-d₆)δppm 1.34(d，J＝6.58Hz，3H)2.33(br.s.，2H)2.46(s，5H)3.13(s，3H)3.46(d，J＝4.82Hz，1H)3.57(br.s.，4H)7.69-8.00(m，2H)8.32(s，1H)8.66(d，J＝2.48Hz，2H)8.74(s，1H)9.65(br.s.，1H)。

Separation of isomers

The isomeric mixtures of N- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide were separated using chiral SFC preparative chromatography. The following conditions were used:

column: IC (21mm X25 cm)

Mobile phase: 65: 35 (A: B)

A: liquid CO₂

B: isopropanol (0.2% diethylamine)

Flow rate: 70mL/min

Oven/column temperature: 40 deg.C

Two separate peaks with two enantiomers were collected, concentrated, and dried under high vacuum to give the two enantiomers. Absolute stereochemistry was not determined. (see example 72)

Example 370: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide

To a 15mL round bottom flask was added 4- (2-fluoro-5- (1-morpholinoethyl) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.100g, 0.314mmol), N- (5-bromo-2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide (0.095g, 0.377mmol), and DMF (2.0 mL). In N₂Will be as followsThe mixture was cooled to 0 ℃. A1.06 m solution of sodium bis (trimethylsilyl) amide (Aldrich) (0.244mL, 1.256mmol) in THF was added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was poured into a beaker, and the flask was filled with 15mL of saturated NH₄And (5) filling Cl. The resulting mixture was stirred at room temperature for 2 h. The precipitate in the solution mixture was collected by filtration. The solid was washed with water and dried in a vacuum oven for 15 h. This crude product was purified by column chromatography (24g, 3% MeOH in DCM) to give the desired product as a yellow solid (120 mg). MS (ESI cation) m/z: 548.9. ¹H NMR(400MHz，DMSO-d₆)δppm 1.34(d，J＝6.46Hz，3H)2.33(br.s.，2H)2.46(s，5H)2.79(s，6H)3.46(br.s.，1H)3.56(br.s.，4H)7.79(br.s.，1H)7.94(br.s.，1H)8.31(d，J＝2.35Hz，1H)8.54(d，J＝2.54Hz，1H)8.75(d，J＝2.15Hz，1H)8.83(d，J＝2.35Hz，1H)9.59(s，1H)12.29(s，1H)。

Separation of isomers

column: OZ-H (21mm X25 cm)

Mobile phase: 50: 50 (A: B)

A: liquid CO₂

B: MeOH (0.2% diethylamine)

Flow rate: 60mL/min

Oven/column temperature: 35 deg.C

The two separate peaks containing the two enantiomers were collected, concentrated, and dried under high vacuum to give the two enantiomers. Absolute stereochemistry was not determined. (see examples 373 and 374). Examples 371 and 372: (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide; and) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

MS (ESI cation) m/z: 520.1.¹H NMR(300MHz，DMSO-d₆)δppm1.34(d，J＝6.58Hz，3H)2.33(br.s.，2H)2.46(s，5H)3.13(s，3H)3.46(d，J＝4.82Hz，1H)3.57(br.s.，4H)7.69-8.00(m，2H)8.32(s，1H)8.66(d，J＝2.48Hz，2H)8.74(s，1H)9.65(br.s.，1H)。

MS (ESI cation) m/z: 520.1.¹H NMR(400MHz，CDCl₃)δppm1.43(br.s.，3H)2.33-2.58(m，3H)2.60(s，4H)3.14(s，3H)3.43(br.s.，1H)3.73(br.s.，4H)5.51(br.s.，2H)6.78(br.s.，1H)8.38(d，J＝1.76Hz，1H)8.56(d，J＝2.35Hz，1H)8.78(d，J＝2.35Hz，2H)12.40(br.s.，1H)。

examples 373 and 374: (R) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide; and (S) -N- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide

MS (ESI cation) m/z: 548.9.¹H NMR(300MHz，CDCl₃)δppm1.36-1.50(m，3H)2.36-2.47(m，2H)2.47-2.57(m，2H)2.61(s，3H)2.96(s，6H)3.42(d，J＝6.72Hz，1H)3.72(t，J＝4.38Hz，4H)5.49(br.s.，2H)8.33(d，J＝2.34Hz，1H)8.43(d，J＝2.34Hz，1H)8.78(d，J＝2.19Hz，1H)8.82(d，J＝2.48Hz，1H)12.35(s，1H)。

MS (ESI cation) m/z: 548.9.¹H NMR(300MHz，CDCl₃)δppm1.43(br.s.，3H)2.30-2.57(m，4H)2.61(s，3H)2.96(s，6H)3.41(br.s.，1H)3.73(br.s.，4H)5.50(br.s.，2H)6.78(br.s.，1H)8.34(br.s.，1H)8.42(d，J＝2.34Hz，1H)8.81(d，J＝2.34Hz，2H)12.36(br.s.，1H)。

example 375: n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide

Step 1: 6- (2-Fluoropyridin-3-Yl) -2-Methylpyrimidin-4-Amines

To a 20mL microwave vial was added 4-chloro-6-chloro-2-methylpyrimidine (Synchem) (0.500g, 3.48mmol), 2-fluoro-3-pyridineboronic acid (Aldrich) (0.687g, 4.88mmol), Amphos (Aldrich) (0.123g, 0.174mmol), potassium acetate (Aldrich) (0.653mL, 10.45mmol), EtOH (12mL), and water (1.2 mL). By adding N₂The vial was degassed by bubbling for 5min, then sealed and microwave heated at 100 ℃ for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g, 20% to 40% acetone in hexanes) to give the desired product as a yellow solid (600 mg)). MS (ESI cation) m/z: 205.1.¹H NMR(300MHz，CDCl₃)δppm 2.59(s，3H)4.96(br.s.，2H)6.89(s，1H)7.34(ddd，J＝7.34，4.93，1.90Hz，1H)8.27(dd，J＝3.00，1.53Hz，1H)8.66(ddd，J＝9.76，7.64，2.05Hz，1H)。

step 2: n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) -2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide

A5 mL microwave vial was charged with 6- (2-fluoropyridin-3-yl) -2-methylpyrimidin-4-amine (0.450g, 2.204mmol), N- (5-bromo-2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide (0.608g, 2.424mmol), 5.0 hydrochloric acid gauge solution (JT Baker) (0.134mL, 4.41mmol), and EtOH (10 mL). The resulting mixture was sealed and microwaved at 160 ℃ for 20 min. The solvent was concentrated. The crude product was purified by column chromatography (40g, 20% to 40% acetone in hexanes) to afford the desired product as a light brown solid (60 mg). MS (ESI cation) m/z: 434.9. ¹H NMR(300MHz，DMSO-d₆)δppm 2.52(s，3H)2.79(s，6H)6.78(s，1H)7.01(dd，J＝7.67，4.90Hz，1H)7.06(br.s.，2H)8.12(d，J＝7.75Hz，1H)8.31(d，J＝4.68Hz，1H)8.51(d，J＝2.19Hz，1H)8.56(s，1H)9.57(s，1H)12.69(s，1H)。

Example 376: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide

Step 1: n- (5-bromo-2-methylpyridin-3-yl) -N- (methylsulfonyl) methanesulfonamide

