EA047819B1 - TRICYCLIC COMPOUNDS AND THEIR APPLICATIONS - Google Patents

Abstract

The present invention relates to tricyclic compounds of formula (I), pharmaceutical compositions containing them, the use of said compounds, methods in vivo or in vitro for inhibiting extracellular signal-regulated kinase (ERK) activity, and methods for treating or preventing a disease responsive to inhibition of extracellular signal-regulated kinase (ERK) using said compounds.

Description

Field of technology

The present invention relates to tricyclic compounds, to a pharmaceutical composition containing them, to a method in vivo or in vitro for inhibiting the activity of extracellular signal-regulated kinase (ERK), and a method for treating or preventing a disease susceptible to inhibition of extracellular signal-regulated kinase (ERK) using said compounds, and their use.

State of the art

The RAS/RAF/MEK/ERK pathway is an evolutionarily conserved signaling cascade that regulates a wide range of processes, including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, and proliferation. It is well known that impaired activation of this pathway is closely associated with various types of cancer. Hyperactivation of the ERK signaling pathway occurs in a large number of tumors, most often due to activating mutations in the KRAS, NRAS, and BRAF genes. RAS mutations have been detected in approximately 30% of all human cancers, with RAS mutations occurring in 90% of pancreatic cancers, 50% of colorectal cancers, 50% of papillary thyroid cancers, 30% of non-small cell lung cancer (NSCLC), and 25% of melanomas, respectively. BRAF mutations are frequently detected in tumors and account for a significant proportion (7%) of all human cancers. This mutation is highly prevalent in hairy cell leukemia (100%), melanoma (50%-60%), papillary thyroid cancer (40%-60%), colorectal cancers (CRC, 5%-10%), pilocytic astrocytoma (10%-15%), and non-small cell lung cancer (NSCLC) (3%-5%). MEK mutations are detected mainly in melanoma, but also in ovarian cancer cell lines and gliomas. Overall, mutations in all upstream elements of the cascade can lead to hyperactivation of the ERK protein, which is responsible for a set of ERK signaling-regulated substrate activation processes and, therefore, is associated with a wide range of tumors.

Targeting the MAPK/ERK pathway has attracted considerable interest in cancer therapy. The clinical benefits of BRAF and MEK inhibitors have shown that targeting these downstream RAS effectors is a promising approach for the treatment of BRAF-mutated cancers. However, recent evidence suggests that inhibition of BRAF or MEK alone is not sufficient to provide clinical benefit in RAS-mutated cancers. Both intrinsic and acquired resistance to BRAF and MEK inhibitors is often associated with the persistence of ERK signaling in the presence of the drug, implying the need for targeting ERK. Initial efficacy of ERK inhibitors has already been observed in clinical trials. In the phase I BVD-523 study, clinical responses were observed in patients with BRAF and NRAS mutations and even in patients whose disease had progressed on prior treatment with BRAF and/or MEK inhibitors. Combination approaches using ERK inhibitors have been investigated, and preclinical data support the efficacy of combination strategies using other targeted inhibitors, such as a CDK4/6 inhibitor, a VEGFR2 inhibitor, a PARP inhibitor, a universal ERBB inhibitor, and an autophagy inhibitor, against KRAS-mutated cancer cells. Thus, ERK inhibitors may have beneficial effects in a broader patient population in the clinical setting.

Accordingly, new compounds and methods for modulating ERK activity and treating disorders associated with it, including cancer, are needed. The present invention satisfies these needs.

Brief description of the invention

The present invention provides a compound of formula (I):

(I) or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

- 1 047819

where R ₁₀ and R11 are independently selected from hydrogen, halogen, -CN, C1.6 alkyl, C1.6 alkoxyl and C1_ ₆ haloalkyl;

L is absent, or L is -NRc, O or S; Rc is hydrogen or C1_ ₆ alkyl;

Ar is heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH(C ₁ . ₆ alkyl), -(C 2 . 6 alkyl) -CN, mercapto, C 1 . ₆ alkyl, C 2 . ₆ alkenyl, C 2 . ₆ alkynyl, C 1 . ₆ alkoxyl, C 1 . ₆ haloalkyl, -(C 1 . ₆ alkyl)-OH, -(C ₁ . ₆ alkyl)-O-(C ₁ . ₆ alkyl), C3. ₈ cycloalkyl, 3-8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said _{C1_6} alkyl, _{C1_6} alkoxyl, _{C1_6} haloalkyl, _C3-8 cycloalkyl, _3-8 -membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more deuterium atoms;

_R1 is selected from hydrogen, _{C1_6alkyl} optionally substituted with one or more deuterium atoms, _{C2_6alkenyl} , _{C2_6alkynyl} , _{C1_6haloalkyl} , -( _{C1_6alkyl} ) _-OH , -(C^ _alkyl ^O^C^alkyl),

-(C^alkylXC^cycloalkyl), -( _{C1_6} alkyl)-(3-8-membered heterocyclyl), -( _{C1_6 alkyl} )phenyl,

-( _{C1_6} alkyl)heteroaryl, _{C3_8} cycloalkyl, 3- to ₈ -membered heterocyclyl, phenyl and heteroaryl, wherein each of said _{C2_6} alkenyl, _{C2_6} alkynyl, _{C3_8} cycloalkyl, _3- to ₈ -membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently _selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH( _{C1_6} alkyl), -(C2_6 alkyl)^-( _{C1_6} alkyl)-OH, -( _{C1_6} alkyl)-O( _{C1_6} alkyl), C3_8 cycloalkyl, _3- to ₈ -membered heterocyclyl, phenyl, heteroaryl _{, C1_6 alkyl} , optionally substituted by one or more deuterium atoms, _{C1_6} alkoxyl and _{C1_6} haloalkyl;

R2 is selected from hydrogen, deuterium, halogen, hydroxy, _amino , -KH( _{C1_6alkyl} ), _{-K(C1_6alkyl)2, -CN, mercapto, C1_6alkyl optionally substituted with one or more deuterium atoms, C2_6alkenyl, C2_6alkynyl, C1_6haloalkyl , - ( C1_6alkyl ) -OH ,} -(C _^ alkyl^O^C^alkyl),

-(C^alkylXC^cycloalkyl), -( _{C1_6} alkyl)-(3-8-membered heterocyclyl), -( _{C1_6 alkyl} )phenyl,

-( _{C1_6} alkyl)heteroaryl, _{C3_8} cycloalkyl, 3- to ₈ -membered heterocyclyl, phenyl and heteroaryl, wherein each of said _{C2_6} alkenyl, _{C2_6} alkynyl, _{C3_8} cycloalkyl, _3- to ₈ -membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently _selected from deuterium, halogen, -CK, hydroxy, mercapto, amino, -KH( _{C1_6} alkyl), -K( _{C1_6} alkyl) ₂ , -( _{C1_6} alkyl)-OH, -( _{C1_6} alkyl)-O( _{C1_6} alkyl), _{C1_6} alkyl, _{C1_6} alkoxyl, _{C1_6} haloalkyl and oxo;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -KH( _{C1_6alkyl} ), -K( _{C1_6alkyl} ) ₂ , -( _{C1_6alkyl} )-OH, -( _{C1_6alkyl} ) _-O- ( _{C1_6alkyl} ), -CK, mercapto, _{C1_6alkyl} , _{C1_6alkoxyl and C1_6haloalkyl} ; or Ra and Rb together with the carbon atom to which they are attached form _{a C3-6} cycloalkyl or a 3-6-membered heterocyclyl, wherein each of said _C3-6 cycloalkyl or _3-6 -membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CK, hydroxy, mercapto, amino, -KH( _{C1_6} alkyl), -K( _{C1_6} alkyl) ₂ , -( _{C1_6} alkyl)-OH _, -( _{C1_6} alkyl)-O- _{(C1_6 alkyl), C1_6 alkyl , C1_6 alkoxyl} and _{C1_6} haloalkyl;

is a double bond or a single bond, and if it is a double bond, then R3 and R5 are absent;

_R3 , R4, R5, R6, R7 and _R8 are independently selected from hydrogen, deuterium, halogen, hydroxy, -CK, mercapto, amino, -KH( _{C1_6alkyl} ), -K( _{C1_6alkyl} ) ₂ , _- ( _{C1_6alkyl} )-OH, -( _{C1_6alkyl} )-O- _{( C1_6alkyl} ), _{C1_6alkyl} , -( _{C1_6alkyl} )phenyl, _{C1_6alkoxy} and _{C1_6haloalkyl} ; or any two of _R3 , R4, R5, _R6 , _R7 and _R8 together with the carbon atom to which they are attached and Ring _B form an 8- to 13-membered spirocyclic

- 2 047819 a spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms independently selected from N, O or S; wherein said spirocyclic, fused or bridged ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C ₁ . ₆ alkyl), -N(C _1-6 alkyl) ₂ , -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl), C ₆ alkyl, C ₆ alkoxy and C _1-6 haloalkyl; or R ₃ and R4 together, R5 and R6 together or R ₇ and R ₈ together are oxo;

n is 0, 1 or 2;

m is 0, 1, 2, 3, 4 or 5;

wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5, 6 or 7 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8-12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other;

wherein said 3-8 membered heterocyclyl is a saturated or partially unsaturated ring containing 3-8 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and containing 1, 2 or 3 rings, wherein the N or S heteroatom is optionally oxidized to different oxidation states;

wherein said 3-6-membered heterocyclyl is a saturated or partially unsaturated ring containing 3-6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and containing 1, 2 or 3 rings, wherein the N or S heteroatom is optionally oxidized to different oxidation states.

The above compounds, as well as the active compounds described in the context of the present invention and included within the scope of the above compounds, are collectively referred to as a compound according to the present invention or any of the compounds according to the present invention.

Also provided is a pharmaceutical composition comprising a compound according to the present invention and, optionally, a pharmaceutically acceptable carrier.

Also provided is a method for in vivo or in vitro inhibition of extracellular signal-regulated kinase (ERK) activity, comprising contacting an effective amount of a compound of the present invention with ERK.

Also provided is a method for treating or preventing a disease susceptible to ERK inhibition, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

Also provided is the use of a compound according to the present invention for the production of a medicament for the treatment or prevention of a disease susceptible to ERK inhibition.

Brief description of graphic materials

The drawing shows the synthetic processes for preparing a compound according to the present invention, wherein X is halogen; Z1, _Z2 , , L, R1, _R2 , _R3 , R4, R5, _R6 , _R7 , _R8 , Ra, Rb, m and n are defined as for the compound of formula (I) and its subformulas (I-1), (I-2) or (I-3); _R9 is defined as for the compound of formula (II) or (III).

Detailed description of the invention

Definitions.

In the present invention, the following words, phrases and symbols have the meanings set forth below unless the context clearly dictates otherwise.

A hyphen (-) that is not between two letters or symbols is used to indicate where a substituent is attached. For example, -O( _C1-6 alkyl) is attached to the rest of the molecule through an oxygen atom.

A dotted line across a chemical bond is used to indicate where the group is attached to the rest of the molecule. For example, Ar could represent

- 3 047819 where the left and right dotted lines indicate the attachment sites to R ₁ -NH- and ring A, respectively.

The term _" alkyl" as used herein refers to _a linear or branched saturated hydrocarbon radical containing 1-18 carbon atoms ( _C1-18 ), preferably 1-10 carbon atoms ( _C1-10 ), and more preferably 1-6 carbon atoms ( _C1.6 ). For example, "alkyl" refers to an alkyl containing 1-6 carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term alkenyl as used herein refers to a linear or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (C=C) and 2-10 carbon atoms ( _C2-10 ), preferably 2-6 carbon atoms ( _C2-6 ), more preferably 2-4 carbon atoms ( _C2-4 ). For example, _C2-6 alkenyl refers to an alkenyl containing 2-6 carbon atoms, which preferably contains 1 or 2 carbon-carbon double bonds; _C2-4 alkenyl refers to an alkenyl containing 2-4 carbon atoms, which preferably contains 1 carbon-carbon double bond. Examples of alkenyls include, but are not limited to, vinyl, 2-propenyl and 2-butenyl. The point of attachment of the alkenyl may, but does not necessarily, be located at a double bond.

The term "alkynyl" as used herein refers to a linear or branched unsaturated hydrocarbon radical containing one or more, such as 1, 2 or 3, carbon-carbon triple bonds (C=C) and 2-10 carbon atoms ( _C2-10 ), preferably 2-6 carbon atoms ( _C2-6 ), more preferably 2-4 carbon atoms ( _C2-4 ). For example, _C2-6 alkynyl refers to an alkynyl containing 2-6 carbon atoms, which preferably contains 1 or 2 carbon-carbon triple bonds; _C2-4 alkynyl refers to an alkynyl containing 2-4 carbon atoms, which preferably contains 1 carbon-carbon triple bond. Examples of alkynyls include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl. The point of attachment of the alkynyl may, but does not necessarily, be located at a triple bond.

The term halogen or halogen- as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

The term "haloalkyl" as used herein refers to an alkyl, as defined herein, in which one or more, such as 1, 2, 3, 4 or 5, hydrogen atoms are replaced with halogen atoms, and if more than one hydrogen atom is replaced with a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl, as defined herein, in which two or more, such as 2, 3, 4 or 5, hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are the same. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl, as defined herein, in which two or more, such as 2, 3, 4 or 5 hydrogen atoms, are replaced with halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyls include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CH3, etc.

The term alkoxyl as used herein refers to the group -O-alkyl, wherein alkyl is as defined above. Examples of alkoxyls include, but are not limited to, C _1-6 alkoxyls such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy and hexyloxy, including their isomers.

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 3-12 ring carbon atoms ( _C3-12 ), such as 3-8 ring carbon atoms ( _C3-8 ), 3-7 ring carbon atoms ( _C3-7 ), or _3-6 ring carbon atoms ( _C3-6 ), which may contain 1 or 2 rings. Cycloalkyl may include a fused ring, a bridged ring, or a spirocyclic ring. The ring(s) in a cycloalkyl may be saturated or may contain one or more, such as one or two, double bonds in the ring(s) (i.e., are partially unsaturated), but is/are not fully conjugated and is/are not aryl as defined herein. In one embodiment, said cycloalkyl is a monocyclic cycloalkyl, preferably a monocyclic _C3-8 cycloalkyl, more preferably a monocyclic _C3-6 cycloalkyl. In another embodiment, said cycloalkyl is a saturated monocyclic cycloalkyl, preferably a saturated monocyclic _C3-8 cycloalkyl, more preferably a saturated monocyclic _C3-6 cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl (such as 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3enyl), cyclohexenyl (such as 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl), cyclohexadienyl. In another embodiment, said cycloalkyl is a bicyclic cycloalkyl, preferably a bicyclic C ₅ -C ₁₂ cycloalkyl, more preferably a bicyclic C ₇ -C ₁₂ cycloalkyl. Examples of bicyclic cycloalkyls include, but are not limited to,

- 4 047819 mi, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, spiro[3.3]heptyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[4.5]decyl and bicyclo[3.1.1]hepta-2-enyl. Most preferably, cycloalkyl is saturated monocyclic C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term heterocycle, heterocyclyl or heterocyclic group as used herein refers to a saturated or partially unsaturated ring containing 3-12 ring atoms (3-12 membered), such as 3-8 ring atoms (3-8 membered), 5-7 ring atoms (5-7 membered), 3-6 ring atoms (3-6 membered) or 4-6 ring atoms (4-6 membered), wherein 1, 2 or 3, preferably 1 or 2, ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and containing one or more, such as 1, 2 or 3, preferably 1 or 2, rings, wherein the N or S heteroatom is optionally oxidized to different oxidation states. The point of attachment of the heterocyclyl may be at the N heteroatom or at the carbon atom. The ring(s) in a heterocyclyl also include a fused ring, a bridged ring, or a spirocyclic ring. The ring(s) in a heterocyclyl may be saturated or contain one or more, for example, one or two double bonds (i.e., are partially unsaturated), but are not fully conjugated and are not a heteroaryl as defined herein. For example, a 3-8 membered heterocyclyl refers to a heterocyclyl containing 3-8 ring atoms and containing 1, 2 or 3, preferably 1 or 2 heteroatoms in the ring independently selected from N, O and S, preferably is a saturated monocyclic 3-8 membered heterocyclyl. Also, for example, 3-6-membered heterocyclyl refers to a heterocyclyl containing 3-6 ring atoms and containing 1 or 2 heteroatoms in the ring independently selected from N, O and S, preferably is a saturated monocyclic 3-6-membered heterocyclyl, such as a saturated monocyclic 3-, 4-, 5- or 6-membered heterocyclyl. Examples of heterocyclyls include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl and tetrahydropyranyl.

The term "aryl" as used herein refers to a carbocyclic hydrocarbon radical containing 6-14 carbon atoms ( _C6-14 ), preferably 6-10 carbon atoms ( _{C6_10} ) and consisting of one ring or more fused rings, wherein at least one ring is aromatic. Examples of aryls _include , but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.

The term heteroaryl as used herein refers to:

a monocyclic heteroaryl, i.e. a monocyclic aromatic hydrocarbon radical containing 5, 6 or 7 ring atoms (5-, 6- or 7-membered), wherein one or more, for example 1, 2 or 3, preferably 1 or 2, of the ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon; preferably a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms (5- or 6-membered), wherein 1, 2 or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O and S, preferably N; and a bicyclic heteroaryl, i.e. to a bicyclic aromatic hydrocarbon radical containing 8-12 ring atoms (8-12-membered), for example containing 8, 9 or 10 ring atoms (8-, 9- or 10-membered), wherein one or more, for example 1, 2, 3 or 4, preferably 2, 3 or 4, atoms in the ring are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining atoms in the ring are carbon, wherein at least one of the rings is aromatic. If the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other. For example, a bicyclic heteroaryl includes a 5- or 6-membered heteroaryl ring fused to a 5- or 6-membered cycloalkyl ring.

Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,3,4-thiadiazolyl), tetrazolyl, triazolyl (such as 1,2,4-triazolyl), triazinyl (such as 1,3,5-triazinyl), thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzodioxolyl, benzoxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, triazolopyridyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrazolopyridyl, tetrahydropyrazolopyridyl, benzofuryl, benzoimidazolinyl, indolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, indolinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, [c]pyrazolyl and 5,6,7,8tetrahydro[1,2,4]triazolo[1,5-a]pyridyl.

Within the scope of the present invention, the terms combined ring, fused ring or fused ring may be used interchangeably herein and refer to

- 5 047 819 saturated, partially unsaturated or aromatic ring system, in which two rings share one common side. In one embodiment, said combined ring, fused ring or fused ring contains 8-13 ring atoms (8-13 membered), such as 9-12 ring atoms (9-12 membered), 8-11 ring atoms (8-11 membered) or 8, 9 or 10 ring atoms (8-, 9- or 10-membered), wherein 1, 2 or 3, preferably 1 or 2, ring atoms are optionally ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon.

The term spirocyclic ring as used herein refers to a saturated or partially unsaturated, preferably saturated, ring system in which two rings have one common atom (called a common spiro center), wherein 1, 2 or 3, preferably 1 or 2, atoms in the ring are optionally ring heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon. In one embodiment, said spirocyclic ring comprises 8-13 ring atoms (8-13 membered), such as 9-12 ring atoms (9-12 membered), 8-11 ring atoms (8-11 membered), or 8, 9, or 10 ring atoms (8-, 9-, or 10 membered), wherein 1, 2, or 3, preferably 1 or 2, of the ring atoms are optionally ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon.

Within the scope of the present invention, the terms bridged ring or bridged ring may be used interchangeably herein and refer to a saturated or partially unsaturated, preferably saturated, ring system in which two rings contain two atoms not directly connected (called bridgehead atoms), wherein 1, 2 or 3, preferably 1 or 2, atoms in the ring are optionally heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon. In one embodiment, said bridged ring or bridged ring comprises 8-13 ring atoms (8-13 membered), such as 9-12 ring atoms (9-12 membered), 8-11 ring atoms (8-11 membered), or 8, 9, or 10 ring atoms (8-, 9-, or 10 membered), wherein 1, 2, or 3, preferably 1 or 2, ring atoms are optionally ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon.

The term hydroxy as used herein refers to the -OH group. The term mercapto as used herein refers to the -SH group. The term oxo as used herein refers to the =O group. The term amino as used herein refers to the -NH2 group. The term cyano as used herein refers to the -CN group.

When a structure in this document contains an asterisk *, it means that the chiral center in the compound designated by * has either the R configuration or the S configuration, and the content of the compound in the specified individual configuration designated by * is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between the specified numerical values).

When a structure in this document contains the designation (RS), it means that the chiral center in the compound designated (RS) is present in both the R configuration and the S configuration.

The term optional or optional as used herein means that the event or condition described herein may or may not occur (be satisfied), and the description includes instances where the event or condition occurs (be satisfied) and instances where it does not occur (be satisfied). For example, an optionally substituted alkyl or an alkyl optionally substituted ... includes both unsubstituted alkyl and substituted alkyl, as defined herein. One skilled in the art will appreciate that the representation of any group containing one or more substituents does not imply the presence of any substituent or substitution pattern that is sterically unacceptable, chemically incorrect, incapable of being synthesized, and/or inherently unstable.

The term "substituted" or "substituted with" ... as used herein means that one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents selected from a specified group of substituents, provided that the normal valence of the specified atom is not exceeded. If the substituent is oxo (i.e. =O), then 2 hydrogen atoms on one atom are replaced by oxo. Combinations of substituents and/or variables are permissible only if the specified combinations provide a chemically correct and stable compound. A chemically correct and stable compound is understood to mean a compound that is sufficiently stable to withstand proper isolation from the reaction mixture.

Unless otherwise specifically stated, the names of substituents are indicated in the main structure. For example, it should be understood that if (cycloalkyl)alkyl is indicated in the list of possible substituents, then the point of attachment of the indicated substituent to the main structure is at the alkyl moiety.

The term "substituted with one or more substituents" as used herein means that one or more hydrogen atoms on a specified atom or group are independently replaced by one or more

- 6,047,819 substituents selected from the specified group of substituents. In some embodiments, substituted with one or more substituents means that the specified atom or group is substituted with 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents independently selected from the specified group of substituents.

The term leaving group refers to the atoms or functional groups that are replaced during a reaction. Examples of leaving groups include, but are not limited to, halogen, alkoxy, and sulfonyloxy. Examples of sulfonyloxy include, but are not limited to, alkylsulfonyloxy (such as methanesulfonyloxy (also called the methanesulfonate group) and trifluoromethanesulfonyloxy (also called the trifluoromethanesulfonate group)) and arylsulfonyloxy (such as p-toluenesulfonyloxy (also called the p-tosylate group) and p-nitrophenylsulfonyloxy (also called the p-nitrophenylsulfonate group)).

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemates of these isomers, individual isomers and mixtures enriched in one of the enantiomers, as well as diastereomers and mixtures partially enriched in particular diastereomers when two chiral centers are present, are included within the scope of the present invention. It will also be appreciated by those skilled in the art that the present invention includes all individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, individual tautomeric forms.

In other words, in some embodiments, the present invention provides compounds with different stereoisomeric purities, i.e., diastereomeric or enantiomeric purities, represented by different ee and diastereomeric purities. In some embodiments, compounds of Formula (I) or Subformula (I-1), (I-2), (I-3), such as those described herein, have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value in between). In some embodiments, the compounds of Formula (I) or Subformula (I-1), (I-2), (I-3), as described herein, have an enantiomeric purity of greater than 99.9% ee. In some embodiments, the compounds of Formula (I) or Subformula (I-1), (I-2), (I-3), as described herein, have a diastereomeric purity of at least 60% d.i. (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% d.i., or any value in between). In some embodiments, the compounds of formula (I) or subformulas (I-1), (I-2), (I-3), such as described herein, have a diastereomeric purity of greater than 99.9% d.i.

The term enantiomeric excess or ee denotes the excess in which one enantiomer is present over the other. In the case of a mixture of R and S enantiomers, the enantiomeric excess in percent is defined as | R - S | * 100, where R and S correspond to the mole or mass fraction of the enantiomers in the mixture, and R + S = 1. If the optical rotation values of a chiral substance are known, the enantiomeric excess in percent is defined as ([a]obs/[a]max) * 100, where [a]obs is the optical rotation of the mixture of enantiomers, and ^]max is the optical rotation of the pure enantiomer.

The term diastereomeric excess or d.e. denotes the excess in which one diastereomer is present over the other, and is defined by analogy with enantiomeric excess. Thus, in the case of a mixture of diastereomers, D1 and D2, the diastereomeric excess in percent is defined as | D1 - D2 | * 100, where D1 and D2 correspond to the mole or mass fraction of the corresponding diastereomers in the mixture, and D1 + D2 = 1.

Diastereomeric and/or enantiomeric excess can be determined by a variety of analytical methods, including NMR spectroscopy, chiral column chromatography and/or optical polarimetry, according to standard protocols known to those skilled in the art.

The racemate may be used as is or resolved into its individual isomers. The separation may yield stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger, N. L., and Eliel, E. L., in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent. Individual isomers may be obtained in chiral form from chiral precursors. Alternatively, the individual isomers may be separated chemically from the mixture by forming diastereomeric salts with a chiral acid (such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts and then obtaining one or both of the separated free bases, optionally repeating the process to thereby obtain either one or both of the isomers substantially free of the other isomer; i.e., an isomer having an optical purity of >95%. Alternatively, the racemate may be covalently linked to a chiral compound (auxiliary) to produce the diastereomeric isomer

- 7,047,819 which can be separated by chromatography or fractional crystallization, after which the chiral auxiliary is removed by chemical methods to obtain pure enantiomers, as is known to those skilled in the art.

The term pharmaceutically acceptable salt includes, but is not limited to, acid addition salts derived from compounds of formula (I) or subformula (I-1), (I-2), (I-3) and an inorganic acid such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and an organic acid such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and salts of alkanedicarboxylic acids of the formula HOOC-(CH ₂ ) _p -COOH, where n is 0-4, etc. In addition, the pharmaceutically acceptable salt includes base addition salts derived from compounds of formula (I) or subformula (I-1), (I-2), (I-3) containing an acidic moiety and pharmaceutically acceptable cations, such as sodium, potassium, calcium, aluminum, lithium and ammonium.

In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid addition salt. Conversely, if the product is a free base, the acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained from the base of the compound by dissolving the free base in a suitable solvent and treating the solution with an acid in accordance with conventional methods for preparing acid addition salts. One skilled in the art will recognize various synthetic procedures that can be used, without undue experimentation, to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.

The term solvates denotes solvent-added forms that contain either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to retain a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is called a hydrate; if the solvent is an alcohol, the solvate formed is called an alkoxide. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, in which the water retains the molecular state of H2O. This combination may result in one or more hydrates, such as a hemihydrate, monohydrate, and dihydrate.