To a solution of 5-bromo-2-methylpyridin-3-amine (PharmaBlock) (2.000g, 10.69mmol) in pyridine (15.0mL) was added 4-dimethylaminopyridine (Aldrich) (0.131g, 1.069mmol) and methanesulfonyl chloride (2.5mL, 32.1 mmol). In N₂Then, the resulting mixture is heated toThe temperature is 100 ℃ for 2 h. The reaction was cooled to room temperature. The reaction mixture was poured into a beaker, which was filled with EtOAc (50ml) and stirred by hand for 10 minutes. The organic layer was decanted into a round bottom flask. The original mixture (black paste) was dissolved in DCM (3ml), then EtOAc (20ml) was added and stirred by hand for 10min before decanting to the same round bottom flask mentioned earlier. The combined organic layers were concentrated in vacuo. The crude product was purified by column chromatography (120g, 10% to 20% acetone in hexanes) to afford the desired product as a light brown solid (1.1 g). MS (ESI cation) m/z: 342.8.¹H NMR(300MHz，CDCl₃)δppm 2.64(s，3H)3.47(s，6H)7.73(d，J＝2.05Hz，1H)8.67(d，J＝2.05Hz，1H)。

step 2: n- (5- (diphenylmethyleneamino) -2-methylpyridin-3-yl) methanesulfonamide

To two 20mL microwave vials were added N- (5-bromo-2-methylpyridin-3-yl) -N- (methylsulfonyl) methanesulfonamide (1.300g, 3.79mmol) (780 mg each), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Acros) (0.219g, 0.379mmol) (121 mg each), tris (dibenzylideneacetone) dipalladium (o) (Strem) (0.173g, 0.189mmol) (104 mg each), sodium tert-butoxide (Fluka) (1.092g, 11.36mmol) (655mg), DMF (12 mL each) and benzophenone imine (Aldrich) (0.699mL, 4.17mmol) (0.420 mL each). Both resulting mixtures were degassed by bubbling N2 for 5min, subsequently sealed, and microwave heated at 130 ℃ for 20 min. LC/MS showed no evidence of starting material and the desired product mass for both vials was shown to be the main peak. The two reaction mixtures were combined and combined in EtOAc with saturated NH₄Partition between Cl. The aqueous layer was extracted with EtOAc (2X 15 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (120g, 20% to 40% acetone in hexanes) to give the desired product as a yellow foamy solid (430 mg). MS (ESI cation) m/z: 365.8.¹H NMR(300MHz，CDCl₃)δppm 2.43(s，3H)2.75(s，3H)6.07(br.s.，1H)7.09-7.21(m，3H)7.29-7.37(m，3H)7.38-7.47(m，2H)7.48-7.56(m，1H)7.75(d，J＝7.02Hz，2H)7.92(d，J＝2.19Hz，1H)。

and step 3: n- (5-amino-2-methylpyridin-3-yl) methanesulfonamide

To a solution of N- (5- (diphenylmethyleneamino) -2-methylpyridin-3-yl) methanesulfonamide (0.430g, 1.177mmol) in THF (10mL) was added hydrochloric acid (JT Baker) (1.765mL, 1.765mmol) (1N). The reaction was stirred in a closed system at room temperature for 20 min. The reaction mixture was washed with EtOAc and saturated NaHCO ₃Are distributed among the devices. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 5% to 10% MeOH in DCM) to give the desired product as a brown solid (70.0 mg). MS (ESI cation) m/z: 202.1.¹H NMR(300MHz，CDCl₃)δppm 2.42(s，3H)3.03(s，3H)3.70(br.s.，2H)6.15(br.s.，1H)7.20(d，J＝2.34Hz，1H)7.87(d，J＝2.34Hz，1H)。

and 4, step 4: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- (2-methoxyethoxy) pyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide

To a 15mL round bottom flask was added 4- (2-fluoro-5- (2-methoxyethoxy) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 335 step 3) (0.050g, 0.179mmol), N- (5-amino-2-methylpyridin-3-yl) methanesulfonamide (0.043g, 0.215mmol) and DMF (2.0 mL). In N₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (0.145mL, 0.716mmol) in THF was then added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was stirred at saturated NH₄Cl and CHCl₃Are distributed among the devices. The aqueous layer was treated with more CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (16g, 5% to 10% MeOH in DCM) to give the desired product as a yellow solid (25 mg). MS (ESI cation) m/z: 461.0. ¹H NMR(300MHz，DMSO-d₆)δppm 2.45(d，J＝2.63Hz，6H)2.52(s，3H)3.06(s，3H)3.61-3.73(m，2H)4.09-4.23(m，2H)7.77(br.s.，1H)7.89(br.s.，1H)8.17(d，J＝2.92Hz，1H)8.33(d，J＝1.75Hz，1H)8.42(d，J＝3.07Hz，1H)8.65(s，1H)9.29(br.s.，1H)11.76(s，1H)。

Example 377: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide

To a 15mL round bottom flask was added 4- (2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.045g, 0.219mmol), N- (5-amino-2-methylpyridin-3-yl) methanesulfonamide (0.049g, 0.241mmol) and DMF (2.0 mL). The mixture was cooled to 0 ℃ under N2. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (0.178mL, 0.877mmol) in THF was then added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH₄Cl quenched and reacted with CHCl in water₃Are distributed among the devices. The aqueous layer was treated with more CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (16g, 5% to 10% MeOH in DCM) to give the desired product as a yellow solid (35 mg). MS (ESI cation) m/z: 387.0.¹H NMR(300MHz，DMSO-d₆)δppm 2.46(d，J＝9.06Hz，6H)3.06(s，3H)3.33(s，3H)6.96(dd，J＝7.60，4.68Hz，1H)7.75(br.s.，1H)7.87(br.s.，1H)8.27-8.41(m，2H)8.67(d，J＝2.05Hz，1H)8.79(dd，J＝7.82，1.53Hz，1H)9.30(br.s.，1H)12.03(s，1H)。

example 378: n- (5- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloropyridin-2-ylamino) -2-methylpyridin-3-yl) methanesulfonamide

To a 15mL round bottom flask was added 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (0.050g, 0.209mmol), N- (5-amino-2-methylpyridin-3-yl) methanesulfonamide (0.046g, 0.230mmol) and DMF (2.0 mL). In N ₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (0.169mL, 0.835mmol) in THF was then added to the solution in one portion. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH₄Cl quenched and reacted with CHCl in water₃Are distributed among the devices. The aqueous layer was treated with more CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 3% MeOH in DCM) to give the desired product as a yellow solid (100 mg). MS (ESI cation) m/z: 421.0.¹H NMR(300MHz，DMSO-d₆)δppm 2.45(s，6H)3.06(s，3H)7.84(br.s.，1H)7.97(br.s.，1H)8.24(d，J＝2.05Hz，1H)8.38(d，J＝2.63Hz，1H)8.64(d，J＝2.19Hz，1H)8.75(d，J＝2.63Hz，1H)9.32(br.s.，1H)11.98(s，1H)。

example 379: n- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

Step 1: 4-chloro-2-methyl-6- (methylthio) pyrimidine

To a solution of 4, 6-dichloro-2-methylpyrimidine (Aldrich) (2.000g, 12.27mmol) in THF (25mL) was added sodium thiomethoxide (Aldrich) (0.903g, 12.88 mmol). At room temperature, in N₂The reaction mixture was stirred for 3 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2X 15 mL). The combined organic layers were dried over MgSO4 and concentrated. Will be coarse The product was purified by column chromatography (120g, 5% to 10% acetone in hexanes) to give the desired product as a white solid (1.3 g). MS (ESI cation) m/z: 174.9.¹H NMR(300MHz，CDCl₃)δppm 2.57(s，3H)2.65(s，3H)7.02(s，1H)。

step 2: 4- (1- (6-fluoro-5- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyridin-3-yl) ethyl) morpholine

A20 mL microwave vial was charged with 4-chloro-2-methyl-6- (methylthio) pyrimidine (0.175g, 1.002mmol), 2-fluoro-5- (1-morpholinoethyl) pyridin-3-ylboronic acid (example 339 step 3) (0.305g, 1.202mmol), trans bis (triphenylphosphine) dichloropalladium (II) (Strem) (0.056g, 0.080mmol), sodium carbonate (JT Baker) (0.531mg, 5.01mmol), DME (10mL), and water (2.5 mL). By adding N₂The vial was degassed by bubbling for 5min, then sealed and microwave heated at 90 ℃ for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 10% to 20% acetone in hexanes) to afford the desired product as a white solid (275). MS (ESI cation) m/z: 349.1.¹H NMR(300MHz，CDCl₃)δppm 1.43(d，J＝6.72Hz，3H)2.33-2.46(m，2H)2.48-2.58(m，2H)2.61(s，3H)2.74(s，3H)3.52(q，J＝6.58Hz，1H)3.71(t，J＝4.46Hz，4H)7.55(s，1H)8.25(s，1H)8.56(dd，J＝9.43，2.27Hz，1H)。

and step 3: n- (2-chloro-5- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

To a flame-dried 15mL round bottom flask was added 4- (1- (6-fluoro-5- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyridin-3-yl) ethyl) morpholine (0.150g, 0.430mmol), N- (5-amino-2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide (0.130g, 0.517mmol), and THF (3.0 mL). In N₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (1.837mL, 1.837mmol) in THF was added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH₄And (4) quenching by Cl. The reaction mixture was dissolved in water with CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, 20% to 30% acetone in hexanes) to afford the desired product as a yellow solid (160 mg). MS (ESI cation) m/z: 578.9.¹H NMR(300MHz，CDCl₃)δppm 1.41(d，J＝6.58Hz，3H)2.34-2.46(m，2H)2.52(br.s.，2H)2.66(s，3H)2.81(s，3H)2.95(s，6H)3.38(d，J＝6.43Hz，1H)3.71(d，J＝4.09Hz，4H)6.78(s，1H)7.45(s，1H)8.00(d，J＝1.61Hz，1H)8.25(s，1H)8.40(d，J＝2.34Hz，1H)8.78(d，J＝2.34Hz，1H)12.38(s，1H)。

and 4, step 4: n- (2-chloro-5- (3- (2-methyl-6- (methylsulfonyl) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

To a 20mL scintillation vial containing N- (2-chloro-5- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide (0.125g, 0.216mmol) was added Oxone (Potassium peroxymonosulfate, Aldrich) (0.265mL, 0.432mmol) and MeOH/water (1: 1, 6 mL). The resulting mixture was capped and stirred in a closed system at room temperature for 1 h. The reaction mixture was in water/CHCl₃Are distributed among the devices. The aqueous layer was treated with more CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (24g, DCM: EtOAc: MeOH ═ 70%: 27%: 3%) to give the product as a yellow solid (110 mg). MS (ESI cation) m/z: 610.8.¹H NMR(300MHz，CDCl₃)δppm 1.42(d，J＝6.58Hz，3H)2.35-2.47(m，2H)2.48-2.62(m，2H)2.95(s，6H)3.00(s，3H)3.34(s，3H)3.37-3.47(m，1H)3.72(t，J＝3.95Hz，4H)6.79(br.s.，1H)8.21(s，1H)8.35(d，J＝7.60Hz，2H)8.44(d，J＝2.34Hz，1H)8.77(d，J＝2.34Hz，1H)12.22(s，1H)。

and 5: n- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

To a 20mL microwave vial was added N- (2-chloro-5- (3- (2-methyl-6- (methylsulfonyl) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide (0.100g, 0.164mmol), 30% ammonium hydroxide (JT Baker) (0.425mL, 3.27mmol), and bisAlkane (3 mL). The vial was sealed and heated in a closed system at 95 ℃ for 1 h. The solvent was concentrated. The crude product was purified by column chromatography (16g, 3% to 10% MeOH in DCM) to give the desired product as a pale yellow solid (80 mg). MS (ESI cation) m/z: 548.0.¹H NMR(400MHz，CDCl₃)δppm1.41(br.s.，3H)2.42(br.s.，2H)2.53(br.s.，2H)2.67(s，3H)2.95(s，6H)3.37(br.s.，1H)3.72(b r.s.，4H)5.00(br.s.，2H)6.64-6.84(m，2H)7.96(b r.s.，1H)8.21(br.s.，1H)8.39(d，J＝2.15Hz，1H)8.79(d，J＝2.35Hz，1H)12.52(br.s.，1H)。

Separation of isomers

column: OZ-H (21mm X25 cm)

Mobile phase: 40: 60 (A: B)

A: liquid CO₂

B: MeOH (0.2% diethylamine)

Flow rate: 45mL/min

Oven/column temperature: 40 deg.C

Two separate peaks with two enantiomers were collected, concentrated, and dried under high vacuum to give the two enantiomers. Absolute stereochemistry was not determined. (see examples 381 and 381)

Example 380: n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) -5-vinylpyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

Step 1: n- (2-chloro-5- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide

To a flame-dried 15mL round bottom flask was added 4- (1- (6-fluoro-5- (2-methyl-6- (methylthio) pyrimidin-4-yl) pyridin-3-yl) ethyl) morpholine (0.160g, 0.459mmol), N- (5-amino-2-chloropyridin-3-yl) methanesulfonamide (0.122g, 0.551mmol), and THF (4.0 mL). In N₂The mixture was cooled down to 0 ℃. 1.0m sodium bis (trimethylsilyl) amide (Aldrich) (1.837mL, 1.837mmol) in THF was then added in one portion to the solution. The now dark wine-red mixture was stirred at 0 ℃ for 10min, then warmed to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH ₄And (4) quenching by Cl. The reaction mixture was dissolved in water with CHCl₃Are distributed among the devices. The aqueous layer was washed with CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g, DCM: EtOAc: MeOH 65%: 32%: 3%) to give the product as a yellow solid (175 mg). MS (ESI cation) m/z: 550.0.¹H NMR(300MHz，CDCl₃)δppm 1.41(d，J＝6.58Hz，3H)2.34-2.48(m，2H)2.49-2.60(m，2H)2.66(s，3H)2.81(s，3H)3.13(s，3H)3.39(d，J＝6.58Hz，1H)3.72(t，J＝4.38Hz，4H)6.75(br.s.，1H)7.45(s，1H)8.01(d，J＝1.90Hz，1H)8.30(d，J＝1.90Hz，1H)8.52(d，J＝2.48Hz，1H)8.76(d，J＝2.48Hz，1H)12.43(s，1H)。

step 2: n- (5- (3- (6-amino-2-methylpyrimidin-4-yl) -5-vinylpyridin-2-ylamino) -2-chloropyridin-3-yl) methanesulfonamide