The term deuterated compounds means compounds in which one or more, for example 1, 2 or 3, hydrogen atoms are replaced by a deuterium isotope. In this case, the content of the deuterium isotope at the position in which it replaces hydrogen (the degree of deuteration) should at least exceed the natural content of the deuterium isotope. In some embodiments, the deuterated compound of formula (I) or subformula (I-1), (I-2), (I-3) has a degree of deuteration of at least 50% (for example, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or any value between the indicated numerical values). In some embodiments, the compound of formula (I) or subformula (I-1), (I-2), (I-3) has a degree of deuteration of greater than 99.9% and up to 100%.

In this document, the terms group, radical and fragment are synonymous and refer to functional groups or molecular fragments that can be attached to other molecular fragments.

The term treatment, treating or method of treating a disease or disorder refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, to a subject suffering from a disease or disorder, or having a symptom of a disease or disorder, to cure, heal, alleviate, alleviate, modify, eliminate, reduce, improve or affect the disease or disorder, the symptoms of the disease or disorder. In some embodiments, the disease or disorder is a disease responsive to ERK inhibition, preferably cancer.

The term "preventing" or "preventing" with respect to a disease or disorder refers to the administration of one or more pharmaceutical substances, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, to a subject who is predisposed to or at risk of developing the disease or disorder, to prevent or slow the onset of the disease or disorder in the subject. In some embodiments, the disease or disorder is a disease susceptible to ERK inhibition, preferably cancer.

The terms treating, contacting and reacting in the context of a chemical reaction mean the addition or mixing of two or more reactants under appropriate conditions to produce a specified and/or desired product. It should be understood that the reaction that results in

- 8 047819 obtaining the specified and/or desired product may not necessarily occur directly upon combining the two initially added reagents, i.e. there may be one or more intermediate compounds that are formed in the mixture, from which the specified and/or desired product is ultimately formed.

The term "effective amount" as used herein refers to an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein, that effectively treats or prevents, as defined above, a disease or disorder responsive to ERK inhibition in a subject. An effective amount may cause any observable or measurable change in a subject, such as those described in the above definitions of treatment, treat, method of treating, preventing, or preventing. For example, in the case of cancer, an effective amount may reduce the number of cancer or tumor cells; reduce the size of a tumor; inhibit or stop the infiltration of tumor cells into peripheral organs, including, for example, the spread of a tumor to soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; alleviate to some extent one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or provide a combination of these effects. An effective amount may be an amount sufficient to alleviate the symptoms of a disease responsive to ERK inhibition. The term effective amount may also refer to an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof described herein that effectively inhibits ERK activity in a subject.

The term inhibition or suppression refers to a decrease in a biological activity or process activity relative to a baseline level. Inhibition of ERK refers to a decrease in ERK activity as a result of a direct or indirect response to the presence of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, compared to ERK activity in the absence of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The decrease in activity may be caused by a direct interaction of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, with ERK, or by an interaction of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, with one or more other factors that in turn affect ERK activity. For example, the presence of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, can reduce ERK activity by directly binding to ERK, by directly or indirectly affecting another factor that reduces ERK activity, or by directly or indirectly decreasing the amount of ERK present in a cell or organism.

The term "subject" as used herein refers to mammals and non-mammalian animals. "Mammal" refers to any member of the class Mammalia, including, but not limited to, humans; non-human primates such as chimpanzees and other monkeys and apes; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs; etc. Examples of non-mammalian animals include, but are not limited to, birds, etc. The term "subject" does not indicate a particular age or sex.

The term pharmaceutically acceptable means that the substance designated by the said term is suitable for the preparation of a pharmaceutical composition and is generally safe, non-toxic and not biologically or otherwise undesirable, in particular for pharmaceutical use in humans.

The term approximately, as used herein, means approximately, on the order of, roughly, or about. When the term approximately is used in relation to a numerical range, it modifies the stated range by extending its boundaries above and below the numerical values presented. In general, the term approximately is used herein to modify a numerical value above and below the stated value by a 20% margin of error.

Technical and scientific terms used herein and not specifically defined have the meanings commonly understood by those skilled in the art to which this invention pertains.

- 9 047819

Variants of implementation of the invention

Implementation variant 1. Compound of formula (I):

(I) or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Z1 and Z2 are independently N or C, and “2- is a 5-membered heteroaryl containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S; said 5-membered heteroaryl being optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH(C1.6 alkyl), -N( _C2.6 alkyl)N-CN, mercapto, C1.6 alkyl, _C2.6 alkenyl, _C1.6 alkynyl, C1.6 alkoxyl, C1.6 haloalkyl, -( _C1.6 alkyl)-OH and

-( _C1.6alkyl )-O-( _C1.6alkyl ), wherein each of said C1.6alkyl, C1.6alkoxyl and C1.6haloalkyl is optionally substituted with one or more deuterium atoms;

L is absent, or L is -NRc, O, or S; Rc is hydrogen or C1.6 alkyl;

Ar is heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -KH( _C1.6 alkyl), -(C2.6 alkyl)^-CN, mercapto, C1.6 alkyl, C2.6 alkenyl, _C2.6 alkynyl, _C1.6 alkoxyl, C1.6 haloalkyl, -( _C1.6 alkyl)-OH, -( _C1.6 alkyl)-O-( _C1.6 alkyl), _C3.8 cycloalkyl, _3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said _C1.6 alkyl, C1.6 alkoxyl, C1.6 haloalkyl, _C3 . ₈ cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl optionally substituted with one or more deuterium atoms;

R1 is selected from hydrogen, _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C2.6 alkenyl, _C2.6 alkynyl, _C1.6 haloalkyl, -(C1.6 alkyl)-OH _, -( _C1.6 alkyl)-O-( _C1.6 alkyl),

-( _C1.6alkyl )-( _{C3.8cycloalkyl} ), -( _C1.6alkyl )-( _3-8 -membered heterocyclyl), -( _C1.6alkyl )phenyl,

-(C1.6 alkyl)heteroaryl, _C3.8 cycloalkyl, _3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said _C2.6 alkenyl, _C2.6 alkynyl, _C3.8 cycloalkyl, 3- to ₈ -membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH( _C1.6 alkyl), -N(C2.6 alkyl)N-(C1.6 alkyl)-OH, -( _C1.6 alkyl)-O(C1.6 alkyl), _C3.8 cycloalkyl, 3- to ₈ -membered heterocyclyl, phenyl, heteroaryl, C1. ₆ alkyl optionally substituted with one or more deuterium atoms, C1.6 alkoxyl and C1.6 haloalkyl;

R2 is selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH(C1_6alkyl), -N(C2_alkyl)^- _{C2_mercapto, C1_6alkyl optionally substituted with one or more deuterium atoms, C2_6alkenyl , C2_6alkynyl} , C1_6haloalkyl, -( _{C1_6alkyl} )-OH, -( _{C1_6alkyl} )-O-( _{C1_6alkyl} ),

-(C ₁ .6 alkyl)-(C ₃ . ₈ cycloalkyl), -(C ₁ .6 alkyl)-(3- to 8-membered heterocyclyl), -(C 1 .6 alkyl)phenyl, -(C 1 . 6 alkyl)heteroaryl, C ₃ . ₈ cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said C ₂ . ₆ alkenyl, C ₂ . 6 alkynyl, C ₃ . ₈ -cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from deuterium, halogen, -C1-hydroxy, mercapto, amino, -NH(C1-6alkyl), -(C1-6alkyl)-( _C1-6alkyl )-OH, -(C1-6alkyl)-O-( _C1-6alkyl ), C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl and oxo;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH( _C1.6 alkyl), -(C1.6 alkyl)-(C1.6 alkyl)-OH, -( _C1.6 alkyl)-O-( _C1.6 alkyl), -C1.6 mercapto, C1.6 alkyl, C1.6 alkoxyl and C1.6 haloalkyl; or Ra and Rb together with the carbon atom to which they are attached form _C3.6 cycloalkyl or 4- to 6-membered heterocyclyl, wherein each of said _C3 . ₆ -cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -C1.6 hydroxy, mercapto, amino, -NH( _C1.6 alkyl), -( _C1.6 alkyl)-( _C1.6 alkyl)-OH, -( _C1.6 alkyl)-O-( _C1.6 alkyl) _{, C1.6 alkyl, C1.6 alkoxyl and C1.6 haloalkyl ; ~~~~~~} represents a double bond or a single bond, and if — — — — — — represents a double bond, then _R3 and _R5 are absent;

_R3 , R4, _R5 , R6, _R7 and _R8 are independently selected from hydrogen, deuterium, halogen, hydroxy, -CH mercapto, amino _{, -KH(C1.6 alkyl), -N(C2-alkyl)N-(C1.6 alkyl ) -OH} , -( _C1.6 alkyl)-O-( _C1.6 alkyl), _C1.6 alkyl, -( _C1.6 alkyl)phenyl, _C1.6 alkoxy and _C1.6 haloalkyl; or any two of _R3 , _R4 , _R5 , _R6 , _R7 and _R8 together

- 10 047819 with the carbon atom to which they are attached and ring B form an 8-13 membered spirocyclic, fused or bridged ring, optionally containing 1-3 heteroatoms in the ring independently selected from N, O or S; wherein said spirocyclic, fused or bridged ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C1_6alkyl) ₂ , -(C2_alkyl)2OH, -(C1_6alkyl)-O- ₍ C1_6alkyl), _{C1_6alkyl , C1_6alkoxyl} and _{C1_6haloalkyl} ; or _R3 and R4 together _, R5 and R6 together or _R7 and _R8 together are oxo;

n is 0, 1 or 2;

m is equal to 0, 1, 2, 3, 4 or 5.

Embodiment 2. The compound of formula (I) according to embodiment 1 or a pharmaceutically acceptable salt or solvates, racemic mixtures, enantiomers, diastereomers or tauto-

measures of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that it is selected from:

wherein R ₁₀ and R11 are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -CN, mercapto, _C1.6 alkyl, _C1.6 alkoxyl, _C1.6 haloalkyl, -( _C1.6 alkyl)-OH and -( _C1.6 alkyl)-O-( _C1.6 alkyl) _{, wherein each of said C1.6 alkyl, C1.6 alkoxyl and C1.6 haloalkyl is} optionally substituted with one or more deuterium atoms.

Embodiment 3. A compound of formula (I) according to embodiment 1 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that

selected from:

- 11 047819

(la-14) (la-15) (la-16) (la-17) (la-19) (la-20) where R ₁₀ and R11 are independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxyl and C _1-6 haloalkyl.

Embodiment 4. A compound of formula (I) according to embodiment 3 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that

represents

and R ₁₀ and R11 are independently selected from hydrogen, halogen and C _1-6 alkyl.

Embodiment 5. A compound of formula (I) according to any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is a monocyclic heteroaryl containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; each of which is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -CN, mercapto, _C1-6 alkyl, _C1-6 alkoxyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -(<\ ₆ alkyl)-(>(<\ ₆ alkyl), _C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said _C1-6 alkyl, _C1-6 alkoxyl, _C1-6 haloalkyl, _C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more deuterium atoms.

Embodiment 6. A compound of formula (I) according to embodiment 5, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazolyl and thiazolyl (more preferably, Ar is selected from pyridyl, pyrimidinyl and 1,3,5-triazinyl), each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl and C _1-6 haloalkyl.

Embodiment 7. A compound of formula (I) according to embodiment 6, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and R ₂₄ are independently selected from hydrogen, halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxy and C _1-6 haloalkyl.

Embodiment 8. A compound of formula (I) according to any of embodiments 1-7 or a pharmaceutically acceptable salt or solvates, racemic mixtures, enantiomers, diastereomers thereof

- 12 047819 or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from C _1-6 alkyl, -(C _1-6 alkyl)-OH, saturated monocyclic C _3-8 cycloalkyl, saturated monocyclic 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said _C3-8 cycloalkyl, 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), 3-6-membered heterocyclyl, _C1-6 alkyl optionally substituted with one or more deuterium atoms, _C1-6 alkoxyl or _C1-6 haloalkyl.

Embodiment 9. A compound of formula (I) according to embodiment 8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₁ is a heteroaryl selected from pyrazolyl, pyridyl, isoxazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 2,4,5,6-tetrahydrocyclopentadieno[c]pyrazolyl and 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5a]pyridyl, wherein each said heteroaryl is optionally substituted with one or more substituents independently selected from Cl _-6 alkyl optionally substituted with one or more deuterium atoms, Cl _-6 haloalkyl, Cl _-6 alkoxyl, halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl) and 3-6-membered heterocyclyl.

Embodiment 10. A compound of formula (I) according to embodiment 9, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₁ is pyrazolyl which is optionally substituted with one or more substituents independently selected from Cl _-6 alkyl optionally substituted with one or more deuterium atoms, Cl _-6 haloalkyl, C _1-6 alkoxyl, halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and oxetanyl.

Embodiment 11. A compound of formula (I) according to any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic C _3-8 cycloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said C _3-8 cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo.

Embodiment 12. A compound of formula (I) according to embodiment 11, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R2 is phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, -CN and _C1-6 alkoxyl.

Embodiment 13. A compound of formula (I) according to embodiment 11, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₂ is heteroaryl selected from 1,2,5-oxadiazolyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, thiazolyl, isothiazolyl, benzo(isoxazolyl) thienyl, indazolyl and pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from _C1-6 alkyl, halogen, oxo and -CN.

Embodiment 14. A compound of formula (I) according to embodiment 11, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₂ is a saturated monocyclic C _3-8 cycloalkyl optionally substituted with one

- 13 047819 or more substituents independently selected from C _1-6 haloalkyl.

Embodiment 15. A compound of formula (I) according to any of embodiments 1-14, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that m is 0, 1 or 2.

Embodiment 16. A compound of formula (I) according to any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are independently selected from hydrogen, halogen, hydroxy and C _1-6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic C ₃₆ cycloalkyl or a 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic C _3-6 cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen.

Embodiment 17. A compound of formula (I) according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that L is absent or L is NH, O or S.

Embodiment 18. A compound of formula (I) according to embodiment 1 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from compounds 1-322.

Embodiment 19. A compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that n is 0, ------ is a double bond, R3 and _R5 are absent, R4 and R6 are independently selected from hydrogen and _C1-6 alkyl.

Embodiment 20. A compound of formula (I) according to embodiment 19, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-1)

(1-1) where

R ₁ is heteroaryl optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, C ₁₆ haloalkyl, C _1-6 alkoxyl, halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and 3- to 6-membered heterocyclyl;

Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl, and C _1-6 haloalkyl;

R ₂ is selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, saturated monocyclic C _3-8 cycloalkyl, phenyl and heteroaryl, wherein each of said saturated monocyclic C _3-8 cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and oxo;

R4 and _R6 are independently selected from hydrogen and _C1-6 alkyl;

R ₁₀ and R11 are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and -(C _1-6 alkyl)-OH;

m is 0, 1 or 2;

Ra and Rb are independently selected from hydrogen, halogen, hydrogen or C _1-6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl or a 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining atoms

- 14 047819 in the ring are carbon; wherein each of said saturated monocyclic C3-6cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen;

L is absent, or L is NH, O, or S;

said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other.

Embodiment 21. A compound of formula (I) according to embodiment 20, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that

R1 is pyrazolyl which is optionally substituted with one or more substituents independently selected from C _1-6 αalkyl;

Ar is pyrimidinyl which is optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, and halogen;

R ₂ is selected from C _1-6 haloalkyl or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen;

R ₁₀ and R11 are hydrogen; m is 0 or 1;

Ra and Rb are independently selected from hydrogen or C _1-6 αalkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl; and

L is absent, or L is NH or O.

Embodiment 22. A compound of formula (I) according to embodiment 20 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from the group consisting of:

- 15 047819

Embodiment 23. A compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that n is 0, represents a single bond, R ₃ , R4, R5 and R6 are independently selected from hydrogen,

C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and -(C _1-6 alkyl)phenyl; or any pair of R ₃ and R 4 or R 5 and R 6 together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl or a saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring.

Embodiment 24. A compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-2) n K 'T' JL

Ri/ \_Z ^N ( ^CR a ^R b) _m -LR ₂ ¹¹ _R ArR ₆ ^R 3 r ₄ r ₅ (1-2) where

R ₁ is selected from C _1-6 alkyl, -(C _1-6 alkyl)-OH, saturated monocyclic C _3-8 cycloalkyl, saturated 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein each of said C _3-8 cycloalkyl, 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl), saturated 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl and C _1-6 haloalkyl;

Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl, and C _1-6 haloalkyl;

R2 is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic _C3-8 cycloalkyl, phenyl or heteroaryl, wherein each of said _C3-8 cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo;

Z ₃ represents CR ₁₀ or N;

_R3 , R4, R5 and R6 are independently selected from hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-O-( _C1-6 alkyl) and -( _C1-6 alkyl)phenyl; or any pair of _R3 and R4 or R5 and R6 together with the carbon atom to which they are attached form a saturated monocyclic _C3-6 cycloalkyl or a saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring;

R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and -(C _1-6 alkyl)-OH;

m is 0, 1 or 2;

Ra and R _b are independently selected from hydrogen, halogen, hydroxy or C _1-6 alkyl; or Ra and R _b together

- 16 047819 with the carbon atom to which they are attached form a saturated monocyclic C3-6cycloalkyl or 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic _{C3-6cycloalkyl} or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen;

L is absent, or L is NH, O, or S;

said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other.

Embodiment 25. A compound of formula (I) according to embodiment 24, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that

Ri is selected from a saturated monocyclic 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and a heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, -(C _1-6 alkyl)-OH, C _1-6 alkoxyl, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S;

Ar is a heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, and halogen;

R2 is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and oxo;

Z ₃ represents CR ₁₀ or N;

_R3 , R4, _R5 and _R6 are independently selected from hydrogen, _C1-6alkyl , _{C1-6haloalkyl} , -( _C1-6alkyl )-O-( _C1-6alkyl ) and -( _C1-6alkyl )phenyl; or any pair of _R3 and R4 or R5 and _R6 together with the carbon atom to which they are attached form a saturated monocyclic C3-6cycloalkyl or a saturated monocyclic 3-6-membered heterocyclyl containing either 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring;

m is equal to 1 or 2;

R _a and Rb are independently selected from hydrogen and halogen; or R _a and Rb together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl;

R ₁₀ and R11 represent hydrogen;

- 17 047819

L is absent, or L is O.

Embodiment 26. A compound of formula (I) according to embodiment 25, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from morpholinyl, thiomorpholinyl and heteroaryl, wherein said heteroaryl is selected from pyrazolyl, 2,4,5,6-tetrahydrocyclopentadieno[c]pyrazolyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5a]pyridyl, 1,3,4-thiadiazolyl and pyridyl, and each said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 haloalkyl, halogen, -(C _1-6 alkyl)OH, ^^alkoxyl, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and oxetanyl.

Embodiment 27. A compound of formula (I) according to embodiment 24, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is a heteroaryl selected from pyridyl, pyrimidinyl and 1,3,5-triazinyl; wherein each said heteroaryl is optionally substituted with one or more substituents selected from ^ _-6alkyl optionally substituted with one or more deuterium atoms and halogen.

Embodiment 28. A compound of formula (I) according to embodiment 27, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of the compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is

_{R20 R23}

R ₂ i or ( ^Ib ' ² ) where R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and R ₂₄ are independently selected from hydrogen, halogen and ^^alkyl optionally substituted with one or more deuterium atoms.

Embodiment 29. A compound of formula (I) according to embodiment 24, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from halogen, n-alkyl, n-haloalkyl, phenyl and heteroaryl, wherein said heteroaryl is selected from isoxazolyl, 1,2,5-oxadiazolyl, pyrazolyl, oxazolyl, pyridyl, thiazolyl, isothiazolyl, thienyl and benzo-isoxazolyl; wherein each of said phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, n-alkyl, n-alkoxyl and oxo.

Embodiment 30. A compound of formula (I) according to embodiment 24 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from:

Connection Structure

- 18 047819

- 19 047819

- 20 047819

- 21 047819

- 22 047819

- 23 047819

- 24 047819

- 25 047819

- 26 047819

- 27 047819

- 28 047819

- 29 047819

- 30 047819

- 31 047819

- 32 047819

- 33 047819

- 34 047819

- 35 047819

- 36 047819

- 37 047819

Embodiment 31. A compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1, is a single bond, R3, R4, R5, K6, _R7 and _R8 are independently selected from hydrogen, halogen, hydroxy, _C1.6 alkyl and _C1.6 alkoxy; wherein said _C1.6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy and _C1.6 alkoxy; or any two of R3, _R4 , R5, R6, _R7 and _R8 together with the carbon atom to which they are attached and ring B form a 9-12 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms selected from N, O or S; said spirocyclic, fused or bridged ring being optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, _C1.6 alkyl and -CN.

Embodiment 32. A compound of formula (I) according to embodiment 31, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-3)

Where

Ri is selected from _C1.6 alkyl, -( _C1.6 alkyl)-OH, saturated monocyclic _C3.8 cycloalkyl, saturated monocyclic _3-8 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl; wherein _each of said _{C3.8 cycloalkyl} , 3-8 membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, _C1-6 alkyl optionally substituted with one or more deuterium atoms, _C1-6 alkoxyl and _C1.6 haloalkyl;

Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -C^ _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C1-6 alkoxyl, and _C1.6 haloalkyl;

R2 is selected from halogen, -C^ _C1.6 alkyl, _C1-6 haloalkyl, saturated monocyclic _{C3.8 cycloalkyl} , phenyl or heteroaryl, wherein each of said saturated monocyclic _{C3.8 cycloalkyl} , phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -C^ _C1.6 alkyl, _C1-6 alkoxyl, _C1-6 haloalkyl and oxo;

_R3 , _R4 , R5, _R6 , _R7 and _R8 are independently selected from hydrogen, halogen, hydroxy, _C1-6 alkyl and _C1-6 alkoxy; wherein said _C1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy and _C1-6 alkoxy; or any two of _R3 , R4, R5, _R6 , _R7 and _R8 together with the carbon atom to which they are attached and Ring B form

- 38 047819

Rd is selected from hydrogen or halogen, t is 0, 1, 2 or 3;

R ₁₀ and Rn are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1.6 alkoxy, C _1-6 haloalkyl and -(C _1-6 alkyl)-OH;

m is 0, 1 or 2;

Ra and Rb are independently selected from hydrogen, halogen, hydroxy, or _C1.6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated _C3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein said 4-6 membered heterocyclyl is a saturated monocyclic ring containing 4-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon; wherein _{each of said saturated C3-6 cycloalkyl} or 4-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen;

L is absent, or L is NH, O, or S;

said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other.

Embodiment 33. A compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that

R ₁ is selected from _C1.6 alkyl, -( _C1.6 alkyl)-OH, saturated monocyclic _{C3.8 cycloalkyl} , saturated monocyclic 3-8-membered heterocyclyl containing 1 or _{2 ring heteroatoms independently selected from N, O and S, and heteroaryl; wherein each of said C3-8 cycloalkyl} , 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, _C1.6 alkoxyl, _C1.6 haloalkyl and _C1.6 alkyl optionally substituted with one or more deuterium atoms;

Ar is a heteroaryl, said heteroaryl being a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other; wherein said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C1.6 alkoxyl and _C1.6 haloalkyl;

R2 is selected from -CN, _C1.6 haloalkyl, saturated monocyclic _C3-8 cycloalkyl, phenyl or heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or ₆ ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other; wherein each of said saturated monocyclic _{C3.8 cycloalkyl} , phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1.6 alkyl and _C1.6 haloalkyl;

_R3 , R4, _R5 , R6, _R7 and R8 are independently selected from hydrogen, halogen, hydroxy, _C1.6 alkyl and _C1.6 alkoxy; wherein said _C1.6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy and _C1.6 alkoxy; or any two of _R3 , R4, _R5 , R6, _R7 and R8 together with the carbon atom to which they are attached and Ring B form

- 39 047819

Rd is selected from hydrogen and halogen, t is 0, 1, 2 or 3;

R ₁₀ and Rii are independently selected from hydrogen, halogen and C _1-6 alkyl; m is 0, 1 or 2;

R _a and R b are independently selected from hydrogen, halogen, hydroxy and C _1-6 alkyl; or R _a and R b together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl or 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic C _3-6 cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen;

L is absent, or L is NH or O.

Embodiment 34. A compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: (1) C _1-6 alkyl, (2) -(C _1-6 alkyl)-OH, (3) saturated monocyclic C _3-8 cycloalkyl which is optionally substituted with one or more substituents independently selected from halogen and C _1-6 alkoxy, (4) saturated monocyclic 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O, and S, and (5) heteroaryl selected from pyrazolyl, pyridyl, and isoxazolyl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 alkyl optionally substituted with one or more deuterium atoms.

Embodiment 35. A compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is a heteroaryl selected from pyridyl and pyrimidinyl; wherein each said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl and C _1-6 haloalkyl.

Embodiment 36. A compound of formula (I) according to embodiment 35, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and R ₂₄ are independently selected from hydrogen, halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxy and C _1-6 haloalkyl.

Embodiment 37. A compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from: (1) -CN, (2) C _1-6 haloalkyl, (3) saturated monocyclic C _3-8 cycloalkyl which is optionally substituted with one or more substituents selected from C _1-6 haloalkyl, (4) phenyl which is optionally substituted with one or more substituents independently selected from halogen and -CN, and (5) heteroaryl selected from 1,2,5-oxadiazolyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, pyrazolyl, indazolyl and pyrrolyl, wherein each said heteroaryl is optionally substituted one or more substituents independently selected from halogen, -CN and C _1-6 alkyl.

Embodiment 38. A compound of formula (I) according to embodiment 32 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from:

- 40 047819

Connection Structure

- 41 047819

- 42 047819

- 43 047819

- 44 047819

- 45 047819

- 46 047819

- 47 047819

- 48 047819

- 49 047819

- 50 047819

- 51 047819

- 52 047819

- 53 047819

Embodiment 39. A pharmaceutical composition comprising a compound according to any one of embodiments 1-38 or a pharmaceutically acceptable salt thereof and, optionally, a pharmaceutically acceptable carrier.

Embodiment 40. A method for inhibiting ERK activity in vivo or in vitro, comprising contacting an effective amount of a compound according to any of embodiments 1-38 or a pharmaceutically acceptable salt thereof with ERK.

Embodiment 41. Use of a compound according to any of embodiments 1-38 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a disease susceptible to ERK inhibition.

Embodiment 42. Use according to embodiment 41, characterized in that said medicinal product is used to treat cancer or an autoimmune disease.

Embodiment 43. The use according to embodiment 42, wherein said cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (such as non-small cell lung cancer), thyroid cancer (such as papillary thyroid cancer) or ovarian cancer.

Embodiment 44. A method for treating or preventing a disease responsive to ERK inhibition, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-38, or a pharmaceutically acceptable salt thereof.