To a 20mL scintillation vial containing N- (2-chloro-5- (3- (2-methyl-6- (methylthio) pyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide (0.150g, 0.273mmol) was added 3-chloroperoxybenzoic acid (0.188g, 0.654mmol) and DCM (8 mL). The resulting mixture was capped and stirred in a closed system at room temperature for 1 h. The reaction mixture was dissolved in water with CHCl₃Are distributed among the devices. The aqueous layer was treated with more CHCl₃(2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (24g, 5% to 20% MeOH in DCM) to give the desired product as a yellow solid (100 mg). This intermediate was then combined with 30% ammonium hydroxide (0.142mL, 3.64mmol) and di The alkanes (2mL) were added together in a 5mL microwave reactor. The vial was sealed and heated in a closed system at 95 ℃ for 1 h. The solvent was concentrated. The crude product was purified by column chromatography (24g, 3% to 10% MeOH in DCM) to give the desired product as a pale yellow solid (30 mg). MS (ESI cation) m/z: 431.9.¹H NMR(300MHz，DMSO-d₆)δppm 2.52(s，3H)3.13(s，3H)5.27(d，J＝11.11Hz，1H)5.89(d，J＝17.54Hz，1H)6.76(dd，J＝17.76Hz，1H)6.89(s，1H)7.05(br.s.，2H)8.24(s，1H)8.42(s，2H)8.60(d，J＝2.05Hz，1H)9.63(s，1H)12.66(s，1H)。

examples 381 and 382: (R) -N- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide; and (S-) N- (2-chloro-5- (3- (6-amino-2-methylpyrimidin-4-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

MS (ESI cation) m/z: 548.0.¹H NMR(400MHz，CDCl₃)δppm1.31-1.51(m，3H)2.45(br.s.，2H)2.55(br.s.，2H)2.66(s，3H)2.95(s，6H)3.39(br.s.，1H)3.73(br.s.，4H)5.02(br.s.，2H)6.77(br.s.，2H)7.98(br.s.，1H)8.21(s，1H)8.40(d，J＝2.35Hz，1H)8.79(d，J＝2.35Hz，1H)12.54(br.s.，1H)。

MS (ESI cation) m/z: 548.0.¹H NMR(400MHz，CDCl₃)δppm1.44(br.s.，3H)2.45(br.s.，2H)2.56(br.s.，2H)2.66(s，3H)2.95(s，6H)3.40(br.s.，1H)3.74(br.s.，4H)5.02(br.s.，2H)6.77(br.s.，2H)8.00(br.s.，1H)8.21(d，J＝2.15Hz，1H)8.39(d，J＝2.35Hz，1H)8.79(d，J＝2.35Hz，1H)12.55(br.s.，1H)。

example 383: 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a ] pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

Step 1: 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a ] pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine

To hexahydro-2H-isothiazolo [2, 3-a ] ]Pyrazine 1, 1-dioxide (reference: WO2007028654, 0.180g, 1.021mmol) in THF (2)50mL, 30.5mmol) the mixture 5- (4- (bis (4-methoxybenzyl) amino) -6-methyl-1, 3, 5-triazin-2-yl) -6- (5-fluoro-6-methoxypyridin-3-ylamino) nicotinaldehyde (prepared as described before, 0.3042g, 0.511mmol) and titanium (IV) ethoxide (0.529mL, 2.55mmol) was stirred and the mixture was heated at 70 ℃ overnight. The resulting mixture was cooled to 0 ℃ and excess sodium cyanoborohydride (0.160g, 2.55mmol) was added, and the entire mixture was stirred at the same temperature for 1h before quenching with MeOH (1.0 mL). The mixture was concentrated and adsorbed onto a silica gel packed column and chromatographed over a silica gel column (100% DCM to 70% ethyl acetate in DCM) to give the desired product 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a) as a yellow slime]Pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridyl) amino) -3-pyridyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine (0.297g, 77%). M/z (ESI, cation) 756(M + H)⁺。

Step 2: 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a ] pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridinyl) amino) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine

Preparation of 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a-dihydroxide) from 4- (5- ((1, 1-hexahydro-5H-isothiazolo [2, 3-a) by a similar deprotection scheme as described previously in example 178 step 4 using trifluoroacetic acid and trifluoromethanesulfonic acid]Pyrazin-5-yl) methyl) -2- ((5-fluoro-6-methoxy-3-pyridyl) amino) -3-pyridyl) -N, N-bis (4-methoxybenzyl) -6-methyl-1, 3, 5-triazin-2-amine the title compound was prepared and isolated as a yellow solid (61mg, 30%). M/z (ESI, cation) 516(M + H)⁺。1H NMR(400MHz，d₆-DMSO)δ11.95(s，1H)8.73(d，J＝2.15Hz，1H)8.42(d，J＝2.15Hz，1H)8.37(dd，J＝12.81，2.05Hz，1H)8.26(d，J＝2.15Hz，1H)7.91(br.s.，1H)7.76(br.s.，1H)3.93(s，3H)3.45-3.62(m，1H)3.00-3.30(m，5H)2.80-3.00(m，2H)2.62-2.74(m，1H)2.44(s，3H)2.23-2.36(m，1H)2.06-2.16(m，1H)1.81-1.96(m，2H)。

Example 384: n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide

Step 1: n- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide

To pass through N₂A20 mL microwave vial degassed by bubbling was charged with N- (5-bromo-2-chloropyridin-3-yl) -N, N-dimethylaminosulfonamide (WO2009155121A 2; 0.500g, 1.589mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Strem; 0.092g, 0.159mmol), tris (dibenzylideneacetone) dipalladium (0) (Strem; 0.073g, 0.079mmol), sodium tert-butoxide (0.458g, 4.77mmol), DMF (8mL) and benzophenone imine (Aldrich; 0.293mL, 1.748 mmol). The resulting mixture was sealed and microwaved at 130 ℃ for 20 min. The resulting mixture was washed with EtOAc and saturated NH ₄Partition between Cl (25 mL). Water (5mL) was added to dissolve the NH that precipitated between the organics and the aqueous layer (pH of aqueous layer between 5 and 6)₄And (4) Cl. The aqueous layer was extracted with more EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (80g silica, 10% to 20% acetone in hexanes) to afford the desired product as a yellow foamy solid (280 mg).¹H NMR(300MHz，CDCl₃)δ2.71(s， 6H)6.62(br.s.，1H)7.14(d，J＝3.80Hz，2H)7.33(d，J＝2.78Hz，4H)7.39-7.47(m，2H)7.49-7.57(m，1H)7.62(s，1H)7.74(d，J＝7.45Hz，2H)。

Step 2: n' - (5-amino-2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide

To a solution of N- (2-chloro-5- (diphenylmethyleneamino) pyridin-3-yl) -N, N-dimethylaminosulfonamide (0.300g, 0.723mmol) in THF (5mL) was added 1N hydrochloric acid (1.085mL, 1.085 mmol). The reaction was stirred in a closed system at ambient temperature. After 30min, the reaction mixture was washed with EtOAc/saturated NaHCO₃BetweenAnd (6) distributing. The aqueous layer was extracted with more EtOAc (2X 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by column chromatography (40g silica gel, 3% MeOH in DCM) to give the desired product as a yellow solid (170 mg).¹H NMR(300MHz，CDCl₃)δ2.87(s，6H)3.82(br.s.，2H)6.67(br.s.，1H)7.30(d，J＝2.05Hz，1H)7.62(d，J＝2.05Hz，1H)。

And step 3: n' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide

To a 100mL round bottom flask were added 4- (5-chloro-2-fluoropyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine (example 356, step 1; 960mg, 4.01mmol), N' - (5-amino-2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide (1004mg, 4.01mmol) and lithium bis (trimethylsilyl) amide (Aldrich; 3352mg, 20.03mmol) dissolved in tetrahydrofuran (20mL) at 0 ℃. After the addition, the reaction mixture was stirred at 0 ℃ for 20 min. The reaction mixture was washed with saturated NH₄Cl (30mL) and CH₂Cl₂(3X 200mL) was extracted. The organic extracts were washed with saturated aqueous NaCl solution (30mL) and Na₂SO₄And (5) drying. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was chromatographed on silica gel with 5% MeOH/CH₂Cl₂Purify by elution to give N' - (5- ((3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5-chloro-2-pyridinyl) amino) -2-chloro-3-pyridinyl) -N, N-dimethylsulfonamide (1.29g, 2.74mmol, 68.5% yield) as a yellow solid. M/z (ESI, cation) 470.0(M + H)⁺.¹H NMR(400MHz，CDCl₃)δ2.61(s，3H)2.95(s，6H)5.48(br.s.，2H)6.80(s，1H)8.31(d，J＝2.74Hz，1H)8.38(d，J＝2.54Hz，1H)8.74(d，J＝2.54Hz，1H)8.85(d，J＝2.74Hz，1H)12.35(s，1H)。

The following assays can be used to determine the degree of activity of each compound as a PI3 kinase and/or mTOR inhibitor as well as to assess selectivity over other kinases.