Implementation option 45. Connection according to any of the implementation options 1-38 or its headlights

- 54 047819 a medically acceptable salt for use in the treatment or prevention of a disease responsive to ERK inhibition.

Embodiment 46. A compound according to any one of embodiments 1-38 or a pharmaceutically acceptable salt thereof for use as a medicine.

Embodiment 47. A compound according to embodiment 46 or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment or prevention of a disease responsive to ERK inhibition.

Embodiment 48. A compound according to embodiment 47 or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment or prevention of cancer or an autoimmune disease.

Embodiment 49. The compound of embodiment 48 or a pharmaceutically acceptable salt thereof, wherein said cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (such as non-small cell lung cancer), thyroid cancer (such as papillary thyroid cancer), or ovarian cancer.

Embodiment 50. A combination comprising a compound according to any one of embodiments 1-38 or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent.

Embodiment 51. The combination according to embodiment 50, characterized in that said additional therapeutic agent is an antineoplastic agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapeutic agent.

Implementation variant 52. Compound of formula (II):

or racemic mixtures or enantiomers thereof, wherein R ₉ is a leaving group; R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, and C _1-6 alkyl; R ₃ , R4, R5, R ₆ , R ₇ and R ₈ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; or any two of R ₃ , R4, R5, R ₆ , R ₇ and R8 together with the carbon atom to which they are attached and Ring B form

or

Rd is selected from hydrogen and halogen, t is 0, 1, 2, or 3; provided that if R ₁₀ and Rn are both hydrogen, then not all of R ₃ , R ₄ , R5, R ₆ , R ₇ , and R8 are hydrogen, and if one of R ₃ , R ₄ , R5, R ₆ , R ₇ , and R ₈ is methyl, then not all of the remaining substituents are hydrogen.

Embodiment 53. A compound of formula (II) according to embodiment 52, selected from:

- 55 047819

or racemic mixtures or enantiomers thereof, wherein R ₉ is a leaving group; R ₁₀ and R11 are independently selected from hydrogen, halogen and ^^alkyl;

_R3 , R4, R5 and _R6 are independently selected from hydrogen, halogen, C1.6 alkyl, C1.6 alkoxyl, C1.6 _haloalkyl or C1.6 alkyl optionally substituted with phenyl; or any pair of R3 and _R4 or R5 and _R6 together with the carbon atom to which they are attached form a saturated _{C3.6 cycloalkyl} or a saturated 3- to 4-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring; provided that not all of _R3 , _R4 , _R5 and _R6 are hydrogen, and if one or two of _R3 , _R4 , _R5 and _R6 are C1.6 alkyl then not all of the remaining substituents are hydrogen.

Embodiment 55. A compound of formula (III) according to embodiment 54, selected from:

General methods for synthesizing compounds.

The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be synthesized from commercially available starting materials by methods well known in the art and described in the patent application. The synthetic methods shown in the figure illustrate a general procedure for preparing the compounds described herein, wherein X is halogen;

Z1, Z, , L, R1, _R2 , _R3 , R4, R5, R6, _R7 , R8, Ra, Rb, m and n are as defined for the compound of formula (I) and subformulas (I-1), (I-2), (I-3); R ₉ is as defined for the compound of formula (II), (III).

As shown in the figure, three kinds of key chemical reactions are mainly used to synthesize these compounds: the incorporation of an amino substituent into the Ar ring, the addition reaction of the Ar ring fragment to the tricyclic system, and the formation of a triazole ring in the tricyclic system. Accordingly, the synthesis of the target compounds can be carried out with different priorities of these reactions depending on the practical situation. As shown in Method 1, some compounds can be obtained in the order in which the addition reaction is first ensured

- 56 047819 cation, then the amino is incorporated and finally the triazole is formed, for example as in Example 8; as shown in Method 2, some compounds can be prepared in the order in which the triazole is first synthesized to form a tricyclic moiety, then an addition reaction is carried out and finally the amino is incorporated, for example as in Examples 13 and 14; as shown in Method 3, some compounds can be prepared in the order in which the amino is first incorporated, then a coupling reaction is carried out and finally the triazole is formed, for example as in Examples 1 and 7; as shown in Method 4, some compounds can be prepared by a combination of Methods 2 and 3, in which the addition reaction is carried out at the very end, for example as in Example 12.

The compounds prepared by the above methods can be further modified at peripheral positions to give other target compounds. Synthetic chemical transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, eds., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions of these works.

Prior to use, the compound of formula (I) and/or its pharmaceutically acceptable salt described herein may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable means.

Pharmaceutical compositions and uses.

A composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof described herein can be administered by various known routes, such as orally, parenterally, by inhalation or implantation. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.

The oral composition may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, pills, powders, emulsions and aqueous suspensions, dispersions and solutions. Carriers commonly used in tablets include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added to tablets. Suitable diluents for oral administration in capsule form include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase using emulsifiers or suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added.

A sterile injectable composition (e.g., an aqueous or oily suspension) can be prepared according to methods known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable composition can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the pharmaceutically acceptable carriers and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils, for example, synthetic mono- or diglycerides, are conventionally used as a solvent or suspending medium. Fatty acids such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil (particularly in polyoxyethylated forms), are suitable for the preparation of an injection composition. Said oil solutions or suspensions may also contain a diluent or dispersing agent based on a long-chain alcohol or carboxymethylcellulose, or similar dispersing agents.

The inhalation composition may be prepared according to methods well known in the field of pharmaceutical formulations, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and/or other solubility enhancing or dispersing agents known in the art, and may also be prepared as a solution in saline.

The topical composition may be prepared in the form of an oil, cream, lotion, ointment, etc. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched fats or oils, animal fats and high molecular weight alcohols (namely, alcohols in which the number of carbon atoms is greater than 12). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. If desired, the composition may contain emulsifiers, stabilizers, wetting agents and antioxidants, as well as agents imparting color or flavor. In addition, skin penetration enhancers can be added to the topical formulations. Examples of such penetration enhancers can be found in U.S. Patents 3,989,816 and 4,444,762.

- 57 047819

Creams can be prepared from a mixture of mineral oil, self-emulsifying beeswax and water, to which is added a mixture of the active ingredient dissolved in a small amount of oil, such as almond oil. One example of said cream includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments can be prepared by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with heated soft paraffin and allowing the mixture to cool. One example of said ointment includes about 30% by weight almond oil and about 70% by weight white soft paraffin.

A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient of the composition (in some embodiments, can stabilize the active ingredient) and is not deleterious to the subject being treated. For example, solubility enhancing agents such as cyclodextrins (which can form a specific complex with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein with increased solubility) can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.

Suitable in vitro assays can be used to preliminarily evaluate the efficacy of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein in inhibiting ERK activity.

For example, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be contacted with an ERK kinase or a cell and the level of inhibition of ERK activity can be determined. In addition, the effectiveness of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein in treating or preventing cancer or an autoimmune disease can be further evaluated in in vivo studies. For example, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be administered to an animal (e.g., in a mouse model) suffering from cancer or an autoimmune disease and the therapeutic effect can be evaluated. Based on the results obtained, an appropriate dosage range and route of administration for animals such as humans can also be determined.

The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be used to provide a beneficial therapeutic or prophylactic effect, for example, in subjects suffering from cancer.

As used herein, the term cancer refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to form new growth centers at other sites. The term cancer includes, but is not limited to, solid tumors and hematological malignancies. The term cancer includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term cancer further includes primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchoalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, advanced epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid cancer, such as papillary thyroid cancer.

Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and blast phase CML (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndrome.

The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be used to provide beneficial therapeutic or prophylactic

- 58 047819 therapeutic action, for example, in subjects with an autoimmune disease.

The term autoimmune disease refers to a disease or condition that results from damage to an individual's tissues or organs caused by the body's immune response to self-antigens. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), asthma, idiopathic thrombocytopenic purpura, and myeloproliferative disease such as myelofibrosis, myelofibrosis following polycythemia vera/essential thrombocythemia (post-PV/ET myelofibrosis).

In addition, a compound of formula (I) (e.g., a compound of subformula (I-1), (I-2), or (I-3) and compounds 1-321) and/or a pharmaceutically acceptable salt thereof described herein can be used in combination with additional therapeutic agents for the treatment of cancer. The additional therapeutic agents can be administered separately from a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein, or can be co-formulated with a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein in a pharmaceutical composition of the invention, such as a fixed dose combination drug product. In some embodiments, the additional therapeutic agents are agents known or shown to be effective in the treatment of ERK-mediated diseases, such as another ERK inhibitor or a compound that is an antagonist of another target associated with said particular disease. The combination may be used to enhance efficacy (e.g., by including in the combination a compound that enhances the activity or efficacy of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), reduce one or more side effects, or reduce the required dose of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein.

In some embodiments, a compound of formula (I) (e.g., a compound of subformula (I-1), (I-2), or (I-3) and compounds 1-321) and/or a pharmaceutically acceptable salt thereof described herein is administered in combination with an antineoplastic agent. As used herein, the term antineoplastic agent refers to any agent that is administered to a subject suffering from cancer to treat the cancer. Antineoplastic agents include, but are not limited to: radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents.

Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and their analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical releasing agents such as bleomycin; nucleoside mimetics (eg, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine (VAIDAZA®), mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogues; vincristine, vinblastine, and related analogues; thalidomide and related analogues (eg, CC-5013 and CC-4047).

Non-limiting examples of immunotherapeutic agents or targeted therapeutic agents include MEK inhibitors, RAF inhibitors, mTOR inhibitors, PAK inhibitors, CDK inhibitors, VEGFR inhibitors, PARP inhibitors, ERBB inhibitors, PI3K inhibitors, AKT inhibitors, autophagy inhibitors, immune checkpoint inhibitors such as PD-1 inhibitors, PD-L1 inhibitors, etc., such as trametinib, cobimetinib, vemurafenib, dabrafenib, rapamycin, temsirolimus, everolimus, palbociclib, ribociclib, fruquintinib, olaparib, niraparib, neratinib, chloroquine, hydroxychloroquine, LXH254, selumetinib, LY3214996, abemaciclib, P1446A-05 (voruciclib), LGX818 (encorafenib), ARRY-162 (binimetinib), cetuximab, gefitinib, panitumumab, BYL719 (alpelisib), bevacizumab, pembrolizumab, atezolizumab, PDR001 (spartalizumab), durvalumab, nivolumab, avelumab, libtayo (cemipilimab), tislelizumab, toripalimab (JS001), sintilimab, camrelizumab, etc.

Examples

The following examples are intended solely to illustrate the invention and should not be construed as limiting it in any way. While attempts have been made to ensure accuracy in terms of the numerical parameters used (e.g., quantities, temperatures, etc.), some experimental errors and deviations should still be taken into account.

Unless otherwise stated, parts are given as mass fractions, temperatures are given in degrees Celsius, and pressures are equal to or approximately equal to atmospheric pressure. All MS (mass spectrometry) data were obtained

- 59 047819 on an Agilent 6120 and/or Agilent 1100. ¹ H NMR spectra were acquired on a nuclear magnetic resonance spectrometer operating at 400 MHz. NMR spectra were acquired in CDCl3 solutions (given in ppm) using chloroform as a reference standard (7.26 ppm) or using tetramethylsilane (0.00 ppm) as an internal standard where appropriate. Other NMR solvents were used when necessary. The following abbreviations have been used to report peak multiplicities: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Spin–spin coupling constants, when given, are reported in hertz (Hz).

All reagents, except intermediates, used in the present invention are commercially available.

The names of all compounds, except for the reagents, were obtained from Chemdraw. If there is any discrepancy between the structure and the name of a compound provided herein, the structure is preferred unless it is clear from the context that the structure is incorrect and the name is correct.

If any atom described in this document has empty valences, the empty valences correspond to hydrogen atoms, which are not listed for convenience.

The following examples use the following abbreviations:

Vos tert-butyloxycarbonyl

BPIN bis(pinacolato)dibor

CDI Α,Α'-carbonyldiimidazole

DCM dichloromethane

DIAD diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DIPEA А'А'-diisopropylethylamine

DMF L'A'-dimethylformamide

EA ethyl acetate

EDCI hydrochloride 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide a

Et ethyl h hour(s)

HATU hexafluorophosphate O-(7-azabenzotriazol-1-yl)-A,A,A ^, ,Atetramethyluronium

NOVT 1-hydroxybenzotriazole

ISCO Chromatographic System TELEDYNE ISCO CombiFlash RF+

LDA lithium diisopropylamide

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min minute(s) MeOH methanol Ms methanesulfonyl NBS TV-bromosuccinimide NaHMDS sodium bis(trimethylsilyl)amide PE petroleum ether _PdCl2 ( _PPh3 ) ₂ bis(triphenylphosphine)palladium(II) dichloride Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium (0)

_Pd ( _dppf ) _Cl2CH2Cl2 complex of 1,G-bis(diphenylphosphino)ferrocene palladium (II) dichloride with dichloromethane Pd(OAc) ₂ palladium(II) acetate Pd( _PPh3 ) ₄ tetrakis(triphenylphosphine)palladium (0) RMV para-methoxybenzyl _PPh3 triphenylphosphine pTLX preparative thin layer chromatography SEM 2-(trimethylsilyl)ethoxymethyl THF tetrahydrofuran TBDPS 77?p<?77?-butyldiphenylsilyl

TFA trifluoroacetic acid

Ts p-toluene sulfonyl

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Intermediate connection 1.

4-χΛορ-Ν-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine.

- 61 047819 (A) 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine.

To a solution of (4-methoxyphenyl)methanol (40.8 g, 295.3 mmol) in THF (200 mL) was added NaH (16.1 g, 402.5 mmol, 60% dispersion in liquid paraffin) in portions at 0 °C. The mixture was stirred for 30 min at the indicated temperature under nitrogen atmosphere. Then the mixture was slowly added to a solution of 2,4-dichloropyrimidine (40.0 g, 268.5 mmol) in THF (200 mL) at 0 °C. After complete addition, the mixture was stirred overnight at room temperature. The reaction was quenched with ice water (200 mL). The mixture was separated and the aqueous layer was extracted with THF (200 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give an off-white solid (73.0 g), which was used directly in the next step.

(B) 4-((4-methoxybenzyl)oxy)-N-(1-methyl-N-pyrazol-5-yl)pyrimidin-2-amine.

To a solution of 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine (73.0 g, which was prepared in the previous step) and 1-methyl-III-pyrazol-5-amine (56.6 g, 582.4 mmol) in 1,4-dioxane (730 mL) were added Pd(OAc)2 (3.27 g, 14.6 mmol), Xantphos (16.8 g, 29.1 mmol) and KOAc (85.7 g, 873.6 mmol). The mixture was purged and then stirred overnight at 90 °C under nitrogen. After cooling, the mixture was filtered and the filter cake was washed with EA (200 mL). The combined filtrates were washed with brine. After separation, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified on an ISCO system (eluted with methanol in water 0%~100%) to give a yellowish solid (38.5 g, 42.4% yield). MS (m/z): 312.1 (M+H) ⁺ .

(C) 4-chloro-N-(1-methyl-N-pyrazol-5-yl)pyrimidin-2-amine.

To a three-neck round-bottomed flask were added 4-((4-methoxybenzyl)oxy)-N-(1-methyl-1H-pyrazol-5yl)pyrimidin-2-amine (38.5 g, 123.7 mmol) and TFA (150 mL). The mixture was then stirred for 3 h at room temperature. The mixture was then concentrated to give a brown solid, which was suspended in POCl ₃ (150 mL). The mixture was stirred for 3 h at 100 °C and then concentrated. The residue was poured into ice water, adjusted to pH = 8~9 with saturated NaHCO ₃ solution. The mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid (23.3 g, yield 89.6%).

MS (m/z): 210.0 (M+H) ⁺ .

The following intermediate compound was prepared according to the method for preparing intermediate compound 1 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MS (m/z) (M+H) ⁺ 2 / [1 I o ' 224,0

Intermediate connection 3.

5-chloro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine.

(A) 5-chloro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine.

To a solution of 1-methyl-III-pyrazol-5-amine (39.4 g, 406 mmol) in anhydrous THF (1500 mL) was added NaHMDS (406 mL, 406 mmol, 1 M in THF) at 0 °C under nitrogen atmosphere and the solution was stirred for 30 min. Then 5-chloro-2-fluoro-4-iodopyridine (87 g, 338 mmol) was added and the resulting mixture was refluxed overnight. The reaction was quenched with methanol/water (40 mL, 1:1) and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=1:1) and ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a light yellow solid (39.8 g, yield 35%). MS (m/z): 334.9 (M+H) ⁺ .

The following intermediate compound was prepared according to the method for preparing intermediate compound 3 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

- 62 047819

Intermediate connection Structure MS (m/z) (M+H) ⁺ 4 / 314.9

Intermediate connection 5.

5-fluoro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine.

(A) N(1-methyl-III-pyrazol-5-yl)acetamide.

To a solution of 1-methyl-1H-pyrazol-5-amine (87 g, 90 mmol) and acetic anhydride (101 g, 99 mmol) in EA (1000 mL) was added NaOAc (81 g, 99 mmol) at room temperature. The mixture was stirred at room temperature overnight. Then the mixture was filtered and the precipitate was washed with EA. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (DCM:MeOH = 25:1) to give the title compound as a light yellow solid (98 g, yield 78%). MS (m/z): 140.1 (M+H)+.

(B) 5-fluoro-4-iodo-N-(1-methyl-III-pyrazol-5-yl)pyridin-2-amine.

To a solution of N-(1-methyl-N-pyrazol-5-yl)acetamide (53 g, 380 mmol) in anhydrous THF/DMF (800 mL, 7:1) was added NaHMDS (354 mL, 354 mmol, 1 M in THF) at 0 °C under nitrogen atmosphere and the solution was stirred at room temperature for 30 min. Then 2,5-difluoro-4-iodopyridine (61 g, 253 mmol) was added and the solution was heated to reflux. The reaction was quenched with methanol/water (200 mL, 1:1) and concentrated in vacuo. The residue was dissolved in methanol/water (200 mL, 1:1). Lithium hydroxide monohydrate (11 g, 253 mmol) was added and the solution was stirred at room temperature for 1 h. The solvent was removed on a rotary evaporator and the residue was purified by silica gel chromatography (PE:EA=1:1) and ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a pink solid (30 g, yield 37.5%). MS (m/z): 319.0 (M+H) ⁺ .

Intermediate connection 6.

4-iodo-N-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridin-2-amine.

(A) 2-bromo-4-iodo-5-(trifluoromethyl)pyridine.

To a solution of diisopropylamine (3.1 g, 30 mmol) in anhydrous THF (150 mL) was added n-butyllithium (12.5 mL, 30 mmol, 2.4 mol/L in THF) at -70 °C under nitrogen atmosphere. The solution was stirred at -10 °C for 30 min. The solution was cooled again to -70 °C and 2-bromo-5-(trifluoromethyl)pyridine (5.6 g, 25 mmol) was added. The resulting dark brown solution was stirred for 2 h at -70 °C. Iodine (6.4 g, 25 mmol) was added portionwise and the solution was stirred for another 1 h. The reaction was quenched with 10% HOAc (50 mL) and a saturated solution of sodium thiosulfate. The mixture was extracted with EA. The organic phases were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 50:1) to give the title compound as a yellow solid (6.1 g, 69% yield). MS (m/z): 351.7, 353.7 (M+H) ⁺ .

(B) 4-iodo-N-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridin-2-amine.

To a solution of N(1-methyl-N-pyrazol-5-yl)acetamide (1.1 g, 4 mmol) in anhydrous THF (50 mL) was added sodium hydride (320 mg, 8 mmol, 60% dispersion in liquid paraffin) in portions at room temperature under nitrogen. The mixture was stirred for 30 min. 2-Bromo-4-iodo-5(trifluoromethyl)pyridine (556 mg, 4 mmol) was added and the mixture was refluxed overnight. The reaction was quenched with methanol. The solvent was removed on a rotary evaporator and the residue was purified by ISCO (eluted with methanol in water 0%~100%) and silica gel chromatography (DCM:MeOH=25:1) to afford the title compound as a brown viscous substance (640 mg, yield 44%). MS (m/z): 368.9 (M+H) ⁺ .

- 63 047819

The following intermediate compound was prepared according to the method for preparing intermediate compound 6 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MS (m/z) (M+H) ⁺ 7 / z 326,0

Intermediate connection 8.

№Cyclopropyl-4-iodo-5-(trifluoromethyl)pyridin-2-amine.

(A) N-cyclopropyl-4-iodo-5-(trifluoromethyl)pyridin-2-amine.

To a solution of 2-bromo-4-iodo-5-(trifluoromethyl)pyridine (352 mg, 1 mmol) and cyclopropanamine (114 mg, 2 mmol) in anhydrous THF (10 mL) was added DIPEA (390 mg, 3 mmol). The solution was heated under reflux overnight. The solvent was removed on a rotary evaporator and the residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (184 mg, 56% yield). MS (m/z): 328.9 (M+H)+.

The following intermediate compounds were prepared according to the method for preparing intermediate compound 8 using the appropriate intermediate compounds and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection 11.

5-ethyl-4-iodo-N(1-methyl-III-pyrazol-5-yl)pyridin-2-amine.

(A) 5-ethyl-2-fluoropyridine.

To a solution of 5-bromo-2-fluoropyridine (5.5 g, 31.3 mmol) and triethylborane (1 M) (62.6 mL, 62.6 mmol) in DMF (30 mL) were added K2CO3 (12.9 g, 94 mmol) and Pd( _PPh3 ) ₄ (1.8 g, 1.6 mmol). The mixture was degassed and stirred under nitrogen at 80 °C overnight, diluted with water, extracted with hexane, washed with water and brine, dried over _{anhydrous Na2SO4} , concentrated and purified by ISCO system (eluted with DCM in PE 0%~100%) to give the title compound as a yellow liquid (3 g, 77% yield). MS (m/z): 126.0 (M+H) ⁺ .

(B) 5-ethyl-2-fluoro-3-iodopyridine.

To a solution of 5-ethyl-2-fluoropyridine (1 g, 8 mmol) in THF (20 mL) was added dropwise LDA (6 mL, 12 mmol, 2 M in THF) under nitrogen at -78 °C. After stirring at -78 °C for 1 h, iodine (3 g, 12 mmol) was added. The mixture was stirred under nitrogen at -78 °C for 2 h, quenched with HOAc and aqueous Na ₂ SO ₃ , and extracted with EA. The organic layer was washed with water and brine.

- 64 047819 solution, dried over anhydrous Na2SO4, concentrated and purified in ISCO system (eluted with EA in PE 0%~100%) to obtain the title compound as a yellow oily substance (1.1 g, yield 55%). MS (m/z): 251.9 (M+H)+.

(C) 5-ethyl-2-fluoro-4-iodopyridine.

To a solution of 5-ethyl-2-fluoro-3-iodopyridine (1.1 g, 4.4 mmol) in THF (20 mL) was added dropwise LDA (3.3 mL, 6.6 mmol, 2 M in THF) under nitrogen atmosphere at -78 °C. The mixture was stirred under nitrogen atmosphere at 78 °C for 2 h, quenched with saturated ammonium chloride solution, and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by ISCO system (eluted with EA in PE 0%~100%) to give the title compound as a yellow oily substance (860 mg, yield 78%).

(D) 5-ethyl-4-iodo-Y-(1-methyl-N-pyrazol-5-yl)pyridin-2-amine.

To a solution of 1-methyl-III-pyrazol-5-amine (648 mg, 6.6 mmol) in THF (40 mL) was added NaHMDS (6.6 mL, 6.6 mmol, 1 M in THF) under nitrogen atmosphere. After stirring at room temperature for 1 h, 5-ethyl-2-fluoro-4-iodopyridine (830 mg, 3.3 mmol) was added. The mixture was heated at reflux overnight, quenched with water and MeOH, concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (100 mg, 9% yield). MS (m/z): 328.9 (M+H) ⁺ .

Intermediate connection 12.

2-bromo-4-iodo-5-methoxypyridine.

(A) 2-bromo-5-methoxypyridine.

To a solution of 6-bromopyridin-3-ol (1.7 g, 10 mmol) in anhydrous DMF (20 mL) was added NaH (600 mg, 15 mmol, 60% dispersion in liquid paraffin) portionwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min. Iodomethane (2.1 g, 15 mmol) was added, and then the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with EA. The organic phases were combined and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EA = 5:1) to give the title compound as a yellow solid (1.7 g, yield 91%). MS (m/z): 188.0, 190.0 (M+H) ⁺ .

(B) 2-bromo-4-iodo-5-methoxypyridine.

To a solution of 2-bromo-5-methoxypyridine (1.5 g, 8 mmol) in anhydrous THF (50 mL) was added LDA (4 mL, 8 mmol, 2 M in THF) at -70 °C under nitrogen atmosphere. The solution was stirred at -70 °C for 2 h. Iodine (2.1 g, 8 mmol) was added portionwise and the solution was stirred for an additional 1 h. The reaction was quenched with 10% HOAc and saturated sodium thiosulfate solution. The mixture was extracted with DCM. The organic phases were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 5:1) to give the title compound as a light yellow solid (900 mg, 39% yield). MS (m/z): 313.8, 315.8 (M+H) ⁺ .

Intermediate connection 13.

8-bromo-2,3,4,5-tetrahydro-1 H-pyrrolo[1,2-a][1,4]diazepin-1-one.

(A) methyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-III-pyrrole-2-carboxylate.

K2CO3 (169 g, 1.23 mol) was added to a mixture of methyl 4-bromo-3-pyrrole-2-carboxylate (100 g, 0.49 mol) and tert-butyl (3-bromopropyl)carbamate (122 g, 0.51 mol) in DMF (500 ml).

The mixture was stirred at room temperature overnight. The K2CO3 was then filtered off and the filtrate was diluted with water and extracted with EA. The organic layer was washed with brine, dried over _{anhydrous Na2SO4} , and concentrated to give the title compound as a yellow solid (166 g, 93.9% yield). MS (m/z): 261.0, 263.0 (M+H) ⁺ .

(B) methyl 1-(3-aminopropyl)-4-bromo-1-(pyrrole-carboxylate).

A mixture of methyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-1-(pyrrole-2-carboxylate) (166 g, 0.46 mol) and TFA (200 mL) was heated at 60 °C for 3 h. The mixture was concentrated and the residue was partitioned between saturated NaHCO ₃ and EA. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to give the title compound as a yellow solid (114.37 g, 95.2% yield). MS (m/z): 261.0, 263.0 (M+H) ⁺ .