Recombinant expression of PI3K enzyme

The full-length p110 subunit of PI3K α, β, and δ, N-terminally tagged with a polyHis tag, was co-expressed with p85 in sf9 insect cells using a baculovirus (Baculo virus) expression vector. The P110/P85 heterodimer can be purified by sequential Ni-NTA, Q-HP, Superdex-100 chromatography. The purified α, β and δ isozymes can be stored at-20 ℃ in 20mM Tris, pH 8, 0.2M NaCl, 50% glycerol, 5mM DTT, 2mM sodium cholate. The N-terminal truncated PI3K gamma, residue 114-1102, labeled with a polyHis tag was expressed in Hi5 insect cells using baculovirus. The gamma isozyme can be purified by continuous Ni-NTA, Superdex-200, Q-HP chromatography. The gamma isozyme can be stored in NaH by freezing at the temperature of-80 DEG C₂PO₄pH 8, 0.2M NaCl, 1% ethylene glycol, 2mM beta-mercaptoethanol.

	α	β	δ	γ
					50mM Tris	pH 8	pH 7.5	pH 7.5	pH 8
MgCl₂	15mM	10mM	10mM	15mM
					Cholesterol acid sodium salt	2mM	1mM	0.5mM	2mM
DTT	2mM	1mM	1mM	2mM
					ATP	1uM	0.5uM	0.5uM	1uM
PIP2	Is free of	2.5uM	2.5uM	Is free of
					Time of day	1hr	2hr	2hr	1hr
[ enzyme]	15nM	40nM	15nM	50nM

In vitro PI3K ALPHASCREENTest of

PI3K AlphaScreenThe assay (PerkinElmer, Waltham, MA) measures a set of four phosphoinositide 3-kinases: PI3K α, PI3K β, PI3K γ, and PI3K δ. Each of these enzymes converts phosphatidylinositol (4, 5) -diphosphate (PIP)₂) To produce phosphatidylinositol (3, 4, 5) -triphosphate (PIP) ₃). This phosphorylation activity was PIP using GST-tag₃Binding proteins (Echelon Biosciences, Salt Lake City, UT), an Acceptor bead (Acceptor bead) against GST tags, and streptavidin donor beads. Biotinylated PIP₃Analog (IP)₄) And PIP₃The interaction of the binding proteins allows the acceptor and donor beads to be generated together after excitation of the donor bead at 680nm, resulting in fluorescent AlphaScreenSinglet oxygen species of the signal. When passing PI₃K let PIP₂Phosphorylation to produce PIP₃In time, PIP₃Biotinylated PIP₃Analog (IP)₄) Contention and PIP₃Binding of binding proteins. In the absence of this interaction, the proximity of the donor and acceptor beads is reduced, yielding PI₃K activity is inversely proportional to the loss of fluorescence signal. The inhibitor reduces the activity of the enzyme, resulting in less PIP production₃And stronger fluorescence.

The enzyme reaction buffer was prepared using sterile water (Baxter, Deerfield, IL) and 50mM TrisHCl pH 7, 14mM MgCl₂2mM sodium cholate and 100mM NaCl. 2mM DTT was added fresh on the day of the experiment. AlphaScreenThe reaction buffer was made using sterile water and 10mM Tris HCl pH 7.5, 150mM NaCl, 0.10% Tween 20 and 30mM EDTA. 1mM DTT was added fresh on the day of the experiment.

The source microplates used for this assay were 384-well Greiner clear polypropylene microplates containing 5mM of test compound diluted 1: 2 at 22 spots. Columns 23 and 24 contain only DMSO as it is designated for positive and negative controls. The source plate was repeatedly manipulated into 384-well microplates (PerkinElmer, Waltham, Mass.), 0.5. mu.L/well to make ready-to-use microplates for the assay.

Various PI3K isoforms were diluted to 2X working solution in enzyme reaction buffer. PI3K α was diluted to 1.6nM, PI3K β was diluted to 0.8nM, PI3K γ was diluted to 15nM, and PI3K δ was diluted to 1.6 nM. Two different 2X substrate solutions were made in enzyme reaction buffer. In one solution, PI (4, 5) P2(Echelon Biosciences, Salt Lake City, UT) was diluted to 10 μ M and ATP was diluted to 20 μ M. This solution was suitable for use in the tests for PI3K α and PI3K β. In the second solution, PI (4, 5) P2 was diluted to 10 μ M and ATP was diluted to 8 μ M. This solution was suitable for use in the tests for PI3K γ and PI3K δ.

AlphaScreenThe reaction solution was obtained from anti-GST AlphaScreenBeads of the kit (Perkinelmer, Waltham, MA). Both solutions were made up to 4X working concentration in Alphascreen reaction buffer. In a solution Biotinylated IP4(Echelon Biosciences, Salt Lake City, UT) was diluted to 40nM and streptavidin donor beads were diluted to 80. mu.g/mL. In a second solution, PIP₃Binding proteins (Echelon Biosciences, Salt Lake City, UT) were diluted to 40nM and anti-GST receptor beads were diluted to 80. mu.g/mL. 10 μ L/well of enzyme reaction buffer was added to 24 columns of the assay plate in place of the enzyme. This operation was performed on microplates in PI3K alpha, beta, and delta experiments.

Add 10. mu.L/well of 2 Xenzyme (PI 3K. alpha.,. beta., Δ) to 1-23 columns of the appropriate assay-ready plate using 384-well dispense Multidrop (Titertek, Huntsville, AL) (for PI 3K. gamma., 10. mu.L to 1-24 columns). Subsequently, 10. mu.L/well of the appropriate substrate solution (solution with 20. mu.M ATP for PI 3K. alpha. and. beta. assays and 8. mu.M ATP for PI 3K. gamma. and. delta. assays) was added to 1-24 columns of the plate. The plate was then incubated for 20 minutes at room temperature.

In the dark, 10. mu.L/well of donor bead solution was added to columns 1-24 of the microplate to quench the enzymatic reaction. The plates were incubated at room temperature for 30 minutes. Also, 10. mu.L/well of the acceptor bead solution was added to columns 1-24 of the microplate, still in the dark. Subsequently, the plate was incubated in the dark for 1.5 hours. The microplate was read on an Envision multi-label microplate reader (PerkinElmer, Waltham, MA) using a 680nm excitation filter and a 520-620nm emission filter.

The activity data for the compounds tested in the assay are provided in table 1 under the designation PI3K alpha AlphaScreenUnder the column (c).

pAkt APLHASCREEN (U87 cells)

pAkt AlphaS creenTest (PerkinElmer, Waltham, MA) determinationWhether Akt is phosphorylated at serine 473 is by recruitment of phosphorylation specific antibodies. This assay was performed using U87MG cells. U87 growth medium consisted of MEM (Gibco, Carlsbad, Calif.) supplemented with 10% FBS (Gibco,), 1 × nonessential amino acids (Gibco,) and 1 × penicillin/streptomycin/glutamine (Gibco). Cells were preserved weekly using 0.05% trypsin (Gibco) and re-coated in 150mm TC treated culture dishes (Corning, NY).