(C) 8-bromo-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

K ₂ CO ₃ (151 g, 1.10 mol) was added to a mixture of methyl 1-(3-aminopropyl)-4-bromo-III-pyrrole-2-carboxylate (114 g, 0.44 mol) in MeOH (800 ml). The mixture was stirred at 80°C for 3 h. Then,

- 65 047819 was filtered with K2CO3 and the filtrate was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and recrystallized to give the title compound as a white solid (70.0 g, 69.9% yield). MS (m/z): 228.9/230.9 (M+H)+.

Intermediate connection 14.

8-bromo-9-chloro-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

(A) methyl 4-bromo-3-chloro-1H-pyrrole-2-carboxylate.

To a mixture of methyl 3-chloro-N-pyrrole-2-carboxylate (10 g, 62.7 mmol) in DMF (400 mL) was added dropwise _Br2 (3.2 mL, 62.7 mmol) at room temperature. The mixture was stirred at room temperature for 8 h. Then the mixture was diluted with water (2.0 L) and extracted with EA (3 x 1.5 L). The organic layer was concentrated and the residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to afford the title compound as a yellow solid (7.0 g, 46.9% yield). MS (m/z): 237.8, 239.8 (M+H) ⁺ .

(B) methyl 4-bromo-1-(3-bromopropyl)-3-chloro-1-(pyrrole-carboxylate).

A mixture of methyl 4-bromo-3-chloro-1H-pyrrole-2-carboxylate (6 g, 25.2 mmol), 1,3-dibromopropane (50.9 g, 252 mmol) and K2CO3 (7.0 g, 50.4 mmol) was heated in CH3CN (150 mL) at 70 °C for 3 h. The reaction mixture was concentrated and partitioned between water (200 mL) and EA (200 mL). The aqueous layer was further extracted with EA (2 x 200 mL). The combined organic layers were concentrated and purified by ISCO purification (eluted with methanol in water 0%~100%) to give the title compound as a white solid (4.2 g, 46.3% yield). MS (m/z): 359.8 (M+H) ⁺ .

(C) 8-bromo-9-chloro-2,3,4,5-tetrahydro-1 H-pyrrolo[2-a][1,4]diazepin-1-one.

A mixture of methyl 4-bromo-1-(3-bromopropyl)-3-chloro-1H-pyrrole-2-carboxylate (500 mg, 1.39 mmol) in ammonium hydroxide (6 mL) and MeOH (10 mL) was heated at 120 °C for 3 h under microwave irradiation. The reaction mixture was concentrated and washed with EA (1 mL) to give the crude title compound as a white solid (500 mg, used directly in the next step). MS (m/z): 262.9, 264.9 (M+H) ⁺ .

The following intermediate compound was prepared according to the method for preparing intermediate compound 14 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MS (m/z) (M+H) ⁺ 15 -ъ5 ⁿ 242.9/244.9

Intermediate connection 16.

8-bromo-9-fluoro-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

(A) Ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-1 H-pyrrole-2-carboxylate.

A mixture of ethyl 3-fluoro-3-pyrrole-2-carboxylate (3.14 g, 20 mmol), tert-butyl (3-bromopropyl)carbamate (7.14 g, 30 mmol) and _Cs2CO3 (9.75 g, 30 mmol) was heated in DMF (20 mL) at 80 _° C overnight. After cooling to room temperature, the mixture was extracted with EA. The organic phase was washed with water and brine, concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (6.28 g). MS (m/z): 315.1 (M+H) ⁺ .

(B) Ethyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-III-pyrrole-2-carboxylate.

To a solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-III-pyrrole-2-carboxylate (6.28 g, 20 mmol) in DMF (15 mL) was added NBS (3.56 g, 20 mL) portionwise at room temperature. The mixture was stirred for 4 h, quenched with aqueous Na ₂ SO ₃ , extracted with EA, and concentrated to give the crude title compound. MS (m/z): 414.9, 416.9 (M+23) ⁺ .

(C) 8-bromo-9-fluoro-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

Concentrated hydrochloric acid was added to a solution of ethyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-III-pyrrole-2-carboxylate (6.1 g, 15.5 mmol) in methanol (10 ml).

- 66 047819 acid (3 mL) and stirred at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was adjusted to pH 8 with aqueous NaHCO ₃ and extracted with DCM. The organic phase was concentrated and the residue was dissolved in MeOH (25 mL) and K2CO3 (6.42 g, 46.5 mmol) was added. The mixture was stirred at 80 °C for 48 h. Then K2CO3 was filtered off and the filtrate was concentrated. The residue was purified in an ISCO system (eluted with EA in PE 50%~100%) to afford the title compound as a white solid (3 g, yield 78.7%). MS (m/z): 247.0, 249.0 (M+H)+.

Intermediate connection 17.

7-bromo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.

(A) Methyl 4-bromo-1-(cyanomethyl)-1-pyrrole-carboxylate.

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (4 g, 19.6 mmol) in DMF (15 mL) was added K2CO3 (5.4 g, 39.2 mmol) and 2-bromoacetonitrile (2.4 g, 19.6 mmol). The mixture was stirred at 80 °C for 3 h, poured into water and extracted with EA. The organic phase was washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound as a yellow solid (5.1 g). MS (m/z): 243.0/245.0 (M+H) ⁺ .

(B) Methyl 1-(2-aminoethyl)-4-bromo-III-pyrrole-2-carboxylate.

To a solution _of methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate (5.1 g, 19.6 mmol) in THF (20 mL) was added dropwise _BH3Me2S (10 mL, 19.6 mmol, 2 M in THF) at room temperature. The mixture was then stirred at 60 °C overnight, quenched with cold aqueous _NaHCO3 at 0 °C, and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous _{Na2SO4 ,} and concentrated to give the title compound as a yellow solid (4.5 g, 93% yield). MS (m/z): 246.9/248.9 (M+H) ⁺ .

(C) 7-bromo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.

Ammonium hydroxide (3 mL) was added to a solution of methyl 1-(2-aminoethyl)-4-bromo-1H-pyrrole-2-carboxylate (4.5 g, 18.2 mmol) in MeOH (20 mL). The mixture was stirred at room temperature overnight, concentrated and purified by ISCO purification (eluted with MeOH in DCM 0%~15%) to give the title compound as a brown solid (3.2 g, 82% yield). MS (m/z): 214.9/216.9 (M+H) ⁺ .

Intermediate connection 18.

8'-bromo-2',3'-dihydro-1 Ή,5Ή-spiro[cyclopropane-1,4'-pyrrolo[1,2-a] [1,4]diazepine]-1'-one.

(A) tert-butyl-((1-(hydroxymethyl)cyclopropyl)methyl)carbamate.

To a solution of (1-(aminomethyl)cyclopropyl)methanol (5 g, 49.5 mmol) in DCM (40 mL) were added Boc ₂ O (10.8 g, 49.5 mmol) and DIPEA (12.8 g, 99 mmol). The mixture was stirred at room temperature for 2 h, concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (9.4 g, yield 94%).

(B) Methyl 4-bromo-1-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-1H-pyrrole-2carboxylate.

To a solution of tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (4.9 g, 24.5 mmol), methyl 4-bromo-1H-pyrrole-2-carboxylate (5 g, 24.5 mmol) and _PPh3 (9.6 g, 36.8 mmol) in THF (20 mL) was added dropwise DIAD (7.4 g, 36.8 mmol) under nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature overnight, concentrated and purified by ISCO system (eluted with EA in PE 0%~100%) to give the title compound as a yellow oily substance (9.2 g, crude).

(C) 8'-bromo-2',3'-dihydro-1H,5Ή-spiro[cyclopropan-1,4'-pyrrolo[1,2-a][1,4]diazepin]-1'-one.

A mixture of methyl 4-bromo-1-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-1H-pyrrole-2-carboxylate (9.2 g, 23.8 mmol) in TFA (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (30 mL), and K2CO3 (9.8 g, 71.3 mmol) and _Et3N (7.2 g, 71.3 mmol) were added. The mixture was stirred at room temperature overnight, concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (4.5 g, 74% yield). MS (m/z): 255.0/257.0 (M+H) ⁺ .

The following intermediate compounds were prepared according to the method for preparing intermediate compound 18 using appropriate intermediate compounds and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MC (m/z) (M+H) ⁺ 19 O NH Br—4 1 ,„.ι 229.0/231.0 20 O /====^ ^4, NH 228.9/230.9 21 o /^C^NH Br—C 1 I 229.0/231.0 22 O /=^GMN Br—6. 1 I 229.0/231.0 23 O /==s<^NH Bg—C I _/Q1 | 243.0/245.0 24 O Br^/^V^NH pj 243.0/245.0 25 O Br^f^NH v— N 243.0/245.0 26 About ^Br 4V ^NH VN^ 242.9/244.9 27 0 Br^/^p^NH 243.0/245.0

- 68 047819

28 O V-N ) \ (R)/ F 247.0/249.0 29 O ^Br - v _N '; \ (S)/ ъ F 246.9/248.9 30 O Vg— 255.0/257.0 31 O ^Br '^'^/ ^<4NH V— N \nirn 255.0/257.0 32 about ^Bg —A^ ^NH Vn^ 257.0/259.0 33 O Vg— V-N\ 257.0/259.0 34 o Bg—<V^ ^NH VN ) F ^F 264.9/266.9 35 O Vg— V-N \ 270.9/272.9 36 ABOUT 304.9/306.9

Intermediate connection 37.

^)-8-bromo-4-methoxy-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

(A) ^)-8-bromo-4-hydroxy-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

_Cs2CO3 (115.0 g, 0.352 mol) was added to a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (60.0 g, 0.294 mol) and ((3)-2-(chloromethyl)oxirane (68.0 g, 0.735 mol) in _EtOH (600 mL). After stirring,

- 69 047819 After heating at 80°C for 2 h, the mixture was diluted with water and extracted with EA. The organic layer was concentrated, the residue was dissolved in EtOH (1000 mL), and ammonium hydroxide (100 mL, 25~28 wt% solution in water) was added. The mixture was stirred at 80°C for 16 h. The mixture was concentrated and the residue was recrystallized (EA and EtOH) to give the title compound as a white solid (25 g, 34.7% yield over two steps). MS (m/z): 245.1/247.1 (M+H)+.

(B) ^)-8-bromo-4-methoxy-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

To a solution of ((3)-8-bromo-4-hydroxy-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepin-1-one (20.0 g, 0.082 mol) in DCM (300 mL) was added CF ₃ SO ₃ Me (20.0 g, 0.122 mol). After stirring at 40 °C for 16 h, the mixture was concentrated. The residue was dissolved in DMF (250 mL) and cooled to 0 °C. NaH (10.0 g, 0.255 mol, 60% dispersion in liquid paraffin) was added at 0 °C and the mixture was stirred at 0 °C for 30 min, after which iodomethane (24.0 g, 0.17 mol) was added. After stirring at room temperature for 3 h, the mixture was diluted with water and extracted with EA. The organic layer was washed with brine and water and concentrated to give a yellow oily substance, which was dissolved in MeOH (300 mL). Concentrated hydrochloric acid (60 mL) was added and the mixture was stirred at 60 °C for 3 h. The mixture was concentrated and redissolved in MeOH (400 mL). K2CO3 (40.0 g, 0.289 mol) was added and the mixture was stirred at 60 °C for 4 h. The mixture was filtered through celite. The filtrate was concentrated and the residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a white solid (10.0 g, yield 47.7% over four steps). MS (m/z): 259.0/261.0 (M+H) ⁺ .

Intermediate connection 38.

8'-bromo-2',3'-dihydro-1 Ή,5Ή-spiro[cyclobutan-1,4'-pyrrolo[1,2-a] [1,4]diazepin]-1'-one.

ABOUT

(A) cyclobutane-1,1-diyldimethanol.

To a suspension of LiAlH4 (2.3 g, 60 mmol) in THF (30 mL) was added dropwise diethyl cyclobutane-1,1-dicarboxylate (8 g, 40 mmol) in THF (40 mL) under nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature overnight, poured into water, adjusted to pH = 3 with 2 N HCl, extracted with EA, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a yellow oily substance (2.9 g, yield 63%). MS (m/z): 117.1 (M+H) ⁺ .

(B) 1,1-bis(4-methylsulfonyloxymethyl)cyclobutane.

To a solution of cyclobutane-1,1-diyldimethanol (2.9 g, 25 mmol) in DCM (30 mL) was added TsCl (10.5 g, 55 mmol) and Et3N (7.6 g, 75 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h, poured into water, extracted with DCM, washed with water and _brine , dried over anhydrous _Na2SO4 , concentrated and purified by ISCO system (eluted with EA in PE 0%~100%) to give the title compound as a white solid (3.5 g, yield 33%).

(C) 8'-bromo-2',3'-dihydro-1 Ή,5Ή-spiro[cyclobutan-1,4'-pyrrolo[1,2-a] [ 1,4]diazepine]-1 '-one.

To a solution of methyl 4-bromo-III-pyrrole-2-carboxylate (1.7 g, 8.2 mmol) in DMF (10 mL) were added K ₂ CO ₃ (3.4 g, 24.7 mmol) and 1,1-bis(4-methylsulfonyloxymethyl)cyclobutane (3.5 g, 8.2 mmol). The mixture was stirred at 100 °C for 5 h, poured into water, and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting yellow oily substance was dissolved in DMF (10 mL) and NaN ₃ (1.1 g, 16.4 mmol) was added. The mixture was stirred at 100 °C overnight, poured into water and extracted with EA. The organic layer was washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was dissolved in EA (30 mL) and _PPh3 (2.2 g, 8.2 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in MeOH (3 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was refluxed for 3 h, concentrated and redissolved in MeOH (10 mL). K2CO3 (3.4 g, 24.7 mmol) and _Et3N (4.2 g, 41.1 mmol) were added. The mixture was heated at reflux overnight, concentrated and purified on an ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (1.2 g, 54.1% yield). MS (m/z): 269.0/271.0 (M+H) ⁺ .

- 70 047819

Intermediate connection 39.

^)-7-bromo-3-(fluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.

(A) Ethyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)^-serinate.

To a solution of ethyl 1-serinate hydrochloride (8.0 g, 47.2 mmol) and Et ₃ N (9.5 g, 94.3 mmol) in DCM (80 mL) was added (Boc) ₂ O (20.6 g, 94.3 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were concentrated and redissolved in DCM (100 mL). N-imidazole (4.7 g, 68.6 mmol) and TBDPSCl (8.3 g, 30.2 mmol) were added at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were concentrated and the residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as an oily substance (5.8 g, yield 26.1%). MS (m/z): 372.1 (M+H-100)+.

(B) tert-butyl-^)-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate.

To a solution of ethyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-N-serinate (5.4 g, 11.4 mmol) in DCM (40 mL) was slowly added DIBAL-H (22.9 mL, 22.9 mmol, 1 M in hexanes) at -78 °C. The mixture was stirred at -78 °C for 30 min and then at room temperature overnight. The reaction mixture was cooled to 0 °C and quenched with 1 mL of water, 1 mL of 15% NaOH solution, and 3 mL of water. The mixture was stirred at room temperature for 15 min, filtered, and the precipitate was washed with DCM (100 mL). The combined filtrates were concentrated and purified on an ISCO system (eluted with EA in PE 0%~100%) to give the title compound as an oily substance (3.1 g, yield 63.3%). MS (m/z): 330.1 (M+H-100) ⁺ .

(C) Methyl (^)-4-bromo-1-(2-((tert-butoxycarbonyl)amino)-3-((tert-butyldiphenylsilyl)oxy)propyl)-111-11pyrrole-2-carboxylate.

To a solution of tert-butyl ((D))-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (2.5 g, 5.8 mmol), methyl 4-bromo-(III)-pyrrole-2-carboxylate (1.2 g, 5.8 mmol), and _PPh3 (2.3 g, 8.7 mmol) in anhydrous THF (100 mL) was slowly added DIAD (1.8 g, 8.7 mmol) at 0 °C. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and partitioned between water (100 mL) and DCM (100 mL). The aqueous layer was additionally extracted with DCM (2 x 100 mL). The combined organic layers were concentrated and purified on an ISCO system (eluted with EA in PE 0%~100%) to give the title compound as a white solid (2.0 g, 55.8% yield). MS (m/z): 515.1/517.1 (M+H-100) ⁺ .

(D) (R)-7-bromo-3-(hydroxymethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.

A solution of methyl ((t)-4-bromo-1-(2-((tert-butoxycarbonyl)amino)-3-((tert-butyldiphenylsilyl)oxy)propyl)-1/3-pyrrole-2-carboxylate (2.0 g, 3.2 mmol) in TFA (40 mL) was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure. The residue was dissolved in MeOH (50 mL), _Et3N (1.6 g, 16.2 mmol) and K2CO3 (2.2 g, 16.2 mmol) were added. The resulting mixture was refluxed for 4 h. The reaction mixture was concentrated and partitioned between water (100 mL) and DCM (100 mL). The aqueous layer was additionally extracted with DCM (2 x 100 mL). The combined organic layers were concentrated and purified on an ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a white solid (0.35 g, 44.2% yield). MS (m/z): 245.0/247.0 (M+H) ⁺ .

(E) (R)-7-bromo-3-(fluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.

To a mixture of (R)-7-bromo-3-(hydroxymethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (450 mg, 1.84 mmol) in DCM (5 mL) was slowly added diethylaminosulfur trifluoride (593 mg, 3.68 mol) at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight under nitrogen atmosphere. The reaction was then quenched with saturated NaHCO ₃ solution and the mixture was extracted with EA. The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (228 mg, 50.2% yield). MS (m/z): 246.9/248.9 (M+H) ⁺ .

The following intermediate compound was prepared according to the method for preparing intermediate compound 39 using the appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MS (m/z) (M+H) ⁺ 40 ABOUT 247.0/249.0

Intermediate connection 41.

7'-bromo-4'H-spiro[cyclobutane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one.

(A) tert-butyl-(1-(hydroxymethyl)cyclobutyl)carbamate.

To a solution of (1-aminocyclobutyl)methanol hydrochloride (2 g, 0.015 mol) and _Et3N (6.2 mL, 0.044 mol) in DCM (40 mL) was added (Boc) _2O (3.5 g, 0.016 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between DCM (30 mL) and saturated aqueous ammonium chloride solution (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized from PE/EA to give the title compound as a white solid (2.4 g, 87.8% yield). ¹ H NMR (400 MHz, DMSO^6) δ 6.57 (s, 1H), 4.64 (t, J=5.9 Hz, 1H), 3.39 (d, J=5.9 Hz, 2H), 2.17-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.75-1.52 (m, 2H), 1.35 (s, 9H).

(B) Methyl 4-bromo-1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrrole-2-carboxylate.

To a solution of tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate (2.1 g, 0.010 mol) in DCM (50 mL) was added Et ₃ N (2.8 mL, 0.020 mol) followed by dropwise addition of MsCl (0.93 mL, 0.012 mol) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (30 mL) and saturated ammonium chloride solution (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was dissolved in DMF (40 mL), methyl 4-bromo-1H-pyrrole-2-carboxylate (2 g, 0.0096 mol) and _Cs2CO3 (6.3 g, 0.0192 mol) were added. The resulting mixture was stirred at 80 °C for 8 _h . The reaction mixture was partitioned between EA (200 mL) and brine (300 mL). The aqueous layer was further extracted with EA (200 mL x 2). The combined organic layers were concentrated and purified using ISCO (PE/EA) to afford the title compound as an oily substance (1.6 g, 41% yield). MS (m/z): 287.0/289.0 (M+H-100)+.

(C) 7'-bromo-4H-spiro[cyclobutan-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one.

A mixture of methyl 4-bromo-1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-1Hpyrrole-2-carboxylate (1.6 g, 0.0041 mol) in TFA (10 mL) was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure. The residue was dissolved in MeOH (20 mL), _Et3N (3 mL) and K2CO3 (2 g, 0.0144 mol) were added. The mixture was refluxed for 6 h and then concentrated. The residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to give the title compound as a white solid (0.7 g, 66.8% yield). MS (m/z): 255.9/257.9 (M+H) ⁺ .

The following intermediate compounds were prepared according to the method for preparing intermediate compound 41 using the appropriate intermediate compounds and reagents under appropriate conditions, which may be known to one skilled in the art.

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Intermediate connection Structure MS (m/z) (M+H) ⁺ 42 O Вг—1 I U-o 256.9/258.9 43 o νη Br—(\ 1 1 V--N./ ¹ F^F 265.0/267.0 44 O / ⁵ = ^! =< ⁴ nh Br—(\ । 1 f^Tf F 282.9/284.9

Intermediate connection 45.

7'-bromo-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one.

(A) Methyl 4-bromo-1-(cyanomethyl)-1 H-pyrrole-2-carboxylate.

A mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (10 g, 49.0 mmol), 2-bromoacetonitrile (6.17 g, 51.5 mmol) and K ₂ CO ₃ (10.1 g, 73.5 mmol) was heated in CH ₃ CN (100 mL) at 80 °C for 3.5 h. The reaction mixture was concentrated, partitioned between water (150 mL) and EA (150 mL). The aqueous layer was further extracted with EA (2 x 150 mL). The combined organic layers were concentrated to give the title compound as a white solid (11.0 g, 92.4% yield). MS (m/z): 242.9/244.9 (M+H)+.

(B) 7'-bromo-4H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2Ή)-one.

To a mixture of methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate (3.0 g, 12.3 mmol) and Ti(OiPr) ₄ (5.2 g, 18.2 mmol) in THF (60 mL) was added dropwise ethylmagnesium bromide (11 mL, 33 mmol, 3 M in THF) at room temperature. After complete addition, the mixture was stirred at room temperature for 1 h. Hydrochloric acid (1 N, 50 mL) was added, THF was removed under reduced pressure and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were concentrated and the residue was purified by ISCO (PE/EA) to give the title compound as a white solid (0.4 g, 10.1% yield). MS (m/z): 241.0/243.0 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-de) δ 8.01 (br.e, 1H), 7.11 (d, J=1.8 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 4.01 (s, 2H), 0.84-0.79 (m, 4H).

The following intermediate compound was prepared according to the method for preparing intermediate compound 45 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MS (m/z) (M+H) ⁺ 46 About V-m 254.9/256.9

Intermediate connection 47.

7-bromo-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one.

(A) Methyl 4-bromo-1-(2-oxopropyl)-1 H-pyrrole-2-carboxylate.

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (2.0 g, 0.010 mol) in DMF (10 ml) was added

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NaH (0.6 g, 0.015 mol, 60% dispersion in liquid paraffin) at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 1-bromopropan-2-one (1.4 g, 0.010 mol) was added. The mixture was stirred at room temperature for 4 h, diluted with water and extracted with EA. The organic layer was washed with water and brine, concentrated to give the title compound as a yellow oily substance (2.5 g). MS (m/z): 259.9/261.9 (M+H)+.

(B) 7-bromo-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one.

To a solution of methyl 4-bromo-1-(2-oxopropyl)-1H-pyrrole-2-carboxylate (2.5 g, 0.001 mol) in MeOH (10 mL) was added a solution of ammonia in MeOH (10 mL, 7 M). The mixture was sealed in an autoclave and stirred at 120 °C for 16 h. The mixture was concentrated and the residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (0.5 g, 22.0% yield over two steps). MS (m/z): 227.0/229.0 (M+H) ⁺ .

Intermediate connection 48.

-(trifluoromethyl)cyclobutane-1-carbohydrazide.

(A) 1-(trifluoromethyl)cyclobutane-1-carbohydrazide.

To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (20 g, 119 mmol) in MeOH (30 mL) was added concentrated H2SO4 (0.75 mL). The mixture was refluxed overnight. Hydrazine hydrate (85%, 30 mL) was added. The mixture was again refluxed overnight. The mixture was diluted with EA, washed with water and brine, dried over anhydrous _Na2SO4 , and concentrated to give the title compound as a yellow solid (19 g, 68% yield). MS (m/ _z ): 183.0 (M+H) ⁺ .

The following intermediate compounds were prepared according to the method for preparing intermediate compound 48 using the appropriate intermediate compounds and reagents under appropriate conditions, which may be known to one skilled in the art.

Intermediate connection Structure MC (m/z) (Μ+Η) ⁺ 49 F O D. JL .ΝΗο F Ν ² FF ^H 161,0 50 π Η 169,0 51 F Ο FU II X .νη ₂ F ES Ν ² FF ^Η 179,0 52 F Ο Λ JL _Χ ΝΗ ₂ |IJ Η 185.1 53 F Ο D. _χ ΝΗ ₂ Μ Ξ Η 199.1

Intermediate connection 54.

-(trifluoromethyl)cyclopropane-1-carbohydrazide.

(A) 1-(trifluoromethyl)cyclopropane-1-carbohydrazide.

To a solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (5.0 g, 0.033 mol) and tert-butyl hydrazinecarboxylate (5.5 g, 0.033 mol) in DCM (50 mL) were added EDCI (6.3 g, 0.033 mol), HOBT (4.4 g, 0.033 mol), and Et ₃ N (6.6 g, 0.066 mol). The resulting mixture was stirred at room temperature for 16 h and then washed with saturated NaHCO ₃ solution and water. The organic layer was concentrated in vacuo. The residue was dissolved in THF (80 mL), and concentrated hydrochloric acid (10 mL) was added. The resulting mixture was stirred at room temperature for 1

- 74 047819 chi. The mixture was then concentrated to give the crude title compound as a yellow solid (5.0 g). MS (m/z): 169.1 (M+H)+.

Intermediate connection 55.

1-(difluoromethyl)-3,3-difluorocyclobutane-1-carbohydrazide.

(A) isopropyl-1-formyl-3,3-dimethoxycyclobutane-1-carboxylate.

To a mixture of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (5.0 g, 17.34 mmol) in DCM (50 mL) was slowly added DIBAL-H (35 mL, 35.0 mmol) at -78 °C. The mixture was stirred at -78 °C for 0.5 h under nitrogen atmosphere. Then the reaction was quenched with 2 N HCl and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by ISCO system (eluted with EA in PE 0%~100%) to give the title compound as a colorless oily substance (1.83 g, yield 45.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (s, 1H), 5.11-5.03 (m, 1H), 3.14 (s, 3H), 3.11 (s, 3H), 2.65-2.58 (m, 4H), 1.24 (d, J=6.3 Hz, 6H).

(B) isopropyl-1-formyl-3-oxocyclobutane-1-carboxylate.

A mixture of isopropyl 1-formyl 3,3-dimethoxycyclobutane-1-carboxylate (1.83 g, 7.95 mmol) in 6N HCl (10 mL, 60 mmol) was stirred at room temperature for 24 h. The mixture was then extracted with DCM. The organic layer was washed with brine, dried over _{anhydrous Na2SO4} , and concentrated to give the title compound as a colorless oil (950 mg). MS (m/z): 185.1 (M+H) ⁺ .

(C) isopropyl-1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylate.