The first day of the experiment, adherent cells were trypsinized, medium was added to the loosened cells and the cells were mixed into a homogenous mixture. 0.5ml of the homogeneous mixture was placed in a Beckman CoulterVi-CELL^TMCounted in XR (Fullerton, Calif.). Cells from 50 plate frames were counted and the number of viable cells was determined. Subsequently, the cells were diluted to 25 ten thousand cells per ml and centrifuged at 200rcf for 5 minutes. The medium was removed and the cells were reconstituted in fresh medium for coating. At a final cell density of 5K cells per well, 20. mu.l of cells per well were plated in a low-volume 384-well white tissue culture microplate (Corning) by PerkinElmer FlexDrop PLUS. The microporous plate was heated at 37 ℃ with 5% CO₂Incubate overnight.

On the next day, compound microplates were prepared, cells were treated with compound and the pAkt reaction mixture was added to the cell lysate. A384-well compound microplate was prepared containing 1. mu.l of compound per well, starting at 5mM and diluted 1: 2 across rows, yielding 22-well serial dilutions. Using PerkinElmerFlexDrop PLUS adds 39 μ l of growth medium to 1-22 rows of compound microplates, resulting in a DMSO concentration of 2.5%. Place cell microplates and diluted compound microplates at V_ELOCITY11^TM VPREP^TMAt 384ST, the compound plates were mixed here and 5 μ Ι of serially diluted compound or control was added to the cell plates. The final concentration of the compound was 25 μ M, which was serially diluted to 11.9pM in 0.5% DMSO. The cell plates were then incubated at 37 ℃ with 5% CO₂The following incubations were performed with compound for two hours. After two hours, BioTek was usedELx405HT microplate washer (Winooski, VT) aspirates the media out of the cell microplate, removing most of the media and compounds without disturbing the adhering U87 cells. The following test reagent is SureFireAkt (Ser 473) phosphorylates the components of the 50K dot kit (TGR BioSciences, Adelaide, Austalia) and the IgG detection kit (PerkinElmer, Waltham, MA). Using PerkinElmer FlexDrop PLUS 5. mu.l of 1x lysis buffer was added to each well. Subsequently, the microplate was incubated on a shaker for ten minutes at room temperature. AlphaScreenThe reaction was prepared under low light conditions (soft or green) and included p-Akt (Ser 473) reaction buffer, dilution buffer, activation buffer, acceptor beads and donor beads in a ratio of 40: 20: 10: 1, respectively. Using PerkinElmerFlexDrop PLUS to AlphaScreenThe reaction solution was added to the cell lysate in 6. mu.l per well. The microplate was placed in a humid environment to reduce edge effects and incubated overnight at room temperature in the dark with a defined air flow.

On the last day of the experiment, in PerkinelmerEnVision^TM2103 Multi-Label reader, Standard AlphaScreenThe reader reads the microplate. Calculate POC and analyze data to report IC for pAkt at serine 473₅₀ IP。

Activity data for compounds tested in the PI3K cell-based Akt assay are provided in table 1 under the column entitled U87.

The compounds of the invention may inhibit mTOR, PI3K, or both. The following assay can be used to determine whether a compound inhibits mTOR. Accordingly, one aspect of the present invention relates to compounds that inhibit PI3K and mTOR. In another aspect, the invention relates to compounds that primarily inhibit mTOR. In another aspect, the invention relates to compounds that primarily inhibit PI 3K. The invention also encompasses the use of the compounds for the treatment of the diseases and conditions disclosed herein, such as cancer.

In vitro MTOR assay

Invitrogen (Carlsbad, CA) mammalian target of rapamycin (mTOR) Lanthascreen assay can be used to quantify mTOR kinase activity in an ex vivo setting. Active mTOR phosphorylates the threonine 46 residue of eukaryotic translation initiation factor 4E binding protein 1(4E-BP 1). This phosphorylation event can be detected with a phosphate-specific terbium (Tb) -labeled Ab, which in turn brings the Tb-tag in close proximity to GFP-labeled 4E-BP1 and allows time-resolved fluorescence resonance energy transfer (TR-FRET), which correlates the level of 4E-BP1 phosphorylation with mTOR kinase activity.

The enzyme reaction buffer may be in a solution containing 50mM HEPES (pH 7.5), 0.01% polysorbate 20, 1mM EGTA and 10mM MnCl₂Is prepared in deionized water.

Dilutions of the compounds to be tested can be prepared in 96-well polypropylene microplates (Fisher Scientific, Waltham, MA). One row represents a 10-point dose of the compound diluted 1: 3 in enzyme reaction buffer and 20% dimethyl sulfoxide (DMSO). The highest concentration was 36 μ M for all compounds. Wells 6 and 12 can be used as no compound (DMSO only) and high compound controls.

mTOR substrate solutions can be prepared in enzyme reaction buffer containing 1600nM of green fluorescent protein labeled eukaryotic translation initiation factor 4E binding protein 1(GFP-4E-BP1) (Invitrogen, Carlsbad, CA) and 28uM Adenosine Triphosphate (ATP) (Calbiochem, Gibbstown, NJ).

The mTOR enzyme (Invitrogen, Carlsbad, Calif.) can be diluted in enzyme reaction buffer to a working concentration of 100 ng/mL.

The enzyme assay can be performed in 384-well low volume assay microplates (Corning, NY). A2.5 uL substrate solution containing GFP-4E-BP1 and ATP can be added to the appropriate wells in the assay plate, followed by 2.5uL of compound dilution. 5 μ L of the appropriately diluted mTOR enzyme can be added and the reaction allowed to proceed for 1 hour at room temperature. In the enzyme assay, the final reagent concentrations were 50ng/mL mTOR, 400nM GFP-4E-BP1, and 7 μ M ATP.

The enzyme assay may be performed by adding 10. mu.L of 20mM EDTA and 4nM Tb labeled anti-phospho-4E-BP 1[ T46]Antibodies (Invitrogen, Carlsbad, CA) were then terminated. The assay plate can then be incubated at room temperature for 1 hour, and read in a Tecan Safire II plate reader (Tecan,switzerland) were read.

The activity data for the compounds tested in the assay are provided in table 1 under the column entitled mTOR.

B-RAF homogeneous time-resolved fluorescence (HTRF) kinase assay

Inhibition of human on the substrate MEK1 for the assay CompoundAbility to mimic mutant B-raf kinase activity, a homogeneous time-resolved fluorescence (HTRF) kinase assay was established. For IC ₅₀Production the assay was started when a 1. mu.L 50 Xcompound dose curve in DMSO was added to a final volume of 40. mu.l of 60pM recombinant HuBrafV600E in kinase reaction buffer. After 60 min incubation at room temperature, the kinase reaction started with the addition of 10 μ l of substrate mixture, yielding a final concentration of 10 μ M ATP (Km ═ about 20 μ M), His-Avitag-MEK1(Δ 32-51, inactivated D190N kinase) at 100nM in a final reaction volume of 50 μ l (Km about 200 nM). The final concentration of the kinase reaction buffer was 50mM Tris-HCl pH 7.5, 10mM MgCl₂0.5% glucose, 0.5mM DTT, 0.01% BSA. The kinase reaction was carried out at room temperature for 60 minutes until the reaction was quenched by the addition of 10. mu.l of stop/detection buffer consisting of kinase reaction buffer to which Tween-20 (final concentration 0.1%), hexokinase (0.01 units), streptavidin-allophycocyanin (final 10nM) and europium-labeled anti-phospho-MEK 1/2 (ser 217/221 from Cell Signaling Technology, Danvers, MA.) antibody (final 300pM) were added. The detection reaction was run for one hour and read on a rubystart (BMG Labtech, Durham, NC) counter. IC of test Compounds ₅₀Generated using Excel-XLFit software. For the single concentration percentage of the control (POC; ═ 100-percent inhibition) assay, compounds were analyzed as described above at a single test concentration of 10 μ M test compound. All experimental data were obtained using N- (3-chlorophenyl) -4-methyl-3- (3- (pyrimidin-4-yl) pyridin-2-ylamino) benzamide (WO 2005113494A2) as a positive control with at least 2 independent ICs₅₀Or the mean of POC determinations.

Data for the compounds tested in the assay are provided in table 2 under the section entitled mutant B-rafHTRF assay.

Kinase panel screening

LabChip was used as the compoundEZ Reader II platform andProfilerPro kinase selectivity test kit (Caliper Lifesciences inc., Hopkinton, MA). Compounds were tested in duplicate at a concentration of 1 μ M and mean data are reported as percent of control (POC).

The data obtained from this kinase screen is set forth in table 3 below entitled kinase panel screen.

The following data show R in the compounds of formula I or pharmaceutically acceptable salts thereof²Groups (particularly methyl groups) unexpectedly and surprisingly provide lipid kinase activity that exceeds protein kinase activity.

TABLE 1

TABLE 2

TABLE 3

Blank-not determined

It should be noted that if the test is performed more than once, the above numbers represent the average of the results of the respective tests.

[2974]

[2977]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein Ar is¹Is a 5 to 10 membered monocyclic or bicyclic ring which can contain 0 to 4 heteroatoms independently selected from O, N or S, and said ring can be unsubstituted or substituted with a group independently selected from: c_1-4Haloalkyl, halo, oxo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R^aIndependently is hydrogen or R^b；

Each R^bIndependently is phenyl, benzyl, C_1-6Alkyl radical, C_4-8Heterocycloalkyl or C_3-8Cycloalkyl radicals in which phenyl, benzyl, C _1-6Alkyl radical, C_4-8Heterocycloalkyl or C_3-8Cycloalkyl is substituted with 0, 1, 2, or 3 substituents independently selected from: halo, -OH, -S (═ O)₂R^b、-OC_2-6Alkyl OR^a、C_1-4Alkyl radical, C_1-3Haloalkyl, -OC_1-4Alkyl, -NH₂-CN or-NR^aR^a；

Each R^cIndependently hydrogen, -OR^a、-NR^aR^a、-CF₃、C_1-6Alkyl radicals or radicals CR^cR^cCan form C_3-8A cycloalkyl ring;

each n is independently 0, 1, 2 or 3;

each Z¹、Z²、Z³Or Z⁴Independently selected from N, NR or CR; or Z¹And Z²、Z²And Z³Or Z³And Z⁴In the case of NR or CR, the two R may, when taken together with the carbon or nitrogen atom to which they are attached, form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CH)₂)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R ^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R is independently selected from hydrogen, oxo, C_1-4Haloalkyl, halo, -OCHF₂-CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-(CR^aR^a)nOR^a、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)²N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_3-8Cycloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cCR^c)_nO(CR^cCR^c)_nCF₃、-(CR^cCR^c)_nN(CR^cR^c)_nOR^a、-(CR^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-8Aryl radical, C_4-8Heterocycloalkyl radical, C_3-8Cycloalkyl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, oxo, C_1-6Alkyl, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY、-(CR^aR^a)nC_3-8Cycloalkyl or- (CR)^aR^a)_nOR^a；

Q is

R²Is methyl or ethyl;

Z⁵is N or CR^c；

Z⁹Is N, NR or CR;

Z¹⁰is N, NR or CR, or Z⁹And Z¹⁰May be at the carbon to which the two R are attached orThe nitrogen atoms taken together form a 5 or 6 membered ring and the ring may contain from 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R) ^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Cycloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_4-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)²N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a(ii) a And the group NR^aR^aMay be a 4 to 6 membered heterocyclic ring, either alone or as part of a larger group, wherein the two R' s^aTaken together with the nitrogen atom to which they are attached, form a ring which may have from 0 to 1 additional heteroatoms selected from N, O or S, and which ring may be substituted or unsubstituted with from 1 to 3 substituents independently selected from: oxo, halo, -CN, nitro, -C (═ O) R^c、-C(＝O)OR^c、-OR^c、-OC(＝O)R^c、-SR^c、-S(＝O)R^c、-S(＝O)₂R^c、-S(＝O)₂NR^cR^c、-NR^cR^c、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl.

2. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein Ar is¹Is a 5 to 10 membered monocyclic or bicyclic ring which can contain 0 to 4 heteroatoms independently selected from O, N or S, and said ring can be unsubstituted or substituted with a group independently selected from: c _1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、O-C _1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Y is 0, 1, 2, containing independently selected from N, O and S,A saturated, partially saturated or unsaturated 5, 6 or 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic ring of 3 or 4 heteroatoms substituted with 0, 1 or 2 substituents independently selected from: c_1-8Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^aor-NR^aC_2-6Alkyl OR^a；

Each R^aIndependently is hydrogen or R^b；

Each R^cIndependently is hydrogen or C_1-6An alkyl group;

each n is independently 0, 1, 2 or 3;

each Z¹、Z²、Z³Or Z⁴Independently selected from N, NR or CR; or Z ¹And Z²、Z²And Z³Or Z³And Z⁴In the case of NR or CR, the two R may, when taken together with the carbon or nitrogen atom to which they are attached, form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)ⁿN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CH)₂)ⁿN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a 、-OR^a 、-OC(＝O)R^b 、-OC(＝O)NR^aR^a 、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Each R is independently selected from hydrogen and C_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C _2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

Q is

R²Is methyl or ethyl;

Z⁵is N or CR^c；

Z⁹Is N, NR or CR;

Z¹⁰is N, NR or CR, or Z⁹And Z¹⁰The two R groups, when taken together with the carbon or nitrogen atom to which they are attached, may form a 5 or 6 membered ring, and the ring may contain 0 to 3 heteroatoms independently selected from O, N or S, and the ring may be unsubstituted or substituted with groups independently selected from: c_1-4Haloalkyl, halo, -CN, nitro, -C (═ O) NR^aR^a、-C(＝O)R^b、-C(＝O)OR^b、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-O-C_1-6Alkyl N (R)^a)C(＝O)OR^b、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)²N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-(CR^cR^c)_nNR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR^aR^a、-NR^aC_2-6Alkyl OR^a、-(CR^cR^c)_nC_3-8Heterocycloalkyl, - (CR)^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nO(CR^cR^c)_nC_5-8Heteroaryl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Heterocycloalkyl radical, C_6-8Aryl or C_5-8Heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from: c_1-4Haloalkyl, halo, cyano, nitro, -C (═ O) R^b、-C(＝O)OR^b、-C(＝O)NR^aR^a、-C(＝NR^a)NR^aR^a、-OR^a、-OC(＝O)R^b、-OC(＝O)NR^aR^a、-OC(＝O)N(R^a)S(＝O)₂R^b、-OC_2-6Alkyl radical NR^aR^a、-OC_2-6Alkyl OR^a、-SR^a、-S(＝O)R^b、-S(＝O)₂R^b、-S(＝O)₂NR^aR^a、-S(＝O)₂N(R^a)C(＝O)R^b、-S(＝O)₂N(R^a)C(＝O)OR^b、-S(＝O)₂N(R^a)C(＝O)NR^aR^a、-NR^aR^a、-N(R^a)C(＝O)R^b、-N(R^a)C(＝O)OR^b、-N(R^a)C(＝O)NR^aR^a、-N(R^a)C(＝NR^a)NR^aR^a、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^a、-NR^aC_2-6Alkyl radical NR ^aR^a、-NR^aC_2-6Alkyl OR^a、-N(R^a)(CR^aR^a)_n-Y、-(CR^aR^a)_nY or- (CR)^aR^a)_nOR^a；