To a mixture of the above isopropyl 1-formyl-3-oxocyclobutane-1-carboxylate (0.95 g) in DCM (5 mL) was slowly added diethylaminosulfur trifluoride (4.46 g, 27.27 mmol) at 0 °C. The mixture was then stirred at room temperature under nitrogen. The reaction was quenched with saturated NaHCO3 solution and the mixture was extracted with DCM. The organic layer was washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound as a brown oil (1.2 g). 1H NMR (400 MHz, CDCl ₃ ) δ 6.15 (t, J=56.2 Hz, 1H), 5.15-5.07 (m, 1H), 3.012.90 (m, 4H), 1.28 (d, J=6.3 Hz, 6H).

(D) 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carbohydrazide.

Hydrazine hydrate (85%, 3 mL) was added to a mixture of the above-prepared isopropyl 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylate (1.20 g) in MeOH (10 mL). The mixture was stirred at 75 °C overnight under nitrogen. MeOH was then removed and the residue was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a yellow oily substance (1.0 g). MS (m/z): 201.0 (M+H) ⁺ .

The following intermediate compounds were prepared according to the method for preparing intermediate compound 55 using the appropriate intermediate compounds and reagents under appropriate conditions, which may be known to one skilled in the art.

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Example 1: Synthesis of compounds 1-35.

Connection 1.

4-(3-(2-fluorophenethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)-N(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine.

(A) 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a] [ 1,4]diazepin-1-one.

A mixture of 8-bromo-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepin-1-one (6 g, 26.19 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (11.97 g, 47.15 mmol), Pd ₂ dba ₃ (2.4 g, 2.62 mmol), tricyclohexylphosphine (1.47 g, 5.24 mmol), and KOAc (7.71 g, 78.58 mmol) in 1,4-dioxane (120 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. The mixture was filtered and the filtrate was diluted with EA (200 mL), washed with water (100 mL) and brine (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to afford the title compound as a white solid (3.55 g, 49.1% yield). MS (m/z): 277.0 (M+H)+.

(B) 8-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-

a][1,4]diazepin-1-one.

To a mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-N-pyrrolo[1,2a][1,4]diazepin-1-one (17.76 g, 64.32 mol) and 4-chloro-N-(1-methyl-N-pyrazol-5-yl)pyrimidin-2-amine (13.50 g, 64.40 mmol) in a mixture of 1,4-dioxane/water (380 mL/70 mL) were added Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (2.63 g, 3.22 mmol) and cesium carbonate (52.40 g, 160.82 mmol). The mixture was then stirred for 2 h at 90 °C under nitrogen atmosphere. The mixture was filtered and the filtrate was diluted with EA, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to afford the title compound as a yellow solid (16.6 g, 79.8% yield). MS (m/z): 324.1 (M+H) ⁺ .

(C) 4-(1-hydrazinyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1-methyl-1H-pyrazol-5yl)pyrimidin-2-amine.

A suspension of 8-(2-((1-methyl-N-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepin-1-one (8.00 g, 24.74 mmol) in POCl ₃ (80 mL) was stirred at 100 °C under nitrogen atmosphere. The mixture was concentrated and the residue was poured into cold saturated NaHCO ₃ solution and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in THF (50 mL) and hydrazine hydrate (50 mL, 85%) was added. The mixture was then heated at reflux overnight under nitrogen atmosphere. The mixture was filtered and the precipitate was washed with THF. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give a brown solid (3.75 g, 47.7% yield). MS (m/z): 338.1 (M+H) ⁺ .

(D) 4-(3-(2-fluorophenethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)N-(1-methyl-III-pyrazol-5-yl)pyrimidin-2-amine.

To a solution of 4-(1-hydrazinyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1-methyl-1Hpyrazol-5-yl)pyrimidin-2-amine (100 mg, 0.30 mmol) and 3-(2-fluorophenyl)propanoic acid (60 mg, 0.35 mmol) in 5 mL of DCM were added HATU (113 mg, 0.30 mmol) and Et ₃ N (58 mg, 0.58 mmol). The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in 5 mL of 1,4-dioxane and then stirred at 60 °C for 1 h. The mixture was concentrated and purified using ISCO (eluted with methanol in water 0%~100%) to give the title compound as a white solid (66.6 mg, 47.1% yield). MS (m/z): 470.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-ab) δ 9.22 (s, 1H), 8.31 (d, J=5.2 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.40-7.32 (m, 3H), 7.28-7.23 (m, 1H), 7.18-7.09 (m, 3H), 6.27 (d, J=1.9 Hz, 1H), 4.37-4.23 (m, 2H), 4.17-4.00 (m, 2H), 3.68 (s, 3H), 3.10-2.98 (m, 4H), 2.29-2.13 (m, 2H).

The following compounds were prepared according to the method for preparing compound 1 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

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Conn. Structure LCMS (m/z) (M+H) ⁺ ‘H NMR 2 HN ^N _W ^N V ⁰ ,/ N=/ 0/ 456.1 Ή NMR (400 MHz, DMSO-ab) δ 9.36 (s, 1H), 8.43 (d, J= 5.1 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H ), 8.06 (d, J= 6.1 Hz, 1H), 7.83 (d, J = 6.1 Hz, 1H), 7.65 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.36-7.33 (m, 2H), 7.25-7.13 (m , 2H), 7.03-6.96 (m, 1H), 6.30 (d, J= 1.9 Hz, 1H), 5.63 (s, 2H), 3.69 (s, 3H). 3 Jfl hn^n><N An 1L/\JF -nA N=/ ¢/ 458.2 Ή NMR (400 MHz, DMSO-de) δ 9.26 (s, 1H), 8.33 (d, J= 4.4 Hz, 1H), 7.82 (s, 1H), 7.40 (t , J= 8.0 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.26 (s, 1H), 7.21 (d, J= 10.4 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.04 - 6.96 (m, 1H), 6.28 6, 26 (m, 1H), 5.42 (s, 2H), 4.46 - 4.41 (m, 4H), 3.68 (s, 3H). 4 XI N |f L IL nn -Λ ^Έ Ο o 460,1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.12 (s, 1H), 7.66 (d, J= 2.1 Hz, 1H), 7.31 (d , J= 1.9 Hz, 1H), 7.27 (d, 7=2.1 Hz, 1H), 6.98 (s, 1H), 6.22 (d, 7= 1.9 Hz, 1H), 4.47-4.34 (m, 2H), 4.19-4.11 (m, 2H), 3, 65 (s, 3H), 3.00-2.80 (m, 4H), 2.41-2.33 (m, 2H), 2.32-2.19 (m, 1H), 2.07-2.03 (m, 1H). 5 ϊΎ As N~.. p HN N Ns—N F F 1 IL ' ' Ji >Cr- _ A ^-N N-^K/^F Oh <> \Z 470.2 Ή NMR (400 MHz, DMSO-de) δ 8.99 (s, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.33 (d, 7 = 1.6 Hz , 1H), 7.27 (d, 7= 1.6 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 4.47-4.39 (m, 2H), 4.29-4.26 (m, 2H), 3.68 (s, 3H), 2.94-2.86 (m, 2H), 2.75-2.67 (m, 2H), 2.34 (s, 3H), 2.19-2.14 (m, 1H), 2.05-1.98 (m, 1H).

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6 O' Jp w / 470.2 Ή NMR (400 MHz, DMSO-ab) δ 9.08 (s, 1H), 8.20 (s, 1H), 7.60 (d, J= 1.8 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.24 - 7.11 (m, 3H), 6.25 (d, J = 1.7 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.18 (s, 2H), 4.12 - 4.06 (m, 2H), 3.66 (s, 3H), 2.30 (s, 3H), 2.28 - 2.23 (m, 2H). 7 / z-\ ¹ t? Λ o 472.2 Ή NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.23 (s, 1H), 7.76 (d, J= 1.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.33 (d, J= 2.0 Hz, 1H), 7.25 (d, J= 1.2 Hz, 1H), 7.23-7.19 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.02-6.97 (m, 1H), 6.27 (d, J= 2.0 Hz, 1H), 5.42 (s, 2H), 4.45 (br, 4H), 3.68 (s, 3H), 2.33 (s, 3H). 8 / L/\ Λ £ Дэ 472.2 Ή NMR (400 MHz, DMSO-de) δ 9.19 (s, 1H), 8.28 (d, J= 5.1 Hz, 1H), 7.66 (s, 1H), 7.51 - 7 .41 (m, 1H), 7.35 - 7.22 (m, 4H), 7.21 - 7.13 (m, 1H), 7.07 (d, J = 5.1 Hz, 1H), 6.26 - 6.24 (m, 1H), 4.39 - 4.26 (m, 2H), 4.22 (s, 2H), 4.14-4.01 (m, 2H), 3, 66 (s, 3H), 2.32-2.18 (m, 2H). 9 ^ci fY ^-Ά. N ₄ F HN ifO ^N \=^\ ⁿ A vy^'-AJ N=/ 475,1 Ή NMR (400 MHz, DMSO-de) δ 8.84 (s, 1H), 8.12 (s, 1H), 7.69 (s, 1H), 7.37 - 7.10 (m, 5H) , 6.99 (s, 1H), 6.94 (s, 1H), 6.23 6.20 (m, 1H), 4.41 - 4.37 (m, 2H), 4.29 4.25 (m, 2H), 4.20 (s, 2H), 3.64 (s, 3H). 10 z O ^z 'V'' z=/ P O ^t \- ^z / 477,1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 7.32 - 7.30 (m, 1H) , 7.21 (s, 1H), 6.96 (s, 1H), 6.23 6.21 (m, 1H), 4.45 (s, 2H), 4.40-4.36 (m, 2H), 4.20-4.15 (m, 2H), 3.64 (s, 3H), 2.342.28 (m, 5H). AND fV JL JL nn NH^VV^ W n^/F Ά ^L o > N=/ 479.2 Ή NMR (400 MHz, DMSO-de) δ 8.88 (s, 1H), 8.13 (s, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.30 (d, J= 2.1 Hz, 1H), 6.98 (s, 1H), 6.23 (d, J= 1.9 Hz, 1H), 5.43 (s, 2H), 4.48 - 4.36 (m, 2H), 4.34 4.25 (m, 2H), 3.66 (s, 3H), 2.36-2.33 (m, 2H).

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12 n*Y to 1 nn f HN N TV—IL J< ^h -A 43 <> ^F 484.1 Ή NMR (400 MHz, DMSO-ab) δ 9.08 (s, 1H), 8.21 (s, 1H), 7.66 (d, J= 1.4 Hz, 1H), 7.40 (d, J= 1.4 Hz, 1H), 7.31 (d, J= 1.4 Hz, 1H), 6.25 (d, J = 1.4 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.08 - 3.99 (m, 2H), 3.66 (s, 3H), 2.92 - 2.88 (m, 2H), 2.75 - 2.66 (m, 2H), 2.35 - 2.24 (m, 5H), 2.17 - 2.13 (m, 1H), 2.01 - 1.97 (m, 1H). 13 Y^ii / to 1 1 Nn F _ HN N YV-i> l·- ¹ -A ^X O <> ^F N=/ 484.1 Ή NMR (400 MHz, DMSO-de) δ 9.06 (s, 1H), 8.30 (d, J= 5.3 Hz, 1H), 7.72 (s, 1H), 7.32 (d, J= 1.9 Hz, 1H), 6.99 (d, J= 5.3 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.86 (t, J= 6.5 Hz, 2H), 3.64 (s, 3H), 2.93-2.89 (m, 2H), 2.79-2.65 (m, 2H), 2.38 (s, 3H), 2.27-2.09 (m, 3H), 2,051.94 (m, 1H). 14 .Cl Ψ P JL IL nn f λ V/n^X^ ^N > 7 VJ <? N=/ ' 485.1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.12 (s, 1H), 7.66 (s, 1H), 7.33 - 7.31 (m, 1H) , 7.18 (s, 1H), 6.98 (s, 1H), 6.48 (t, J= 55.8 Hz, 1H), 6.23 - 6.21 (m, 1H), 4, 36 - 4.26 (m, 2H), 4.07 - 3.99 (m, 2H), 3.65 (s, 3H), 2.75 - 2.67 (m, 2H), 2.55 - 2.53 (m, 2H), 2.31 - 2.25 (m, 2H), 2.19 - 2.08 (m, 1H), 2.01 - 1.90 (m, 1H). 15 / ^ζ Ά ^t I 4 ^Z Hint ъ 485.2 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.10 (s, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.34-7 .27 (m, 3H), 7.23-7.17 (m, 4H), 6.97 (s, 1H), 6.22 (d, J= 1.9 Hz, 1H), 4.40- 4.26 (m, 2H), 4.18-4.09 (m, 2H), 3.65 (s, 3H), 3.61-3.53 (m, 1H), 2.21-2, 10 (m, 1H), 2.03-1.94 (m, 1H), 1.63 (d, J= 7.0 Hz, 3H). 16 |b 4γι ^τ Ζ- ^Ζ / 486.1 Ή NMR (400 MHz, DMSO-de) δ 9.09 (s, 1H), 8.30 (d, J= 3.6 Hz, 1H), 7.72 (s, 1H), 7.44-7 .40 (m, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.27-7.12 (m, 2H), 7.04-6.96 (m, 2H), 6.19 (d, J= 1.9 Hz, 1H), 5.42 (s, 2H), 4.13-4.06 (m, 4H), 3.65 (s, 3H), 2.43 (s, 3H), 2.322.28 (m, 2H).

- 79 047819

17 L Jb Chg, ^t I- ² / 486.2 Ή NMR (400 MHz, DMSO-ab) δ 9.09 (s, 1H), 8.21 (s, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.48 (d, J= 1.9 Hz, 1H), 7.43-7.39 (m, 1H), 7.32 (d, J= 1.8 Hz, 1H), 7.25-7.14 (m, 2H), 7.02-6.96 (m, 1H), 6.26 (d, J= 1.9 Hz, 1H), 5.40 (s, 2H), 4.46-4.37 (m, 2H), 4.37-4.29 (m, 2H), 3.67 (s, 3H), 2.38-2.28 (m, 5H). 18 .CI to JL nn g 1 HN ^ yV// \\ kJ) Ϊ L/ ^,,Α, Ν 1 1 ^Ν ' / \ J ^0Η Ν=/ 487.2 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.10 (s, 1H), 7.61 (d, J= 2.0 Hz, 1H), 7.38 -7 .34 (m, 4H), 7.31-7.25 (m, 2H), 7.19 (d, J= 2.0 Hz, 1H), 6.96 (s, 1H), 6.59 ( d, J = 5.0 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 6.04 (d, J = 5.0 Hz, 1H), 4.38-4, 31 (m, 1H), 4.28-4.25 (m, 1H), 4.24-4.18 (m, 1H), 3.96-3.90 (m, 1H), 3.64 (s, 3H), 2.22-2.12 (m, 1H), 2.12-1.97 (m, 1H). 19 7^11 F to L _ Ν'Ν Ί ΗΝ Ν Τίν--4 3k 5^/¼¾. -Λ ^L O m Ν=/ 488.2 Ή NMR (400 MHz, DMSO-de) δ 9.21 (s, 1H), 8.33 - 8.28 (m, 1H), 7.70 (s, 1H), 7.61 - 7.57 ( m, 1H), 7.34 - 7.30 (m, 3H), 7.25 7.08 (m, 3H), 6.29 - 6.25 (m, 1H), 4.43 (m, 2H ), 4.38-4.34 (m, 2H), 4.32-4.27 (m, 2H), 3.67 (s, 3H), 2.35-2.31 (m, 2H). 20 / Ζ' ^Ζ \ I 1 489,0 Ή NMR (400 MHz, DMSO-de) δ 8.85 (br, 1H), 8.13 (s, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.07 (d, J= 1.6 Hz, 1H), 6.96 (s, 1H), 6.22 (d, J = 1.6 Hz, 1H), 4.45-4.36 (m, 2H), 4.28-4.25 (m, 2H), 3.65 (s, 3H), 2.92-2.84 (m, 2H), 2.72-2.65 (m, 2H), 2.17-2.10 (m, 1H), 2.05-1.91 (m, 1H). 21 Ρ ο \=^ Q ζ—kkl ¹ Ζ' ^ζ / 489.1 Ή NMR (400 MHz, flMC0-d6) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.66 (d, J= 2.1 Hz, 1H), 7.31 (d ,J= 1.9 Hz, 1H), 7.24 (d, ./=2.1 Hz, 1H), 6.97 (s, 1H), 6.22 (d, J= 1.9 Hz, 1H), 4.47 - 4.34 (m, 2H), 4.34 - 4.21 (m, 2H), 3.65 (s, 3H), 2.40 - 2.25 (m, 2H) , 1.63 1.49 (m, 2H), 1.49-1.35 (m, 2H). 22 ΐ ιΓ JL JL , ν-ν f _c '«Λ ^l O ^j λ ^f Ν=/ 491,1 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.33 - 7.30 (m, 1H) , 7.12 (s, 1H), 6.97 (s, 1H), 6.24 6.21 (m, 1H), 4.35 - 4.19 (m, 4H), 3.66 (s, 3H), 2.37 - 2.24 (m, 2H), 1.72 (s, 6H).

- 80 047819

23 / z-\ ¹ Ul /===< Q a. l o 491.2 Ή NMR (400 MHz, DMSO-ab) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.74 (d, J= 1.6 Hz, 1H), 7.42-7.37 (m, 1H), 7.33 (d, J= 2.0 Hz, 1H), 7.26-7.19 (m, 1H), 7.15 (t, J= 8.0 Hz, 1H), 7.06 (d, J= 1.6 Hz, 1H), 7.03-6.97 (m, 1H), 6.96 (s, 1H), 6.23 (d, J= 2.0 Hz, 1H), 5.42 (s, 2H), 4.45 (br, 4H), 3.66 (s, 3H). 24 ^Cl L 1. nn f ] -nA K/y N \ J ° ^H N=/ 493,1 Ή NMR (400 MHz, flMC0-d6) δ 8.85 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.33 - 7.31 (m, 1H) , 7.18 (s, 1H), 6.97 (s, 1H), 6.24 6.21 (m, 1H), 4.46 - 4.21 (m, 5H), 3.65 (s, 3H), 2.35 - 2.22 (m, 2H), 2.15 - 2.04 (m, 1H), 2.01 - 1.92 (m, 1H), 1.92 - 1.80 ( m, 1H), 1.67 - 1.75 (m, 1H), 1.66 - 1.55 (m, 2H), 1.36 - 1.24 (m, 2H), 1.17 - 1.01 (m, 3H). 25 ^Cl N |< LJL - NN ί F ^Η, |^^ΐίΎ-4 Αό-ΑΑ -Д ^L O N=/ 493,1 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.64 (d, J= 1.8 Hz, 1H), 7.32 (d, J= 1.6 Hz, 1H), 7.26 (d, J= 1.8 Hz, 1H), 6.96 (s, 1H), 6.22 (d, J= 1.6 Hz, 1H), 4.86 (s, 2H), 4.45 - 4.35 (m, 2H), 4.31 4.21 (m, 2H), 4.14 (q, J = 9.3 Hz, 2H), 3.65 (s, 3H), 2.34 - 2.30 (m, 2H). 26 ^ci N |< JL 1 . nn f HN^# U j£ Λ ''N, 7 ^N \ J ^* ^0H N=/ ' 493,1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.12 (s, 1H), 7.70 (d, J= 1.9 Hz, 1H), 7.46 (s , 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 6.97 (s, 1H), 6.22 (d , J = 1.9 Hz, 1H), 4.59-4.35 (m, 2H), 4.33-4.24 (m, 2H), 3.65 (s, 3H), 2.38- 2.21 (m, 2H), 1.85 (s, 3H). 27 {T\--& Z^\ I. ¹ V ^Z / 496.1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.85 (d, J= 7.4 Hz, 1H), 7.65-7 .63 (m, 2H), 7.48 -7.46 (m, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.31 - 7.29 (m, 1H), 7.20 (s, 1H), 6.97 (s, 1H), 6.23 - 6.21 (m, 1H), 4.37 - 4.35 (m, 4H), 4.17 - 4, 16 (m, 2H), 3.64 (s, 3H), 2.29-2.28 (m, 2H). 28 j. A NN F HN N WA 1 Jx ^F -A Oo ^: N=/ ' 498.2 Ή NMR (400 MHz, DMSO-de) δ 8.96 (s, 1H), 8.21 (s, 1H), 7.68 (d, J= 1.9 Hz, 1H), 7.35-7.27 (m, 2H), 6.25 (d, J= 1.9 Hz, 1H), 4.33-4.16 (m, 4H), 3.68 (s, 3H), 2.72-2.59 (m, 2H), 2.40-2.26 (m, 7H), 1.82-1.60 (m, 4H).

- 81 047819

29 XX / ⁿ 'n -A N=/ 500,2 Ή NMR (400 MHz, DMSO-ab) δ 9.08 (s, 1H), 8.29 (d, J= 5.1 Hz, 1H), 7.70 (s, 1H), 7.35-6 .98 (m, 6H), 6.20 - 6.17 (m, 1H), 5.90-5.88 (m, 1H), 4.08-3.98 (m, 4H), 3.64 (s, 3H), 2.39 (s, 3H), 2.23-2.19 (m, 2H), 1.74 (d, 7= 6.2 Hz, 3H). 30 I x \.z / 503,1 Ή NMR (400 MHz, DMSO-de) δ 8.84 (s, 1H), 8.13 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.98 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H), 4.35-4.28 (m, 2H), 4.09-3.97 (m, 2H), 3.65 (s, 3H), 2.92-2.88 (m, 2H), 2.73-2.69 (m, 2H), 2.35-2.24 (m, 2H), 2.22-2.09 (m, 1H), 2.03-1.95 (m, 1H). 31 χι Ϊ lT JL JL .. nn f _c -A ^x Ot> ^F N=/ '' 517.2 Ή NMR (400 MHz, DMSO-de) δ 8.84 (s, 1H), 8.12 (s, 1H), 7.69 (d, 7= 1.9 Hz, 1H), 7.31 (d, 7= 1.8 Hz, 1H), 7.15 (d, 7= 1.9 Hz, 1H), 6.97 (s, 1H), 6.22 (d, 7= 1.8 Hz, 1H), 4.27 (t, 7= 6.1 Hz, 2H), 4.20 (t, 7= 6.1 Hz, 2H), 3.65 (s, 3H), 2.70-2.59 (m, 2H), 2.39-2.26 (m, 4H), 1.78-1.59 (m, 4H). 32 ,CI N |< JL JL n-n f -Λ 4 \ <> N=/ S< ° F F 523,0 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.15 (s, 1H), 7.87 (d, 7= 1.9 Hz, 1H), 7.32 (d, 7= 1.9 Hz, 1H), 7.12 (d, 7= 1.9 Hz, 1H), 6.94 (s, 1H), 6.70 (t, 7= 55.1 Hz, 1H), 6.22 (d,7= 1.9 Hz, 1H), 5.10-4.97 (m, 4H), 4.83 (t, J = 13.2 Hz, 2H), 4.44 (t, J = 12.8 Hz, 2H), 3.64 (s, 3H). 33 XI JL JL n- _n y J -A ^L O N=/ 523,1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.64 (d, 7= 2.0 Hz, 1H), 7.43-7 .34 (m, 2H), 7.30-7.23 (m, 2H), 7.16 (d, 7= 2.0 Hz, 1H), 6.98 (s, 1H), 6.22 ( d, J = 1.8 Hz, 1H), 4.42-4.35 (m, 2H), 4.31-4.24 (m, 2H), 4.20 (s, 2H), 3.64 (s, 3H), 2.362.32 (m, 2H). 34 .Cl N |< _F JL JL , ^N ~ ^N bF HN \\ ·οΑ<γ 1 IL.,' n /X -N A O N=/ 533,1 'NMR (400 MHz, DMSO-de) δ 8.81 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.33 - 7.31 (m, 1H) , 7.25 (s, 1H), 6.96 (s, 1H), 6.23 6.21 (m, 1H), 4.83 (s, 2H), 4.40 - 4.38 (m, 2H), 4.26 - 4.25 (m, 2H), 3.65 (s, 3H), 2.51 - 2.48 (m, 4H), 2.34 - 2.30 (m, 4H) . 35 / tH _z Г \\ p=\ QA o-£} 541.2 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.13 (s, 1H), 7.81 (d, 7= 7.7 Hz, 1H), 7.72 (s , 1H), 7.66-7.64 (m, 2H), 7.57 - 7.53 (m, 1H), 7.33-7.31 (m, 2H), 6.99 (s, 1H ), 6.23 (s, 1H), 4.54-4.42 (m, 4H), 3.65 (s, 3H), 2.43-2.38 (m, 2H).

Example 2: Synthesis of compounds 36-38.

Connection 36.

^-(1-methyl-III-pyrazol-5-yl)-4-(3-(phenoxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepin-10-yl)pyrimidin-2-amine.

- 82 047819 (A) 4-(3-(chloromethyl)-6,7-dihydro-5H-pyrrolo[1,2-а][1,2,4]triazolo[3,4-с][1,4 ]diazepin-10-yl)-U-(1methyl-1 H-pyrazol-5-yl)pyrimidin-2-amine.

To a solution of 4-(1-hydrazinyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1-methyl-1Hpyrazol-5-yl)pyrimidin-2-amine (500 mg, 1.48 mmol) in DCM (50 mL) was added DIPEA (287 mg, 2.22 mmol), followed by slow addition of 2-chloroacetyl chloride (201 mg, 1.78 mmol) at 0 °C. The mixture was stirred overnight at room temperature and then heated under reflux for 3 h. The mixture was diluted with THF (100 mL) and water (100 mL). The aqueous layer was extracted with THF. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a brown oil (587 mg), which was used directly in the next step. MS (m/z): 454.2 (M+H)+.

(B) N-(1-methyl-1H-pyrazol-5-yl)-4-(3-(phenoxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)pyrimidin-2-amine

Cesium carbonate (151 mg, 0.46 mmol) and phenol (34.9 mg, 0.37 mmol) were added to a solution of 4-(3-(chloromethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)-N-(1-methyl-N-pyrazol-5-yl)pyrimidin-2-amine (73.4 mg, 0.19 mmol) in DMF (5 mL). The resulting mixture was stirred at 60°C for 1 h. After cooling, the reaction mixture was purified directly on an ISCO system (eluted with methanol in water 0%~100%) and by pTLC (DCM:MeOH=12/1) to give the title compound as a light yellow solid (19.1 mg, yield 22.7%). MS (m/z): 396.2 (M+H) ⁺ . ^1H NMR (400 MHz, DMSO-46) δ 9.26 (s, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 7.42 (s, 1H), 7.37-7.24 (m, 3H), 7.15-7.04 (m, 3H), 7.03-6.92 (m, 1H), 6.28 (s, 1H), 5.30 (s, 2H), 4.45-4.34 (m, 2H), 4.34-4.24 (m, 2H), 3.68 (s, 3H), 2.38-2.27 (m, 2H).