And the group NR^aR^aMay be a 4 to 6 membered heterocyclic ring, either alone or as part of a larger group, wherein the two R' s^aTaken together with the nitrogen atom to which they are attached, form a ring which may have from 0 to 1 additional heteroatoms selected from N, O or S, and which ring may be substituted or unsubstituted with from 1 to 3 substituents independently selected from: oxo, halo, -CN, nitro, -C (═ O) R^c、-C(＝O)OR^c、-OR^c、-OC(＝O)R^c、-SR^c、-S(＝O)R^c、-S(＝O)₂R^c、-S(＝O)₂NR^cR^c、-NR^cR^c、-C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6Alkynyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z¹Is N; and Z is²、Z³And Z⁴Is CR.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z¹Is N; and Z is²、Z³And Z⁴Is CH.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z¹、Z²And Z⁴Is CR; and Z is³Is N.

8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z ¹Is N; z²And Z³Is CR; and Z is⁴Is N.

9. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z¹Is N; z²And Z⁴Is CH; and Z is³Is CR.

10. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z¹Is N; z²And Z⁴Is CH; z³Is CR; and R is selected from hydrogen, C_1-6Alkyl radical, C_1-6Substituted alkyl, halo, C_1-4Haloalkyl, - (CR)^cR^c)_nC_4-8Heterocycloalkyl, - (CR)^cR^c)_nO(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nC_5-8Heteroaryl, - (CR)^cR^c)_nSubstituted C_4-8Heterocycloalkyl, - (CR)^cR^c)_nO(CR^cR^c)_nSubstituted C_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nSubstituted C_6-8Aryl, - (CR)^cR^c)_nN(R^a)(CR^cR^c)_nSubstituted C_5-8Heteroaryl group, C_2-6Alkenyl or- (CR)^cR^c)_nNR^aR^a。

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl or indazolyl, which groups may be unsubstituted or substituted.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzo(ii) an oxazolyl or indazolyl group, which groups may be unsubstituted or substituted with a group selected from: -OR ^aHalogen, -NR^aR^a、C_1-4Haloalkyl, -N (R)^a)C(＝O)R^bor-N (R)^a)C(＝O)NR^aR^a。

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CH; and

15. The compound according to any one of claims 1, 2 or 5 to 12, or a pharmaceutically acceptable salt thereof, wherein R²Is methyl.

16. The compound according to any one of claims 1, 2 or 5 to 12, or a pharmaceutically acceptable salt thereof, wherein Q is

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N;

Z²and Z⁴Is CH;

Ar¹is a substituted pyridyl group; and

Z³is CR.

19. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzoOxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiadiazolyl, which groups may be unsubstituted or substituted.

20. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ar is¹Selected from pyrazolyl, indolyl, phenyl, pyridyl, pyrimidinyl, benzo(ii) an oxazolyl, indazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiadiazolyl group, which may be unsubstituted or substituted by a group selected from: -OR^aHalogen, -NR^aR^a、C_1-4Haloalkyl, -N (R)^a)C(＝O)R^b、-N(R^a)S(＝O)₂R^b、-N(R^a)S(＝O)₂NR^aR^aor-N (R)^a)C(＝O)NR^aR^a。

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CH; and

23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is

Z¹Is N; and Z is²、Z³And Z⁴Is CR; and

24. A compound, or a pharmaceutically acceptable salt thereof, selected from:

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-yl) -1H-indol-4-amine;

3- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) pyridin-2-ylamino) phenol;

3- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-ylamino) phenol;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (3- (4-amino-6-methyl-1, 3, 5-triazin-2-yl) -5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) Pyridin-2-yl) benzo [ d]Oxazol-6-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) pyridin-2-amine;

n- (5-chloro-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

n- (5-bromo-3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) -1H-indazol-4-amine;

2-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-2-yl) pyrimidin-5-amine;

(6- (1H-indazol-4-ylamino) -5- (2-methyl-9H-purin-6-yl) pyridin-3-yl) methanol;

n- (3- (2-methyl-9H-purin-6-yl) -5-morpholinopyridin-2-yl) -1H-indazol-4-amine;

n- (4- (3- (2-methyl-9H-purin-6-yl) pyridin-2-ylamino) phenyl) acetamide;

N- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indazol-4-amine;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyridin-4-yl) -1H-indol-4-amine;

n- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) -1H-indazol-4-amine;

6-methoxy-N- (3- (2-methyl-9H-purin-6-yl) pyridin-4-yl) pyridin-3-amine;

n- (3- (6-amino-2-methylpyrimidin-4-yl) pyrazin-2-yl) -1H-indazol-4-amine; or

N- (6-methoxypyridin-3-yl) -3- (2-methyl-9H-purin-6-yl) quinolin-2-amine.

25. A compound, or a pharmaceutically acceptable salt thereof, selected from:

5-chloro-N- (6-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

3- (6-amino-2-methyl-4-pyrimidinyl) -N-1H-indazol-4-yl-2-quinoxalinamine;

n- (5-methoxy-3-pyridyl) -3- (2-methyl-9H-purin-6-yl) -2-pyridylamine;

4- (2- ((6-methoxy-3-pyridinyl) amino) -5- ((1-oxo-4-thiomorpholinyl) methyl) -3-pyridinyl) -6-methyl-1, 3, 5-triazin-2-amine;

26. A compound, or a pharmaceutically acceptable salt thereof, selected from:

N- (2-chloro-5- (3- (2-methyl-9 h-purin-6-yl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide;

n- (2-chloro-5- (3- (2-methyl-9 h-purin-6-yl) -5- (1-morpholinoethyl) pyridin-2-ylamino) pyridin-3-yl) methanesulfonamide;

n' - (2-chloro-5- ((3- (2-methyl-9 h-purin-6-yl) -5- (1- (4-morpholinyl) ethyl) -2-pyridinyl) amino) -3-pyridinyl) -N, N-dimethylsulfonamide;

4- (5- (3, 6-dihydro-2 h-pyran-4-yl) -2- (5-fluoro-6-methoxypyridin-3-ylamino) pyridin-3-yl) -6-methyl-1, 3, 5-triazin-2-amine;

27. A compound of formula II or a pharmaceutically acceptable salt thereof,

wherein X¹Is fluorine or hydrogen;

y1 is hydrogen or methyl; and

Z¹is hydrogen or methyl.

28. A compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein X¹Is fluorine; y is¹Is hydrogen or methyl; and Z is¹Is hydrogen or methyl.

29. A compound of formula IIa or a pharmaceutically acceptable salt thereof,

wherein X¹Is fluorine or hydrogen;

Y¹is hydrogen or methyl; and

Z¹Is hydrogen or methyl.

30. A compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein X¹Is fluorine; y is¹Is hydrogen or methyl; and Z is¹Is hydrogen or methyl.

31. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

32. A method of treating: melanoma, ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, pancreatic cancer, lung cancer, gastric cancer, glioblastoma, liver cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, or thyroid cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.