The following compounds were prepared according to the method for preparing compound 36 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 37 / oG g O 472.2 Ή NMR (400 MHz, DMSO-ab) δ 9.22 (s, 1H), 8.30 (d, J = 4.7 Hz, 1H), 7.71 (s, 1H), 7.46 - 7 .36 (m, 2H), 7.32 (s, 1H), 7.25 - 7.17 (m, 1H), 7.17-7.12 (m, 1H), 7.10 (d, J = 4.7 Hz, 1H), 7.05 - 6.93 (m, 1H), 6.26 (s, 1H), 5.38 (s, 2H), 4.43 - 4.35 (m, 2H), 4.35 - 4.28 (m, 2H), 3.67 (s, 3H), 2.38 - 2.28 (m, 2H). 38 .Cl ΐ |Γ F k JL nn \ -A ^L OM N=/ 505.2 Ή NMR (400 MHz, DMSSMb) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.65 (s, 1H), 7.46-7.35 (m, 1H), 7 .31 (s, 1H), 7.26 (s, 1H), 7.24-7.10 (m, 2H), 7.02 - 6.93 (m, 2H), 6.22 (s, 1H ), 5.39 (s, 2H), 4.47 - 4.37 (m, 2H), 4.37 - 4.23 (m, 2H), 3.65 (s, 3H), 2.39 - 2.26 (m, 2H).

Example 3: Synthesis of compounds 39-40.

Compound 39.

^)-4-(3-(1-(2-fluorophenoxy)ethyl)pyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazin-9-yl)-N-(1-methyl-pyrazol-5-yl)pyrimidin-2-amine.

O

about CI

(A) 7-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazin-1(2H)-one.

In a solution of 7-bromopyrrolo[1,2-a]pyrazin-1(2H)-one (21.3 g, 100 mmol) in anhydrous DMF (100 ml)

- 83 047819 NaH (6 g, 150 mmol, 60% dispersion in liquid paraffin) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 2-(trimethylsilyl)-ethoxymethyl chloride (21.6 g, 130 mmol) was added. The mixture was stirred at room temperature overnight and poured into ice water, extracted with EA, concentrated and purified in an ISCO system (PE/EA = 5:1) to give the title compound as a yellow solid (16 g, yield 47%). MS (m/z): 342.9/344.9 (M+H)+.

(B) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2a]pyrazine -1(2H)-on.

A mixture of 7-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (8.5 g, 24.8 mmol), BPIN (9.44 g, 37.2 mmol), _Pd2 (dba) ₃ (0.68 g, 7.44 mmol), KOAc (4.86 g, 49.6 mmol), and tricyclohexylphosphine (0.417 g, 1.488 mmol) in 1,4-dioxane (120 mL) was stirred at 100°C for 4 h under nitrogen. The mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified using ISCO (PE/EA=5:1) to give the title compound as a yellow solid (8.1 g, 84% yield). MS (m/z): 391.1 (M+H) ⁺ .

(C) 7-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2 -a]pyrazin-1 (2H)-one.

A mixture of 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (627 mg, 3 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazin1(2H)-one (1170 mg, 3 mmol), Pd(dppf) _{Cl2 -CH2Cl2 (} 122 mg, 0.15 mmol), and _Na2CO3 (636 mg, 3 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100°C for 3 h under nitrogen. _The mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified using ISCO (DCM/MeOH=20:1) to give the title compound as a brown solid (800 mg, 61% yield). MS (m/z): 438.2 (M+H) ⁺ .

(D) 7-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one.

A solution of 7-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (800 mg, 1.8 mmol) in TFA (3 mL) was stirred at room temperature for 0.5 h. The volatiles were removed under reduced pressure and ammonium hydroxide was added. The precipitate was filtered and washed with water and dried to give the title compound as a yellow solid (500 mg). MS (m/z): 380.0 (M+H) ⁺ .

(E) ^)-4-(3-(1-(2-fluorophenoxy)ethyl)pyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazin-9-yl)-Y-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine.

A mixture of 7-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyrrolo[1,2a]pyrazin-1(2H)-one (93 mg, 0.3 mmol) in POCl ₃ (2 mL) was stirred at 100 °C for 1 h. The volatiles were removed under reduced pressure and aqueous NaHCO ₃ was added, adjusting to pH = 8. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated. The residue was dissolved in EtOH (5 mL) and {(N)-2-(2-fluorophenoxy)propanehydrazide (59 mg, 0.30 mmol) was added. The resulting mixture was refluxed overnight. The volatiles were removed under reduced pressure and the residue was purified on an ISCO system (eluted with MeOH in water 0~100%) to give the title compound as a yellow solid (85 mg, 60% yield). MS (m/z): 470.1 (M+H) ⁺ . 1H NMR (400 MHz, CD3OD) δ 8.31 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.77 (d, J=6.0 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J=2.0 Hz, 1 H), 7.20-6.97 (m, 5H), 6.35 (d, J=2.0 Hz, 1H), 5.97-5.92 (m, 1H), 3.75 (s, 3H), 1.88 (d, J=6.8 Hz, 3H).

The following compound was prepared according to the method for preparing compound 39 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure lx-ms (m/z) (M+H) ⁺ Ή NMR 40 / 0 472.1 Ή NMR (400 MHz, DMSO-ab) δ 9.34 (s, 1H), 8.43 (d, J= 5.2 Hz, 1H), 8.26 (d, J= 1.6 Hz, 1H ), 8.06 (d, J= 6.0 Hz, 1H), 7.82 (d, J= 6.0 Hz, 1H), 7.65 (s, 1H), 7.44 - 7.43 (m, 1H), 7.42 - 7.41 (m, 1H), 7.36 - 7.31 (m, 3H), 7.04 - 6.98 (m, 1H), 6.29 (d , J= 1.6 Hz, 1H), 5.66 (s, 2H), 3.69 (s, 3H).

Example 4: Synthesis of compounds 41-43.

Connection 41.

N(2-fluorophenyl)-9-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazin-3-amine.

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Hydrazine hydrate (2 mL, 85%) was added to a solution of 4-(1-chloropyrrolo[1,2-a]pyrazin-7-ηλ)-Ν-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (130 mg, 0.40 mmol) in THF (5 mL), and the mixture was heated at 80 °C for 4 h. The mixture was then extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM (5 mL), 1-fluoro-2-isocyanatobenzene (70 mg, 0.51 mmol) and POCl ₃ (3 mL) were added, and the resulting mixture was heated at 60 °C for 3 h. The volatiles were removed under reduced pressure, and the residue was adjusted to pH 8 with aqueous NaHCO3. The aqueous layer was extracted with _DCM . The organic layer was dried over anhydrous _Na2SO4 and concentrated. The residue was purified by ISCO purification (eluted with MeOH in water 0~100%) to give the title compound as a yellow solid (15.0 mg, 10.0% yield). MS (m/z): 441.1 (M+H)+. ¹ H NMR (400 MHz, DMSO-ab) δ 9.32 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.17 (d, J=1.2 Hz, 1H), 7.89-7.85 (m, 1H), 7.84 (d, J=6.4 Hz, 1H), 7.66 (d, J=6.4 Hz, 1h), 7.50 (s, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.21-7.18 (m, 1H), 7.11-7.07 (m, 1H), 6.91-6.86 (m, 1H), 6.30 (d, J =2.0 Hz, 1H), 3.69 (s, 3H).

The following compounds were prepared according to the method for preparing compound 41 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 42 Jks. X J N-N\fl HN N U ". J) N=/ ' 471,0 Ή NMR (400 MHz, DMSO-ab) δ 9.08 (s, 1H), 8.49 (s, 1H), 8.29 (d, J= 4.7 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.32 (s, 1H), 7.17 - 6.92 (m, 4H), 6.19 (s, 1H), 4.13 - 4.09 (m, 2H), 3.94 - 3.90 (m, 2H), 3.65 (s, 3H), 2.43 (s, 3H), 2.27 - 2.24 (m, 2H). 43 Y JL . n-n G W -A g N=/ 490,1 'NMR (400 MHz, DMSO-ab) δ 8.83 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.63 (s, 1H), 7.56 7.52 (m, 1H), 7.32 (s, 1H), 7.24 - 7.15 (m, 2H), 7.12 - 7.06 (m, 1H), 6.98 (s, 1H), 6.95 - 6.88 (m, 1H), 6.23 (s, 1H), 4.43 - 4.32 (m, 2H), 4.14 4.01 (m, 2H), 3.66 (s, 3H), 2.36 - 2.27 (m, 2H).

Example 5: Synthesis of compounds 44-52.

Connection 44.

(S)-4-(3-(1-(2-fluorophenoxy)ethyl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepine-1 0-η.ι)-Ν-(1-methyl-1 H-pyrazol-5-yl)pyrimidin-2-amine.

(A) 4-(1-chloro-4,4-dimethyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1-methyl-1Hpyrazol-5-yl)pyrimidin-2-amine.

The title intermediate was prepared according to the method described in Example 1 using the appropriate intermediates and reagents.

(B) (S)-4-(3-(1-(2-fluorophenoxy)ethyl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepine-1 0-η.ι)-N-(1-methyl-1 H-pyrazol-5-yl)pyrimidin-2-amine.

A mixture of 4-(1-chloro-4,4-dimethyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1-methyl-N-pyrazol-5-yl)pyrimidin-2-amine (111 mg, 0.3 mmol) and (N)-2-(2-fluorophenoxy)propanehydrazide (59 mg, 0.3 mmol) in EtOH (10 mL) was refluxed overnight. The mixture was concentrated and the residue was purified over an ISCO system (eluted with MeOH in water 0~100%) to give the title compound as a yellow solid (40 mg, 26% yield). MS (m/z): 514.2 (M+H) ⁺ . 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=5.2 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.24-7.20 (m, 1H), 7.17 -7.09 (m, 2H), 7.07-7.00 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.81-5.76 (m, 1H), 4.00 (s, 2H), 3.92 (s, 2H), 3.74 (s, 3H), 1.81 (d, J=6.8 Hz, 3H), 1 ,11 (s, 3H), 1.16 (s, 3H).

The following compounds were prepared according to the method for preparing compound 44 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (Μ+Η) ⁺ Ή NMR 45 ϊΠΓ ΗΝ Ν ц ^F \ __zL· Ν N-->v/ F ^Ν Ο <>№> \Ζ 450,1 Ή NMR (400 MHz, DMSO-ab) δ 9.20 (s, 1H), 8.31 (s, 1H), 8.24 (d, J= 1.6 Hz, 1H), 7.92 (d , J= 6.0 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J= 6.0 Hz, 1H), 7.35 (d, J= 2.0 Hz, 1H ), 6.56 (t, J= 56 Hz, 1H), 6.28 (d, J= 2.0 Hz, 1H), 3.68 (s, 3H), 2.78-2.60 (m , 4H), 2.38 (s, 3H), 2.22-2.13 (m, 1H), 2.01-1.91 (m, 1H). 46 XXL· ν. g Α. *~Ν Ν-\^Λ Ν У_/ <\ F 471,0 Ή NMR (400 MHz, flMCO-d6) δ 8.81 (s, 1H), 8.12 (s, 1H), 7.72 (s, 1H), 7.33 - 7.30 (m, 1H) , 7.03 (s, 1H), 6.95 (s, 1H), 6.46 (t, J= 56.0 Hz, 1H), 6.22 - 6.20 (m, 1H), 4, 38 - 4.36 (m, 2H), 4.25 - 4.24 (m, 2H), 3.65 (s, 3H), 2.69 - 2.67 (m, 2H), 2.52 - 2.48 (m, 2H), 2.11 - 2.10 (m, 1H), 1.96 - 1.93 (m, 1H). 47 ϊΎ Α χΑ^Χ Ν'Μ Γ ΗΝ Ν Ν F _F --Ν^\ ^Ν \^ / ^Ν /\ ^F '№* / \Ζ 484.1 Ή NMR (400 MHz, DMSO-de) δ 9.10 (s, 1H), 8.23 (s, 1H), 7.77 (d, J= 1.5 Hz, 1H), 7.33 (d , J= 1.8 Hz, 1H), 7.27 (d, J= 1.5 Hz, 1H), 6.26 (d, J= 1.8 Hz, 1H), 4.77-4.75 (m, 1H), 4.36-4.32 (m, 1H), 4.11-4.07 (m, 1H), 3.67 (s, 3H), 2.88-2.84 (m , 2H), 2.72-2.68 (m, 2H), 2.34 (s, 3H), 2.17-2.13 (m, 1H), 2.02-1.95 (m, 1H), 1.38 (d, J= 6.6 Hz, 3H). 48 ϊΎ Α Α^χ ν·. _μ with ΗΝ Ν -<* fl ^F \.F Λς ^F *№* / X/ 484.1 Ή NMR (400 MHz, flMCO-d6) δ 9.10 (s, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 7.33 (d, J= 1.8 Hz , 1H), 7.27 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 4.78 - 4.74 (m, 1H), 4.36 4.32 (m , 1H), 4.11 - 4.07 (m, 1H), 3.67 (s, 3H), 2.89 - 2.83 (m, 2H), 2.75 - 2.69 (m, 2H ), 2.34 (s, 3H), 2.16-2.12 (m, 1H), 2.03 - 1.95 (m, 1H), 1.36 (d, J= 6.5 Hz, 3H). 49 χ^. ΐ ιΓ JL JL - ^Ν ~Ν F. F Ά ^χ ο <> Ν=/ 499,1 Ή NMR (400 MHz, flMCO-d6) δ 8.81 (s, 1H), 8.11 (s, 1H), 7.66 (d, J= 2.0 Hz, 1H), 7.31 (d , J= 1.9 Hz, 1H), 7.15 (d, J= 2.0 Hz, 1H), 6.95 (s, 1H), 6.21 (d, J= 1.9 Hz, 1H ), 4.35-4.24 (m, 2H), 4.08-3.96 (m, 2H), 3.64 (s, 3H), 2.80-2.69 (m, 2H), 2.65-2.59 (m, 2H), 2.30-2.21 (m, 2H), 2.07-1.86 (m, 2H), 1.50 (t,J = 19.2 Hz, 3H). 50 / b Ж λ 503,1 Ή NMR (400 MHz, flMCO-d6) δ 8.84 (s, 1H), 8.14 (s, 1H), 7.76 (s, 1H), 7.32 (d, J= 1.8 Hz , 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.23 (d, J = 1.8 Hz, 1H), 4.75-4.71 (m, 1H) , 4.36-4.32 (m, 1H), 4.11-4.07 (m, 1H), 3.66 (s, 3H), 2.87-2.83 (m, 2H), 2 .73-2.69 (m, 2H), 2.16-2.12 (m, 1H), 2.03-1.99 (m, 1H), 1.40 (d, J =8.6 Hz, 3H).

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Ή NMR (400 MHz, DMSO-ab) δ 8.83 (s, 1H), 8.11 (s, 1H), 7.53 (d, J= 2.0 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 7.28 (d, J= 2.0 Hz, 1H), 6.98 (s, 1H), 6.42 (t, J= 56 Hz, 1H), 6.22 (d, J= 2.0 Hz, 1H), 4.26 (s, 2H), 3.96 (s, 2H), 3.65 (s, 3H), 2.67-2.60 (m, 2H), 2.52-2.45 (m, 2H), 2.13-2.06 (m, 1H), 1.97-1.85 (m, 1H), 0.74 - 0.70 (m, 4H).

Ή NMR (400 MHz, DMSO-de) δ 8.90 (s, 1H), 8.13 (s, 1H), 7.71 (d, J= 1.6 Hz, 1H), 7.32 (d , J= 1.6 Hz, 1H), 7.19 (d, J= 1.6 Hz, 1H), 7.00 (s, 1H), 6.23 (d, J= 1.6 Hz, 1H ), 4.63 - 4.58 (m, 1H), 4.06 - 3.99 (m, 2H), 3.66 (s, 3H), 2.95 - 2.88 (m, 2H), 2.74 2.69 (m, 2H), 2.44 - 2.39 (m, 1H), 2.24 2.11 (m, 2H), 2.01 - 1.95 (m, 1H), 1.46 (d, J =6.4 Hz, 3H).

Example 6: Synthesis of compounds 53-54. Compound 53.

5-chloro-4-(3-(indolin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine-10ηλ)-Ν-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine.

(A) 5-chloro-4-(1-chloro-4,5-dihydro-3H-pyrrolo[1 ,2-a][1,4]diazepin-8-yl)-N(1-methyl-1I-ι 1yrazol-5yl)pyridin-2-amine.

The title intermediate was prepared according to the method described in Example 1 using the appropriate intermediates and reagents.

(B) indoline-1-carbohydrazide.

To a solution of indoline (500 mg, 4.2 mmol) in DMF (5 mL) and DIPEA (0.76 mL, 4.6 mmol) was added portionwise CDI (750 mg, 4.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and diluted with water (100 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in THF (10 mL) and hydrazine hydrate (20 mL, 85%) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was partitioned between EA (50 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (600 mg, crude), which was used directly in the next step without further purification. MS (m/z): 178.1 (M+H)+.

(C) 5-chloro-4-(3-(indolin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)A'-(1-methyl-111-11yrazol-5-yl)11iridin-2-amine.

A mixture of 5-chloro-4-(1-chloro-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepin-8-yl)-N-(1methyl-N-pyrazol-5-yl)pyridin-2-amine (60 mg, 0.16 mmol) and indoline-1-carbohydrazide (43 mg, 0.24 mmol) in POCl3 ( ₅ mL) was stirred at 60°C for 3 h and then at 90°C for 4 h. The volatiles were removed under reduced pressure and the residue was adjusted to pH 10 with 2 M NaOH and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL), concentrated and purified by tLLC (DCM/MeOH=13/1) to give the title compound as a yellow solid (12 mg, 15% yield). MS (m/z): 498.2 (M+H) ⁺ .

^1H NMR (400 MHz, DMSO^b) δ 8.83 (s, 1H), 8.13 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.32 ( d, J=1.9 Hz, 1H), 7.25-7.21 (m, 2H), 7.04 (t, J=1.1 Hz, 1H), 6.99 (s, 1H), 6.80 (t, J=7.4 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 6.23 (d, J=1.9 Hz, 1H), 4, 49-4.40 (m, 2H), 4.14-4.05 (m, 2H), 3.93 (t, J=8.3 Hz, 2H), 3.66 (s, 3H), 3.13 (t, J=8.2 Hz, 2H), 2.34-2.30 (m, 2H).

The following compound was prepared according to the method for preparing compound 53 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 54 JL JL nn rfl -A ^L OV N=/ 512.2 Ή NMR (400 MHz, DMSO-ab) δ 8.83 (s, 1H), 8.13 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 6.24 - 6.20 (m, 2H), 4.45 4.36 (m, 2H), 3.97 - 3.87 (m, 2H), 3.66 (s, 3H), 3.61 - 3.53 (m, 2H), 2.83 (t, J= 6.4 Hz, 2H), 2.28 - 2.24 (m, 2H), 2.02 - 1.98 (m, 2H).

Example 7: Synthesis of compounds 55-210.

Connection 55.

5-chloro-N-(1-methyl-1H-pyrazol-5-yl)-4-(3'-(1-(trifluoromethyl)cyclobutyl)-5Ή,7Ή-spiro[cyclobutan1,6'-pyrrolo[1, 2-a][1,2,4]triazolo[3,4-c][1,4]diazepine]-10'-yl)pyridin-2-amine.

(A) 8'-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-2',3'-dihydro-1Ή,5Ή-spiro[cyclobutan-1,4'-pyrrolo[1,2-a][1,4]diazepin]-1'-one.

The title intermediate was prepared according to the method described in Example 1 using the appropriate intermediates and reagents.

(B) 5-chloro-N-(1-methyl-1H-pyrazol-5-yl)-4-(3'-(1-(trifluoromethyl)cyclobutyl)-5Ή,7Ή-spiro[cyclobutane-1, 6'-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine]-10'-yl)pyridin-2-amine.

A mixture of 8'-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-2',3'-dihydro-1H,5'H-spiro[cyclobutane-1,4'-pyrrolo[1,2-a][1,4]diazepine]-1'-one (55 mg, 0.14 mmol) and 1(trifluoromethyl)cyclobutane-1-carbohydrazide (25 mg, 0.14 mmol) in POC13 (3 mL) was stirred at 100°C for 30 min. The volatiles were removed under reduced pressure and the residue was adjusted to pH 8 with NaHCO ₃ solution and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was dissolved in EtOH (3 mL) and acetic acid (2 drops) and the resulting mixture was stirred at 100 °C for 1.5 h under microwave irradiation. The mixture was then concentrated and the residue was purified by ISCO (eluted with MeOH in water 0-100%) and by pTLC (DCM/MeOH = 15:1) to afford the title compound as a yellow solid (20 mg, 27% yield). MS (m/z): 543.1 (M+H)+.

1H NMR (400 MHz, DMSO^6) δ 8.85 (s, 1H), 8.12 (s, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.31 (d , J=1.6 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 6.97 (s, 1H), 6.22 (d, J=1.6 Hz, 1H ), 4.40 (s, 2H), 4.06 (s, 2H), 3.64 (s, 3H), 2.92 - 2.85 (m, 2H), 2.80-2.74 ( m, 2H), 2.20-2.13 (m, 1H), 2.03-1.96 (m, 2H), 1.89-1.79 (m, 5H).

The following compounds were prepared according to the method for preparing compound 55 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

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Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 56 —Λ.Ν -А мУ' F 457,0 Ή NMR (400 MHz, DMSO-ab) δ 8.83 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 6.96 (s, 1H), 6.23 (d, J = 1.9 Hz, 1H), 5.30-5.21 (m, 1H), 4.83-4.48 (m, 4H), 3.65 (s, 3H), 1.62-1.49 (m, 2H), 1.43-1.28 (m, 2H). 57 Υ C1 ΞΕ / 457.2 Ή NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 7.30 - 7.28 (m, 1H) , 7.02 (s, 1H), 6.82 (s, 1H), 6.21 - 6.18 (m, 1H), 5.58 - 5.19 (m, 1H), 4.76 - 4 .46 (m, 4H), 2.64 2.48 (m, 2H), 2.28 (s, 3H), 1.15-1.04 (m, 3H). 58 / Z' ^H \ I ΐλ ^ζ \ f=\ ^χ - 467,0 Ή NMR (400 MHz, DMSO-de) δ 8.88 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.32 (d, J= 1.3 Hz, 1H), 7.27-6.93 (m, 3H), 6.22 (d, J= 1.3 Hz, 1H), 4.57 (t, J = 5.7 Hz, 2H), 4.49 (t, J = 5.7 Hz, 2H), 3.65 (s, 3H). 59 .,.^γ ^α JL JL NN F ^Η Γιίν< kA -Д ^L O △ N=/ 471,1 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.337.30 (m, 1H), 7.21 (s, 1H), 6.96 (s, 1H), 6.22 - 6.20 (m, 1H), 6.03 - 5.75 (m, 1H), 4.45 - 4.29 (m , 2H), 4.29 4.17 (m, 2H), 3.64 (s, 3H), 2.38 - 2.24 (m, 2H), 1.40 - 1.26 (m, 2H) , 1.26 1.14 (m, 2H). 60 / Z'\ I И < ^Ζ Ύ 'AS y=z ΤΊ 475,1 Ή NMR (400 MHz, DMS-6) δ 8.51 (s, 1H), 7.93 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.30-7.02 (m, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.84 (s, 1H), 6.19 (d, J = 1.9 Hz, 1H), 4.35 (dt, J = 13.9, 3.6 Hz, 2H), 4.12 (ddd, J = 14.0, 7.5, 3.4 Hz, 2H), 3.64 (s, 3H), 2.72-2.61 (m, 1H), 2.28 (d, 7= 0.4 Hz, 3H), 1.03 (d, 7= 7.0 Hz, 3H). 61 Y Y o A ¹ 'z' ^z / 477,1 Ή NMR (400 MHz, DMSSMb) δ 8.85 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.32 - 7.30 (m, 1H), 7 .14 (s, 1H), 6.96 (s, 1H), 6.23 - 6.21 (m, 1H), 5.46 - 5.12 (m, 1H), 4.81 - 4.41 (m, 4H), 3.64 (s, 3H), 2.61 - 2.49 (m, 2H), 1.11-1.02 (m, 3H). 62 LL Y Y |у ^ш in ΞΕ _Z -Z / 479.4 Ή NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.94 (s, 1H), 7.53 (s, 1H), 7.30 - 7.28 (m, 1H) , 7.26 - 7.00 (m, 1H), 7.08 (s, 1H), 6.81 (s, 1H), 6.20 - 6.18 (m, 1H), 5.37 - 5 .32 (m, 1H), 4.73 4.43 (m, 4H), 3.64 (s, 3H), 2.28 (s, 3H). 63 LL y Y X ^z> c, ¹ z' ^z / 483,0 Ή NMR (400 MHz, DMSO-de) δ 8.68 (s, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.30 - 7.13 (m, 3H) , 7.02 (s, 1H), 6.21 - 6.19 (m, 1H), 5.35 - 5.34 (m, 1H), 4.71 4.48 (m, 4H), 3, 64 (s, 3H).

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64 n-μ —(/ ,Ν -ά F 483.1 Ή NMR (400 MHz, DMSO-ab) δ 8.80 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.32 - 7.30 (m, 1H) , 7.05 (s, 1H), 6.95 (s, 1H), 6.22 - 6.20 (m, 1H), 4.98 - 4.95 (m, 1H), 4.68 - 4 .32 (m, 4H), 3.64 (s, 3H), 2.97 (s, 3H), 2.72 - 2.59 (m, 2H), 2.42 - 2.21 (m, 2H ), 1.84 - 1.65 (m, 2H). 65 V <*\d' ^s,TF 487,0 Ή NMR (400 MHz, DMSO-ab) δ 8.52 (s, 1H), 7.93 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.31 - 7 .03 (m, 3H), 6.86 (s, 1H), 6.20 (d, J =1.9 Hz, 1H), 5.18 5.12 (m, 2H), 3.64 (s , 3H), 2.63 - 2.56 (m, 1H), 2.39 - 2.20 (m, 6H), 2.00 1.89 (m, 2H). 66 LL “> 7> / 487,1 'H NMR (400 MHz, flMCO-d6) δ 8.52 (s, 1H), 7.93 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.29 - 7.27 (m, 2H), 7.27 - 7.00 (m, 1H), 6.86 (s, 1H), 6.20 (d, J = 2.0 Hz, 1H), 4.33 (s, 2H), 4.31 (s, 2H), 3.64 (s, 3H), 2.28 (s, 3H), 0.84 0.79 (m, 2H), 0.78 - 0 .72 (m, 2H). 67 _N =/ ¹ > 487,1 Ή NMR (400 MHz, DMSO-de) δ 8.53 (s, 1H), 7.92 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.33 - 7 .04 (m, 3H), 6.86 (s, 1H), 6.19 (d, J = 1.6 Hz, 1H), 5.16 - 5.12 (m, 2H), 3.64 ( s, 3H), 2.62 2.55 (m, 1H), 2.35-2.23 (m, 6H), 1.97 - 1.92 (m, 2H). 68 » i£, ΞΕ ' _Z -Z / 491,1 Ή NMR (400 MHz, DMSO-46) δ 8.57 (s, 1H), 7.95 (s, 1H), 7.73 - 7.68 (m, 2H), 7.56 (d, J= 1.6 Hz, 1H), 7.47 7.37 (m, 2H), 7.30 (d, J= 2.0 Hz, 1H), 7.03 (d, J= 1.6 Hz, 1H ), 6.83 (s, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.64 - 4.61 (m, 2H), 4.51 - 4.48 (m, 2H), 3.65 (s, 3H), 2.29 (s, 3H).

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69 He C ¹ ζ' ^ζ / 491,1 Ή NMR (400 MHz, DMSO-ab) δ 8.64 (s, 1H), 8.03 (d, J= 5.3 Hz, 1H), 7.78 - 7.64 (m, 3H), 7 .46 - 7.38 (m, 2H), 7.31 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.02 (dd, J= 5.3, 1.4 Hz, 1H), 6.89 (s, 1H), 6.20 (d, J= 1.9 Hz, 1H), 5.27 - 5.08 (m, 1H ), 4.52 - 4.38 (m, 2H), 3.65 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). 70 N=/FF ^F 492.2 Ή NMR (400 MHz, DMSO-de) δ 9.11 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.76 - 7.65 (m, 2H), 7.48 - 7.36 (m, 2H), 7.35 - 7.25 (m, 2H), 6.26 (d, J = 1.6 Hz, 1H), 4.70 - 4.59 (m, 2H), 4.58 - 4.47 (m, 2H), 3.67 (s, 3H), 2.33 (s, 3H). 71 .ΧΙγγΛ Π ~ό ЧУ 492.2 Ή NMR (400 MHz, DMSO-de) δ 9.24 (s, 1H), 8.35 (d, J= 5.0 Hz, H), 7.88 (s, 1H), 7.73 - 7 .70 (m, 2H), 7.48 - 7.29 (m, 4H), 7.17 (d, J = 5.0 Hz, 1H), 6.27 (d,J= 1.9 Hz, 1H), 5.23-5.19 (m, 1H), 4.50 - 4.47 (m, 2H), 3.67 (s, 3H), 1.29 (d, J =5.8 Hz, 3H). 72 γ'Ύ' _c to J1 ν-ν ^{f Η} ΐ ^χ ^ιΓΥ-^ λΛ -Λ 'L l Ν=/ 7\ / F 493,1 Ή NMR (400 MHz, DMSSMb) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.60 (s, 1H), 7.31 - 7.28 (m, 1H), 7 .27 - 7.02 (m, 1H), 7.09 (s, 1H), 6.83 (s, 1H), 6.21 - 6.18 (m, 1H), 4.56 - 4.30 (m, 4H), 3.64 (s, 3H), 2.30 (s, 3H), 1.59 (d, J= 21.6 Hz, 3H). 73 ^ ^Cl -λ ЧЭ Ν—' 495,0 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.31 - 7.29 (m, 1H), 7.23 (s, 1H), 6.96 (s, 1H), 6.22 6.20 (m, 1H), 5.57 (s, 2H), 4.34 (br, 2H), 4.21 (br, 2H), 3.64 (s, ZN), 2.27 (broad, 2H). 74 ^Ν π A JL Μ - Λ. “-Ν ϊ <*> ^Ν Ο 4? ^{ν Ν} γ _ρ 496,0 Ή NMR (400 MHz, DMSSMb) δ 8.93 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.35 - 7.33 (m, 1H), 7 .15 (s, 1H), 6.99 (s, 1H), 6.25 - 6.23 (m, 1H), 4.87 (t, J = 12.9 Hz, 2H), 4.59 (t, J = 12.9 Hz, 2H), 3.67 (s, 3H), 3.00 - 2, 90 (m, 4H), 2.36 - 2.21 (m, 1H), 2.16 - 2.00 (m, 1H).

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75 / ζ'\ ΞΓ h 497,1 Ή NMR (400 MHz, DMSO-ab) δ 8.64 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.29 - 7.27 (m, 1H) , 7.16 (s, 1H), 6.88 (s, 1H), 6.21 - 6.19 (m, 1H), 5.64 - 5.53 (m, 1H), 4.78 - 4.49 (m, 4H), 3.65 (s, 3H), 2.29 (s, 4H). 76 k. LL m -<* Ν FF -A уС ^f Ν=/ ) ^FF F 497,1 Ή NMR (400 MHz, DMSO-ab) δ 8.52 (s, 1H), 7.94 (s, 1H), 7.53 (s, 1H), 7.28 (d, J= 1.8 Hz , 1H), 7.10 (s, 1H), 6.81 (s, 1H), 6.18 (d, J= 1.8 Hz, 1H), 5.37 5.35 (m, 1H), 4.74-4.38 (m, 4H), 3.63 (s, 3H), 2.27 (s, 3H) . 77 / Z'\ X ^V A VsZ τι -η 497,1 Ή NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.92 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.27 (d , J = 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.84 (s, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.59 - 4.55 (m, 1H), 4.04 - 3.97 (m, 2H), 3, 63 (s, 3H), 2.95 - 2.87 (m, 2H), 2.73 - 2.67 (m, 2H), 2.44 - 2.35 (m, 1H), 2.28 (s, 3H), 2.20 - 2.10 (m, 2H), 2.04 - 1.92 (m, 1H), 1.45 (d, J= 6.8 Hz, 3H) . 78 / Q“\_ /y z^^ ^<4 H: “Π 497,1 Ή NMR (400 MHz, DMSO-de) δ 8.57 (s, 1H), 7.98 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.31 - 7.04 (m, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 6.21 (d, J = 2.0 Hz, 1H), 4.87 (t, J = 13.2 Hz, 2H), 4.75 (t, J = 12.4 Hz, 2H), 3.66 (s, 3H), 2.31 (s, 3H). 79 LL C ¹ Z- ^Z / 499,0 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.41 - 6.89 (m, 4H) , 6.23 - 6.21 (m, 1H), 5.37 - 5.34 (m, 1H), 4.84 - 4.42 (m, 4H), 3.64 (s, 3H). 80 LL € ^T z' ² / 499,0 Ή NMR (400 MHz, DMSO-de) δ 8.87 (s, 1H), 8.17 (s, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.42 - 6 .93 (m, 4H), 6.24 (d, J = 1.8 Hz, 1H), 5.73 - 5.51 (m, 1H), 4.65 - 4.57 (m, 4H), 3.67 (s, 3H).

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81 u. S / 499,1 'NMR (400 MHz, DMSO-ab) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.67 (s, 1H), 7.33 - 7.29 (m, 1H) , 7.11 (s, 1H), 6.96 (s, 1H), 6.47 - 6.10 (m, 2H), 4.32 - 4.18 (m, 4H), 3.65 (s, 3H), 2.43 - 2.39 (m, 2H), 2.31 - 2.27 (m, 2H) , 2.20 - 2.16 (m, 2H), 1.80 - 1.55 (m, 4H). 82 ϊ^Γ ГК.. _c k ^F ώ ^F F 501,1 'NMR (400 MHz, DMSO-ab) δ 8.51 (s, 1H), 7.94 (s, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.29 (d , J= 1.8 Hz, 1H), 6.97 (d, J= 1.5 Hz, 1H), 6.81 (s, 1H), 6.19 (d, J= 1.8 Hz, 1H), 5.05 - 4.90 (m, 1H), 4.64 - 4.35 (m, 4H), 3.63 (s , 3H), 3.01 - 2.87 (m, 2H), 2.70 - 2.67 (m, 2H), 2.27 (s, 3H), 2.19-2.11 (m, 1H), 2.02 -1.98 (m, 1H). 83 / ^Z ' ^Z \ ¹ И r ^z v T! }=Z -aE 505,1 'NMR (400 MHz, flMCO-d6) δ 8.57 (s, 1H), 7.97 (s, 1H), 7.82 - 7.68 (m, 2H), 7.57 (s, 1H) , 7.49 - 7.39 (m, 2H), 7.32 (d, J = 1.3 Hz, 1H), 7.10 (s, 1H), 6.86 (s, 1H), 6.24 - 6.20 (m, 1H), 5.26 - 5.16 (m, 1H), 4.55 - 4, 42 (m, 2H), 3.66 (s, 3H), 2.31 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H). 84 V ^ '' 505,1 ‘HNMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.92 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.29 - 7.27 (m, 2H), 6.84 (s, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.32 (s, 2H), 4.30 (s, 2H), 3.63 (s, 3H), 2.27 (s, 3H), 0.83 (t, J = 5.6 Hz, 2H), 0.74 (t, J =5.6 Hz, 2H). 85 / z-\ ¹ -π -η 505,1 'NMR (400 MHz, DMSO-de) δ 8.67 (s, 1H), 8.08 (d, J= 3.0 Hz, 1H), 7.70 (t, J= 2.2 Hz, 1H ), 7.30 (d, J= 1.9 Hz, 1H), 7.10 (dd, J = 1.8, 0.8 Hz, 1H), 7.02 (d, J= 5.5 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 5.55 - 5.35 (m, 1H), 4.65 - 4.43 (m, 2H), 4.40 - 4.30 (m, 1H), 4.21 - 4.04 (m, 1H), 2.97 (dd, J= 21.0, 9.8 Hz, 1H), 2.89 - 2.69 (m, 3H), 2.22 -2.11 (m, 1H), 2.07 - 1.92 (m, 1H) .

- 93 047819

86 cx _w ^Z= \ ^LL V ^w c, ¹ 'z' ^z / 505.2 Ή NMR (400 MHz, DMSO-ab) δ 8.55 (s, 1H), 7.98 (s, 1H), 7.73 - 7.56 (m, 6H), 7.34 - 7.31 ( m, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 6.24 - 6.21 (m, 1H), 5.39 - 5.33 (m, 1H), 4.73 - 4.53 (m, 4H), 3.67 (s, 3H), 2.31 (s, 3H). 87 to JL - Nn ^f \ F ^HN UV-H K X _F -A ^L O ^j △ N=/ 7\ FF 505.3 Ή NMR (400 MHz, DMSO-ab) δ 8.55 (s, 1H), 7.95 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.80 (s, 1H), 6.19 (d, J = 1.9 Hz, 1H), 4.77 (t, J = 13.2 Hz, 2H), 4.65 (t, J = 13.2 Hz, 2H), 3.64 (s, 3H), 1.63-1.60 (m, 2H), 1.38-1.35 (m, 2H). 88 AUL O -A N=/ \ FF ^F 506,0 Ή NMR (400 MHz, DMSO-de) δ 9.10 (s, 1H), 8.24 (d, J= 0.4 Hz, 1H), 7.84 (d, J= 1.6 Hz, 1H ), 7.76 - 7.68 (m, 2H), 7.45 - 7.39 (m, 2H), 7.34 (d, J= 1.6 Hz, 1H), 7.32 (d, J= 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.30 - 5.12 (m, 1H), 4.54.4.49 ( _m , 2H), 3.67 (s, 3H), 2.33 (s, 3H), 1.29 (d, J= 6.7 Hz, 3H). 89 A Z. z I / 506.2 Ή NMR (400 MHz, DMSO-de) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.82 (d, J = 1.4 Hz, 1H), 7.64 - 7 .61 (m, 1H), 7.57 - 7.44 (m, 3H), 7.35 - 7.32 (m, 2H), 6.25 (d,7=1.8 Hz, 1H), 5.16-5.13 (m, 1H), 4.52 - 4.42 (m, 2H), 3, 65 (s, 3H), 2.32 (s, 3H), 1.24 (d, J= 6.6 Hz, 3H). 90 ζ^-Ο p c. ¹ 'z' ^z / 507,0 Ή NMR (400 MHz, DMSO-de) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.67 - 7 .63 (m, 2H), 7.60 - 7.54 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 7.03 (d, J= 1.6 Hz, 1H), 6.82 (s, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4 .66 4.63 (m, 2H), 4.51 - 4.48 (m, 2H), 3.65 (s, 3H), 2.29 (s, 3H).

- 94 047819

91 / τ 4 ^: S 507.2 Ή NMR (400 MHz, DMSO-ab) δ 8.64 (s, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.31 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.89 (s, 1H), 6.20 (d, J = 1.9 Hz, 1H), 5.29 5.12 (m, 1H), 4.51 -4.39(m, 2H), 3.65 (s, 3H), 1.31 (d, J =6.6 Hz, 3H). 92 1 if hA^w ⁿ i Vx F 507.2 Ή NMR (400 MHz, DMSO-de) δ 8.84 (s, 1H), 8.16 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.42 - 7 .30 (m, 3H), 7.29 - 7.15 (m, 2H), 7.06 (d, J = 1.6 Hz, 1H), 6.98 (s, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.27 - 5.09 (m, 1H), 4.74 - 4.18 (m, 6H), 3.68 (s, 3H). 93 N^Y ^CI JL JI nn hn^^ uV-4 Jk zt 507,5 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.14 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.42 (d , J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.30 - 7.02 (m, 1H), 7.02 (s, 1H), 6.24 (d, J = 2.0 Hz, 1H), 4.37 (s, 2H), 4.32 (s, 2H ), 3.67 (s, 3H), 0.86 - 0.73 (m, 4H). 94 N=/ F F 508.2 Ή NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.24 (s, 1H), 7.88 - 7.80 (m, 2H), 7.69 - 7.62 ( m, 2H), 7.60 - 7.50 (m, 1H), 7.37 - 7.25 (m, 2H), 6.26 (d, J = 1.6 Hz, 1H), 4.69 - 4.60 (m, 2H), 4.59 - 4.46 (m, 2H), 3.67 (s , 3H), 2.33 (s, 3H). 95 bjf £ ^x 'z' ^z / 508.2 Ή NMR (400 MHz, DMSO-de) δ 9.28 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.93 7.90 (m, 2H), 7, 68 - 7.61 (m, 3H), 7.41 - 7.36 (m, 2H), 7.20 (d, J= 5.2 Hz, 1H), 6.33 - 6.28 (m, 1H), 5.26 - 5.24 (m, 1H), 4.55 - 4.52 (m, 2H), 3 .71 (s, 3H), 1.34 (d, J =6.6 Hz, 3H). 96 / Z-\ I b mb A uo 509.2 Ή NMR (400 MHz, DMSO-de) δ 8.72 (s, 1H), 8.05 (d, J= 5.2 Hz, 1H), 7.83 - 7.67 (m, 3H), 7 .52 - 7.38 (m, 2H), 7.37 - 7.32 (m, 1H), 7.24 (s, 1H), 7.03 (d, J= 4.7 Hz, 1H), 6.92 (s, 1H), 6.25 6.21 (m, 1H), 5.53 - 5.34 (m, 1H), 4.81 - 4.55 (m, 4H), 3.66 (s, 3H).

- 95 047819

97 4 ΛΪ 510,0 Ή NMR (400 MHz, DMSO-ab) δ 9.35 (s, 1H), 8.46 (d, J= 3.3 Hz, 1H), 7.93 (t, J= 1.7 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.45 - 7.39 (m, 2H), 7.34 (d, J = 1.9 Hz, 1H), 7.27 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.27 - 5.17 (m, 1H), 4.61 - 4.48 (m, 2H), 3.67 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H). 98 N=/ > ^FF F 510.2 Ή NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 8.47 (d, J= 3.3 Hz, 1H), 7.94 7.91 (m, 1H), 7, 72 - 7.53 (m, 5H), 7.35 (d, J= 3.3 Hz, 1H), 7.25 (s, 1H), 6.27 (d, J= 1.9 Hz, 1H), 5.49 - 5.35 (m, 1H), 4.87 - 4.50 (m, 4H), 3, 68 (s, 3H). 99 ^h ^^Vw ⁿ 1 tV -da F 510.2 Ή NMR (400 MHz, DMSO-de) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.29 (d , J= 1.9 Hz, 1H), 7.10 (s, 1H), 7.08 (d, J = 1.7 Hz, 1H), 6.81 (s, 1H), 6.19 (d, J = 1.9 Hz, 1H), 5.43 - 5.30 (m, 1H), 4.73 - 4.46 (m, 4H), 3.64 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H). 100 o -A ⁴ wYf N=/ > ^FF F 510.2 Ή NMR (400 MHz, DMSSMb) δ 9.24 (s, 1H), 8.34 (d, J= 5.2 Hz, 1H), 7.87 (d, J= 1.6 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.45 - 7.42 (m, 2H), 7.36 (d, J= 1.6 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6, 27 (d, J= 1.9 Hz, 1H), 5.46 - 5.35 (m, 1H), 4.80 - 4.56 (m, 4H), 3.67 (s, 3H). 101 / Z'\ I Й lb T ^: S 511,1 Ή NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.94 (s, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.28 (d , J= 2.0 Hz, 1H), 7.08 (d, J= 1.6 Hz, 1H), 6.81 (s, 1H), 6.18 (d, J= 2.0 Hz, 1H), 5.48 - 5.37 (m, 1H), 4.77 - 4.49 (m, 4H), 3, 63 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H).

- 96 047819

102 —Ζ'Ν'Ν Ν ^<ίΓ \_—ci -А N=/ \ FF 512.2 Ή NMR (400 MHz, DMSO-ab) δ 9.13 (s, 1H), 8.87 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.83 (d, J= 1.6 Hz, 1H), 7.37 (d, J= 1.6 Hz, 1H), 7.33 (d, J= 1.8 Hz, 1H), 6.26 (d, J= 1.8 Hz, 1H), 4.93 4.80 (m, 1H), 4.48 - 4.34 (m, 2H), 3.67 (s, 3H), 2.33 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H). 103 t £ / 513,0 Ή NMR (400 MHz, DMS-6) δ 8.85 (s, 1H), 8.15 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H), 5.26 - 5.17 (m, 1H), 4.51 (d, J = 2.8 Hz, 2H), 3.64 (s, 3H), 2.43 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). 104 LL h . I * V ^z / 513,1 Ή NMR (400 MHz, DMSSMb) δ 8.53 (s, 1H), 8.37 (t, J= 2.8 Hz, 1H), 7.96 (s, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.30 (d, 7= 1.9 Hz, 1H), 7.10 (d, J= 1.7 Hz, 1H), 6.83 (s, 1H), 6.52 (dd, J = 5.8, 3.0 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 5.26 - 5.14 (m, 1H), 4.66 (d, J = 14.2 Hz, 1H), 4.64 - 4.42 (m, 3H), 3.65 (s, 3H), 2.30 (s, 3H). 105 N=/ 513,1 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.31 (d , J= 1.9 Hz, 1H), 7.05 (d, J= 2.0 Hz, 1H), 6.97 (s, 1H), 6.22 (d, J= 1.9 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.46 - 4.37 (m, 1H), 4, 21 4.11 (m, 1H), 3.64 (s, 3H), 2.83 - 2.79 (m, 1H), 2.71 - 2.54 (m, 3H), 2.38 2.16 (m, 2H), 2.07-1.88 (m, 2H), 1.49 (t, J= 19.2 Hz, 3H), 1.05 (d, J= 7.0 Hz , 3H). 106 A zz A £ ^T z' ² / 515,0 Ή NMR (400 MHz, DMSO-de) δ 8.89 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.89 (s , 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.35 - 7.33 (m, 1H), 7.15 (s, 1H), 6.97 (s, 1H), 6.25 - 6.23 (m, 1H), 5.62 (s, 2H), 4.89 - 4.64 (m, 4H), 3.67 (s, 3H).

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107 N^Y ^CI to JL . NN HN ΐΓν-Λ -A ^l, O i N=> 7\ FF 515,0 Ή NMR (400 MHz, DMSO-ab) δ 8.90 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.97 (s, 1H), 6.23 (d, J = 1.9 Hz, 1H), 5.51 (s, 2H), 4.82 (t, J = 13.2 Hz, 2H), 4.72 (t, J = 13.2 Hz, 2H), 3.66 (s, 3H). 108 <Y Λ N^yF -А CHYALA N 7 \ < ^ό γ A N=/ \ FF 515,0 Ή NMR (400 MHz, DMSO-de) δ 8.90 (s, 1H), 8.74 (d, J= 4.2 Hz, 1H), 8.14 (s, 1H), 8.00 (d , J= 4.2 Hz, 1H), 7.82 (d, J= 1.4 Hz, 1H), 7.32 (d, J= 1.8 Hz, 1H), 7.22 (d, J = 1.4 Hz, 1H), 7.00 (s, 1H), 6.23 (d, J= 1.8 Hz, 1H), 4.91 4.74 (m, 1H), 4.48 - 4.30 (m, 2H), 3.65 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H). 109 o Z ^-Z .^LL t=С ^ш < / 515.2 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.71 (s, 1H), 8.09 (d, J = 2.9 Hz, 1H), 8.01 (s , 1H), 7.86 - 7.69 (m, 1H), 7.30 (d, J= 1.9 Hz, 1H), 7.21 (s, 1H), 7.06 (d, 7 = 5.5 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.54 - 4.31 (m, 2H), 3.65 (s, 3H), 1.14 (d, 7=6.7 Hz, 3H). 110 / Z-\ I Й /=/^2 .A A 516,0 'H NMR (400 MHz, DMSSMb) δ 8.85 (s, 1H), 8.50 - 8.48 (m, 1H), 8.14 (s, 1H), 7.82 (d, J = 1 .5 Hz, 1H), 7.56 7.54 (m, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H) , 6.96 (s, 1H), 6.22 (d, J = 1.8 Hz, 1H), 5.44 - 5.32 (m, 1H), 4.76 - 4.49 (m, 4H ), 3.65 (s, 3H). 111 ^h a ⁿ ιΓΥΎ ¹ '» 'V- ^ci 6 C Λ F 516,0 Ή NMR (400 MHz, DMSSMb) δ 9.25 (s, 1H), 8.80 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.01 (s, 1H ), 7.85 (d, J = 1.3 Hz, 1H), 7.41 (d, J = 1.3 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 5.16-5.11 (m, 1H), 4.77 - 4 .36 (m, 4H), 3.67 (s, 3H).

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112 / z'\ t δ 1=(^- Hi 1 516.2 Ή NMR (400 MHz, DMSO-ab) δ 9.27 (s, 1H), 8.84 (s, 1H), 8.16 - 8.14 (m, 1H), 7.84 (d, J= 1.6 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 1, 7 Hz, 1H), 6.97 (s, 1H), 6.24 (d, J= 1.9 Hz, 1H), 5.42 5.36 (m, 1H), 4.81-4.51 (m, 4H), 3.66 (s, 3H). FROM / Z'H ¹ IL?“\ A /=\ Ω Γ^'Ύ -πΛ_ λ _τ A “Π 517,0 ‘HNMR (400 MHz, flMCO-d6) δ 8.90 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.40 - 6.89 (m, 4H), 6.24 (d, J = 1.8 Hz, 1H), 4.92 (t, J = 13.2 Hz, 2H), 4.76 (t, J = 12.6 Hz, 2H), 3.66 (s, 3H). 114 XI <γ —/.N ^F \/ -Λ ^1ν ;3ΑΑ N у \ < ^R 7 A N=/ ) ^FF F 517,0 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.14 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.32 (d , J = 1.9 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 6.95 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H ), 5.48 - 5.28 (m, 1H), 4.77 - 4.40 (m, 4H), 3.64 (s, 3H). 115 / I Й /=( Q -ηΑ V ysz 517,1 Ή NMR (400 MHz, DMSO-de) δ 8.98 (s, 1H), 8.15 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.32 (d , J= 1.9 Hz, 1H), 7.28 (d, J= 1.9 Hz, 1H), 7.03 (s, 1H), 6.23 (d, J= 1.9 Hz, 1H ), 5.64 - 5.53 (m, 1H), 4.70 - 4.57 (m, 4H), 3.66 (s, 3H). 116 Cl N- _{M c} ^H A^v-ei V y A F 517,5 Ή NMR (400 MHz, DMSO-de) δ 8.82 (s, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.33 - 7.30 (m, 1H) , 7.06 (s, 1H), 6.96 (s, 1H), 6.23 - 6.21 (m, 1H), 4.93 - 4.91 (m, 1H), 4.65 - 4 .40 (m, 4H), 3.65 (s, 3H), 2.79 - 2.77 (m, 2H), 2.61 - 2.59 (m, 2H), 2.05 - 1.83 (m, 2H), 1.48 (t, J = 19.2 Hz, 3H). 117 LI /4 , ^N ~NF hn^'yV-Z > ^F Ά ^L O o ^F N ⁼ ' /\ FF 519.3 Ή NMR (400 MHz, DMSO-de) δ 8.54 (s, 1H), 7.95 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 1.7 Hz, 1H), 6.80 (s, 1H), 6.18 (d, J = 1.8 Hz, 1H), 4.78 (t, J = 13.2 Hz, 2H), 4.47 (t, J = 13.2 Hz, 2H), 3.64 (s, 3H), 2.89-2.86 (m, 2H), 2.83-2.78 (m, 2H), 2.29 (s, 3H), 2.19 - 2.11 (m, 1H), 2.03-1.98 (m, 1H).

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118 / ζ- ^ζ \ τ £ 521,1 Ή NMR (400 MHz, DMSO-ab) δ 8.53 (s, 1H), 7.95 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.69 - 7 .62 (m, 2H), 7.60 - 7.55 (m, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.83 (s, 1H), 6.19 (d, J= 1.8 Hz, 1H), 5.28 5.11 (m, 1H), 4.57 - 4.39 (m, 2H), 3.64 (s, 3H), 2.29 (s, 3H), 1.32 (d, J= 6.6 Hz, 3H). 119 LL Z=( Α ^ζ ~γ. о 2==^ 4<1 / 521,1 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.13 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.30 (d , J= 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.29 - 7.02 (m, 1H), 6.98 (s, 1H), 6 .22 (d, J = 2.0 Hz, 1H), 4.45 (s, 2H), 4.37 (s, 2H), 3.64 (s, 3H), 2.02 - 1.80 ( m, 6H). 120 yA ^ci 11 nn f hn — liNs—1L 1 -A 4j <> ^F D 521,1 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.22 (d, 7 = 1.9 Hz, 1H), 6.98 (s, 1H), 6.50 (t, 7= 55.6 Hz, 1H), 6.22 (d, 7 = 1.6 Hz, 1H), 4.43 - 4.26 (m, 2H), 4.17 - 4.03 (m, 2H), 3.65 (s, 3H), 3.46 3.43 (m, 4H), 2.33 - 2.30 (m, 2H). 121 .Cl /А Jk ^N 'MF ^H A^fW JV A Ar F 521,1 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.13 (s, 1H), 7.79 (s, 1H), 7.32 - 7.30 (m, 1H) , 7.10 (s, 1H), 6.96 (s, 1H), 6.23 - 6.21 (m, 1H), 4.98 - 4.97 (m, 1H), 4.72 - 4 .33 (m, 4H), 3.64 (s, 3H), 2.96 - 2.93 (m, 2H), 2.69 - 2.67 (m, 2H), 2.14-1.99 (m, 2H). 122 N^ ^C ' JL JL nn f -nA ^lf ' 1 O ^F 4 / As/ ¹ V N^ : F 521,1 Ή NMR (400 MHz, DMSO-de) δ 8.95 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.31 - 7.29 (m, 1H) , 7.09 (s, 1H), 7.01 (s, 1H), 6.22 - 6.20 (m, 1H), 5.50 - 5.39 (m, 1H), 4.64 - 4 .28 (m, 3H), 4.13 4.11 (m, 1H), 3.65 (s, 3H), 2.95 - 2.93 (m, 1H), 2.81 - 2.76 ( m, 3H), 2.16 2.13 (m, 1H), 2.01 - 1.99 (m, 1H).

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123 N^ ^C ' to JL NN F \LA ^{F N} , 7 W \Z 14= ⁷ F 521,5 Ή NMR (400 MHz, DMSO-ab) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.35 - 7.33 (m, 1H) , 7.13 (s, 1H), 6.97 (s, 1H), 6.25 - 6.23 (m, 1H), 5.53 -5.41 (m, 1H), 4.63 - 4 .30 (m, 3H), 4.22 4.11 (m, 1H), 3.67 (s, 3H), 3.00 - 2.97 (m, 1H), 2.83 - 2.79 ( m, 3H), 2.19 2.16 (m, 1H), 2.02 -1.99 (m, 1H). 124 / J - ^Ά 0^=^--7 522,0 Ή NMR (400 MHz, DMSO-ab) δ 8.51 (s, 1H), 8.10 (d, J = 7.1 Hz, 1H), 7.95 (s, 1H), 7.69 - 7.60 (m, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.82 (s, 1H), 6.51 - 6.44 (m, 2H), 6.19 (d, J = 1.8 Hz, 1H), 5.50 - 5.37 (m, 1H), 4.85 - 4.61 (m, 3H), 4.57 - 4.46 (m, 1H), 3.64 (s, 3H), 2.29 (s, 3H). 125 vUx O -A ^L w'>n N=/ \ FF ^Cl 522.2 Ή NMR (400 MHz, DMSSMb) δ 9.13 (s, 1H), 8.25 (s, 1H), 7.89 - 7.84 (m, 2H), 7.68 - 7.64 (m, 2H), 7.62 - 7.55 (m, 1H), 7.35 - 7.32 (m, 2H), 6.27 (d, J = 1.8 Hz, 1H), 5.28 - 5 .20 (m, 1H), 4.58 - 4.48 (m, 2H), 3.68 (s, 3H), 2.35 (s, 3H), 1.32 (d, J= 6.6 Hz, 3H). 126 / z-\ I b Ji X -Ц ⁼ ^ Ьэ 523,1 Ή NMR (400 MHz, DMSO-de) δ 8.50 (s, 1H), 7.94 (s, 1H), 7.75 - 7.68 (m, 2H), 7.56 (d, J= 1.5 Hz, 1H), 7.42 7.39 (m, 2H), 7.29 (d, J= 1.8 Hz, 1H), 7.04 (d, J= 1.5 Hz, 1H ), 6.81 (s, 1H), 6.19 (d, J= 1.8 Hz, 1H), 5.49 - 5.33 (m, 1H), 4.76 - 4.54 (m, 4H), 3.64 (s, 3H), 2.28 (s, 3H). 127 , ^ν ή /===\ -A Yv F 523.2 Ή NMR (400 MHz, DMSO-de) δ 8.56 (s, 1H), 7.97 (s, 1H), 7.66 - 7.51 (m, 5H), 7.34 - 7.30 ( m, 1H), 7.07 (s, 1H), 6.85 (s, 1H), 6.24 - 6.20 (m, 1H), 5.41 - 4.38 (m, 1H), 4 .73 - 4.58 (m, 4H), 3.67 (s, 3H), 2.31 (s, 3H).

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128 / I uf “Π 523.2 Ή NMR (400 MHz, DMSO-ab) δ 8.54 (s, 1H), 7.95 (s, 1H), 7.75 - 7.71 (m, 2H), 7.56 (s, 1H) , 7.43 - 7.40 (m, 2H), 7.31 - 7.28 (m, 1H), 7.04 (s, 1H), 6.83 (s, 1H), 6.22-6 .19 (m, 1H), 5.37 - 5.33 (m, 1H), 4.67 - 4.54 (m, 4H), 3.65 (s, 3H), 2.29 (s, 3H ). 129 Ν^Ί< JL JL . nn f HN ^ yVA lx ^F -A ^X O <> ^F N=/ AA 523.2 Ή NMR (400 MHz, DMSO-ab) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.29 (d , J= 1.6 Hz, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.85 (s, 1H), 6.20 (d, J= 2.0 Hz, 1H ), 4.38 (s, 2H), 4.06 (s, 2H), 3.64 (s, 3H), 2.93 - 2.85 (m, 2H), 2.81 - 2.75 ( m, 2H), 2.29 (s, 3H), 2.21 - 2.14 (m, 1H), 2.04 - 1.96 (m, 2H), 1.92 - 1.77 (m, 5H). 130 Ж z _x z € ^T 'z' ^z / 524,0 Ή NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.24 (s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.80 - 7 .70 (m, 1H), 7.40 - 7.24 (m, 4H), 6.26 (d, J = 1.8 Hz, 1H), 5.32 - 5.14 (m, 1H), 4.58 - 4.48 (m, 2H), 3.66 (s, 3H), 2.33 (s, 3H), 1.31 (d, 7=6.7 Hz, 3H). 131 -4X9 F 524,0 Ή NMR (400 MHz, DMSSMb) δ 9.10 (s, 1H), 8.24 (s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.45 - 7.39 (m, 2H), 7.32 - 7.31 (m, 2H), 6.25 (d, J = 2.0 Hz, 1H), 5, 45 - 5.39 (m, 1H), 4.84 - 4.55 (m, 4H), 3.66 (s, 3H), 2.33 (s, 3H). 132 / ^Z ' ^Z \ ¹ Э 524.1 Ή NMR (400 MHz, dmso-de) δ 9.11 (s, 1H), 8.23 (s, 1H), 7.80 (d, J = 1.7 Hz, 1H), 7.74 - 7 .66 (m, 2H), 7.50 - 7.32 (m, 3H), 7.30 (d, J = 1.8 Hz, 1H), 6.24 (d, J = 1.7 Hz, 1H), 5.68 5.50 (m, 1H), 4.83 - 4.48 (m, 4H), 3.66 (s, 3H), 2.32 (s, 3H).

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133 / ί 524.2 Ή NMR (400 MHz, DMSO-ab) δ 8.55 (d, J = 4.5 Hz, 1H), 8.51 (s, 1H), 8.09 - 7.99 (m, 1H), 7 .96 (s, 1H), 7.86 7.77 (m, 1H), 7.56 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 1.9 Hz, 1H ), 7.05 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 6.20 (d, J = 1.9 Hz, 1H), 5.50 - 5.20 (m, 1H), 4.77 _ 4D9 ( _m , 4H), 3.65 (s, 3H), 2.30 (s, 3H). 134 ' _N =/ FF ^r 524.2 Ή NMR (400 MHz, DMSODb) δ 9.12 (s, 1H), 8.25 (s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.71 - 7.45 (m, 3H), 7.35 (d, J= 1.5 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 6.27 (d, J= 1.9 Hz , 1H), 5.33 5.14 (m, 1H), 4.54 - 4.51 (m, 2H), 3.67 (s, 3H), 2.34 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H). 135 Z. Z^z ό \=^ ^τ 'z' ^z / 525,0 Ή NMR (400 MHz, DMSODb) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.50 - 7.36 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H) , 6.99 (s, 1H), 6.24 (d, J= 1.8 Hz, 1H), 5.26 5.17 (m, 1H), 4.54-4.48 (m, 2H) , 3.66 (s, 3H), 1.31 (d, J =6.6 Hz, 3H). 136 / Z-\ ΞΕ Ji ¹ 525,1 Ή NMR (400 MHz, DMSODb) δ 8.85 (s, 1H), 8.11 (s, 1H), 7.53 (s, 1H), 7.31 - 7.29 (m, 1H), 7 .27 (s, 1H), 6.97 (s, 1H), 6.22 - 6.20 (m, 1H), 4.24 (s, 2H), 3.97 (s, 2H), 3, 64 (s, 3H), 2.71 - 2.52 (m, 4H), 2.02 - 1.95 (m, 1H), 1.91 1.85 (m, 1H), 1.49 (t , J = 19.2 Hz, 3H), 0.72 - 0.65 (m, 4H). 137 -З^^Ц'тР F 525.2 Ή NMR (400 MHz, DMSODb) δ 8.89 (s, 1H), 8.17 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.70 - 7.59 (m, 5H), 7.35 (d, 7= 1.9 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.00 (s, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.40 - 5.35 (m, 1H), 4.81 - 4.50 (m, 4H), 3.68 (s, 3H).

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138 HA T || A ^T / 525.2 'NMR (400 MHz, DMSODb) δ 8.77 (s, 1H), 8.06 (d, J= 5.4 Hz, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.78 (d, J= 1.3 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.64 - 7.58 (m, 1H), 7.34 (d, J= 1.8 Hz, 1H), 7.23 (d, J= 1.3 Hz, 1H), 7.05 (d, J= 5.4 Hz, 1H), 6.95 (s, 1H), 6 .24 (d, J= 1.8 Hz, 1H), 5.49 - 5.43 (m, 1H), 4.78 - 4.61 (m, 4H), 3.68 (s, 3H). 139 / z- ^z \ I ъ /==\ - A A 525.2 'NMR (400 MHz, DMSODb) δ 8.82 (s, 1H), 8.14 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.49 - 7.37 (m, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.20 - 7.09 (m, 2H), 7.05 (d, J = 1.7 Hz, 1H) , 6.97 (s, 1H), 6.23 (d, J= 1.9 Hz, 1H), 5.30 5.25 (m, 1H), 4.79 - 4.61 (m, 2H) , 4.56 - 4.36 (m, 2H), 4.26 - 4.14 (m, 2H), 3.65 (s, 3H). 140 / Z'\ ΞΓ ΙΛ.Ζ \ /=\ — XX -A_Xf ΤΊ ¹ 525.2 'NMR (400 MHz, DMSODb) δ 8.93 (s, 1H), 8.21 (m, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 6.99 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 4.86 (t, J = 13.2 Hz, 2H), 4.70 (t, J = 13.2 Hz, 2H), 3.69 (s, 3H), 1.66-1.63 (m , 2H), 1.421.41 (m, 2H). 141 / z- ^z \ IX /X'2 Jjg 1 ^: *o 526,0 'HNMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.68 (d, J= 4.6 Hz, 1H), 8.13 (s, 1H), 8.10 - 8.03 (m, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.82 (d, J= 1.6 Hz, 1H), 7.66-7.59 (m, 1H), 7.31 (d, J= 1.9 Hz, 1H), 7.14 (d, J= 1.6 Hz, 1H), 6.98 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H), 5.55 5.29 (m, 1H), 4.79 - 4.52 (m, 4H), 3.64 (s, 3H). 142 AAw^o '0 F 526.2 'NMR (400 MHz, DMSODb) δ 9.28 (s, 1H), 8.38 (d, J= 5.2 Hz, 1H), 7.92 7.90 (m, 2H), 7.69 - 7.66 (m, 2H), 7.63 - 7.60 (m, 1H), 7.43 - 7.34 (m, 2H), 7.20 (d, J= 5.2 Hz, 1H) , 6.32 - 6.29 (m, 1H), 5.50 -5.44 (m, 1H), 4.84 - 4.58 (m, 4H), 3.71 (s, 3H).

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143 / Z'\ I 526.2 Ή NMR (400 MHz, DMSO-ab) δ 9.36 (s, 1H), 8.47 (d, J= 3.3 Hz, 1H), 7.94 (s, 1H), 7.87 (d , J= 7.5 Hz, 1H), 7.68 7.65 (m, 2H), 7.61 - 7.54 (m, 1H), 7.35 (d, J= 1.9 Hz, 1H ), 7.28 (s, 1H), 6.27 (d, J = 1.9 Hz, 1H), 5.32 - 5.20 (m, 1H), 4.62 - 4.60 (m, 2H), 3.68 (s, 3H), 1.31 (d, 7=6.6 Hz, 3H). 144 / ^ss5:S \^o ,r ² z' ^z / 527,0 Ή NMR (400 MHz, dmso-de) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.98 (s, 1H), 7.89 - 7.86 (m, 1H) , 7.67 - 7.65 (m, 2H), 7.60 - 7.56 (m, 1H), 7.37 (s, 1H), 7.20 (ymnp.s, 1H), 6.35 (yiimp.s, 1H), 5.50 - 5.44 (m, 1H), 4.84 (d, 7 = 14.2 Hz, 1H), 4.73 (d, 7 = 4.7 Hz, 1H), 4.65 - 4.60 (m, 2H), 3.68 (s, 3H). 145 n/pwiO -5 ρϋσ F 527,1 'NMR (400 MHz, DMSODb) δ 8.67 (s, 1H), 8.11 - 8.06 (m, 1H), 7.79 7.65 (m, 3H), 7.46 - 7.37 (m, 2H), 7.30 (d, 7= 1.9 Hz, 1H), 7.15 (s, 1H), 7.03 (d, 7= 5.2 Hz, 1H), 6.20 (d.7=l.9 Hz, 1H), 5.44 - 5.40 (m, 1H), 4.81 - 4.56 (m, 4H), 3.64 (s, 3H). 146 ?v -Д ^l QA ^{F N=/} 7\ FF 527,1 Ή NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.11 (s, 1H), 7.88 (d, 7 = 2.0 Hz, 1H), 7.28 (d, 7 = 1.6 Hz, 1H), 7.12 (d, 7 = 2.0 Hz, 1H), 6.89 (s, 1H), 6.24 (d, 7 = 1.9 Hz, 1H), 4.83-4.72 (m, 4H), 3.65 (s, 3H), 1.74 (s, 6H). 147 / Z'\ X ^x °4X pZ τι -η 527,5 Ή NMR (400 MHz, DMSO-de) δ 8.57 (s, 1H), 7.98 (s, 1H), 7.39 (s, 1H), 7.31 - 7.29 (m, 1H) , 6.91 (s, 1H), 6.75 (s, 1H), 6.22 - 6.20 (m, 1H), 4.44 - 4.08 (m, 4H), 3.93 - 3 .88 (m, 1H), 3.66 (s, 3H), 3.05 - 2.97 (m, 1H), 2.87 - 2.67 (m, 5H), 2.21 - 2.14 (m, 1H), 2.05 1.97 (m, 1H), 1.14 (t, 7= 7.2 Hz, 3H). 148 нЛру7;м θ 'ό F 528,0 Ή NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.46 (d, 7= 3.3 Hz, 1H), 7.93 (s, 1H), 7.77 - 7.67 (m, 2H), 7.48 7.39 (m, 2H), 7.34 (d, 7= 1.9 Hz, 1H), 7.25 (s, 1H), 6.25 (d, 7= 1.8 Hz, 1H), 5.48 - 5.39 (m, 1H), 4.88 - 4.56 (m, 4H), 3.67 (s, 3H).

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149 X ЧУ)П Ν=/ F ^F F 528,0 Ή NMR (400 MHz, DMSO-ab) δ 9.29 (s, 1H), 8.38 (d, J= 5.2 Hz, 1H), 7.93 (s, 1H), 7.83 - 7 .66 (m, 2H), 7.48 7.39 (m, 3H), 7.37 (d, J= 2.0 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H ), 6.61 - 6.26 (m, 2H), 5.74 - 5.55 (m, 1H), 4.97 4.85 (m, 1H), 4.78 - 4.62 (m, 1H), 3.70 (s, 3H). 150 --4· ^ν 'ν ^f \^x Χ_ ^l n nAxj F 528,1 Ή NMR (400 MHz, DMSO-de) δ 8.91 (s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.40 - 7.28 (m, 2H) , 7.27 - 7.04 (m, 3H), 5.25-5.07 (m, 1H), 4.71 - 4.10 (m, 7H), 3.58 (s, 3H), 2 .61 - 2.51 (m, 2H), 2.46 - 2.40 (m, 2H), 2.35 - 2.20 (m, 5H). 151 F 528.9 Ή NMR (400 MHz, DMSO-de) δ 8.53 (s, 1H), 7.97 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.55 (d , J= 1.6 Hz, 1H), 7.31 (d, J= 1.9 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.83 (s, 1H), 6.21 (d, J= 1.9 Hz, 1H), 5.20 - 5.08 (m, 1H), 4.69 (d, J = 14.0 Hz, 1H), 4.62 (d, J = 5.1 Hz, 1H), 4.50 (d, J = 5.1 Hz, 1H), 4.44 - 4.43 (m, 1H), 3.66 (s, 3H), 2.30 (s, 3H). 152 / ^Ζ ' ^Ζ \ ¹ ? o 529,0 Ή NMR (400 MHz, DMSO-46) δ 8.52 (s, 1H), 8.49 (d, J= 2.7 Hz, 1H), 7.96 (s, 1H), 7.54 (s , 1H), 7.30 (s, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.20 (s, 1H), 5.27 - 5.14 (m, 1H), 4.70 - 4.38 (m, 4H), 3.65 (s, 3H), 2.29 (s, 3H). 153 / z- ^z \ I i -n^ _z -Z 9 o 529.2 Ή NMR (400 MHz, DMSSMb) δ 8.80 (s, 1H), 8.51 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.53 (d , J= 1.6 Hz, 1H), 7.29 (d, J= 1.9 Hz, 1H), 7.08 (d, J= 1.6 Hz, 1H), 6.81 (s, 1H ), 6.19 (d, J = 1.9 Hz, 1H), 5.21 - 5.05 (m, 1H), 4.69 - 4.40 (m, 4H), 3.64 (s, 3H), 2.28 (s, 3H).

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154 / z- ^z \ I ъ /==( - JU 529.2 Ή NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.14 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 6.96 (s, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.22 (d, J = 1.9 Hz, 1H), 5.42 - 5.23 (m, 1H), 4.75 - 4.52 (m, 4H), 3.84 (s, 3H), 3.64 (s, 3H). 155 Z=\ z ^H -\ Ύ Ф^°\ о к ²¹ ' ^x 'z' ^H / 529,5 Ή NMR (400 MHz, DMSODb) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.73 (s, 1H), 7.32 - 7.30 (m, 1H), 7 .04 (s, 1H), 6.95 (s, 1H), 6.23 - 6.21 (m, 1H), 4.41 (d, J = 14.6 Hz, 1H), 4.22 ( d, J= 14.6 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.81 - 3.78 (m, 1H), 3.65 (s, 3H), 3.34 (s, 3H), 2.90 2.86 (m, 1H), 2.65 - 2.61 (m, 3H), 2.02 - 1.98 (m, 1H), 1.93 - 1.89 (m, 1H), 1.51 (t, J= 19.1 Hz, 3H) . 156 HN^N^SrfX—N^\—Cl -i ^x CC ^m F 530.2 Ή NMR (400 MHz, DMSODb) δ 9.12 (s, 1H), 8.81 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.82 (d , J= 1.5 Hz, 1H), 7.37 (d, J= 1.5 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.26 5.05 (m, 1H), 4.77 - 4.41 (m, 4H), 3.67 (s, 3H), 2.32 (s, 3H ). 157 / Z' ^Z \ I -n^zz 9 o 530.9 Ή NMR (400 MHz, DMSODb) δ 8.89 (s, 1H), 8.85 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.82 (s , 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H), 6.99 (s, 1H), 6.23 (d , J = 1.8 Hz, 1H), 4.92 - 4.82 (m, 1H), 4.48 - 4.30 (m, 2H), 3.65 (s, 3H), 1.14 ( d, J= 6.6 Hz, 3H). 158 XI 1 ιΓ ⁿ MuL 0 -A u ^N V\ N=/ ) ^FF F 531,0 Ή NMR (400 MHz, DMSODb) δ 8.88 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.98 (s, 1H), 6.22 (d, J = 2.0 Hz, 1H), 5.49 - 5.39 (m, 1H), 4.79 - 4.52 (m, 4H), 3.64 (s, 3H), 2.44 (s, 3H).

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159 ^N Η JL JL nn f _ AdA 531,1 Ή NMR (400 MHz, DMSO-ab) δ 8.85 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.30 (d , J= 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.98 (s, 1H), 6.21 (d, J = 2.0 Hz, 1H ), 4.10 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 - 2.84 (m, 2H), 2.77 - 2.67 ( m, 2H), 2.18 2.11 (m, 1H), 2.02-1.95 (m, 1H), 1.02 (s, 6H). 160 A A 1 . nn HN (уЧ Λχ/^F -nA <AO f ^<F N=/ 531,1 Ή NMR (400 MHz, DMSODb) δ 8.86 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.35 - 7.33 (m, 1H), 7 .09 (s, 1H), 7.00 (s, 1H), 6.26 - 6.24 (m, 1H), 4.62 -4.58 (m, 1H), 4.47 - 4.43 (m, 1H), 4.20 4.17 (m, 1H), 3.68 (s, 3H), 3.16 - 3.05 (m, 2H), 2.78 - 2.68 (m, 2H), 2.39 2.28 (m, 4H), 2.18-2.16 (m, 1H), 1.94 -l.90(m, 1H), 1.12 (d, 7= 6.5 Hz, 3H). 161 IrA(UL O -nA YES N=/ > ^FF F 532.1 Ή NMR (400 MHz, DMSODb) δ 8.87 (s, 1H), 8.17 (d, J = 3.1 Hz, 1H), 8.14 (s, 1H), 8.10 - 8.04 (m, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 1.7 Hz , 1H), 6.97 (s, 1H), 6.22 (d, J= 1.9 Hz, 1H), 5.47 - 5.33 (m, 1H), 4.80 - 4.52 ( m, 4H), 3.64 (s, 3H). 162 N^Y ^CI ΑΛ ,N~N ^Af ^NG |^^AGU^ A/NZ ^f Ά v ^FF F 533,0 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.77 (d, J= 4.4 Hz, 1H), 8.14 (s, 1H), 8.00 (d , J= 4.4 Hz, 1H), 7.79 (d, 7= 1.8 Hz, 1H), 7.32 (d, 7= 1.8 Hz, 1H), 7.29 (d, 7 = 1.8 Hz, 1H), 6.96 (s, 1H), 6.22 (d, 7= 1.8 Hz, 1H), 5.44 (d, 7= 44.1 Hz, 1H), 4.72 - 4.52 (m, 2H), 4.43 - 4.19 (m, 2H), 3.65 (s, 3H). 163 Cl Ϊ1 ^Η ΐ ^>4 ιΓΥ-A ό ψ F 533,0 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.70 (d, 7= 4.4 Hz, 1H), 8.14 (s, 1H), 8.00 (d, 7= 4.1 Hz, 1H), 7.81 (d, 7= 1.5 Hz, 1H), 7.32 (d, 7= 1.8 Hz, 1H), 7.20 (d, 7= 1.5 Hz, 1H), 6.95 (s, 1H), 6.22 (d, 7= 1.8 Hz, 1H), 5.13 5.07 (m, 1H), 4.73 - 4.44 (m, 4H), 3.64 (s, 3H).

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164 λ z- ^z . Ll_ ?=C“ γ^ \lc, ^T z' ^z / 533,0 Ή NMR (400 MHz, DMSO-ab) δ 8.80 (s, 1H), 8.72 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.31 - 7.28 (m, 1H), 7.20 (s, 1H), 7.05 (d, J= 5.0 Hz, 1H), 6.21 - 6, 19 (m, 1H), 5.31 - 5.01 (m, 1H), 4.77 - 4.42 (m, 4H), 3.65 (s, 3H). 165 ft Ύ V°\ ^zr О )= ^{7 T} z' ^z / 533,1 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.12 (s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.31 (d , J= 1.9 Hz, 1H), 7.09 (d, J= 1.8 Hz, 1H), 6.95 (s, 1H), 6.21 (d, J= 1.9 Hz, 1H ), 4.43-4.39 (m, 1H), 4.31 - 4.24 (m, 1H), 4.17 - 4.06 (m, 2H), 3.93 - 3.83 (m , 1H), 3.64 (s, 3H), 3.27 (s, 3H), 3.00 - 2.97 (m, 1H), 2.79-2.75 (m, 3H), 2.19 - 2.10 (m, 1H), 2.03-1.99 (m, 1H). 166 v l F 534,0 Ή NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 8.81 (s, 1H), 8.46 (d, J = 3.3 Hz, 1H), 8.01 (s , 1H), 7.91 (t, J = 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.29 (s, 1H), 6.26 (d , J= 1.9 Hz, 1H), 5.22 - 5.12 (m, 1H), 4.80 (d, J = 14.0 Hz, 1H), 4.52 - 4.45 (m, 3H), 3.67 (s, 3H). 167 N=/ ) ^FF F 536,0 Ή NMR (400 MHz, DMSO-de) δ 9.14 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72 - 7.57 (m, 2H) , 7.37 - 7.30 (m, 2H), 7.24 - 7.10 (m, 2H), 6.30 - 6.27 (m, 1H), 5.45 - 5.37 (m, 1H), 4.91 - 4.50 (m, 4H), 3.70 (s, 3H), 3.67 (s, 3H), 2.36 (s, 3H). 168 N^V A 1 nn f hn^^A<V__7 JL L 6 ^N ^ ^N V FF 537,1 Ή NMR (400 MHz, DMSO-de) δ 8.54 (s, 1H), 7.94 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.31 - 7 .03 (m, 1H), 7.28 (d, 7= 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.85 (s, 1H), 6 .20 (d, J = 2.0 Hz, 1H), 4.50 (s, 2H), 4.47 (s, 2H), 3.64 (s, 3H), 2.74 - 2.55 ( m, 4H), 2.29 (s, 3H).

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169 JL JI nn ^{f n=/} l l 537,1 'NMR (400 MHz, DMSO-ab) δ 8.54 (s, 1H), 7.95 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.80 (s, 1H), 6.46 (t, J = 55.2 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 4.78 (t, J = 13.2 Hz, 2H), 4.54 (t, J = 12.7 Hz, 2H), 3.63 (s, 3H), 3 44.3.35 ( _m , 4H), 2.28 (s, 3H). 170 Ά ^x ”Ц'Х'м F 539.1 'NMR (400 MHz, DMSO-de) δ 8.57 (s, 1H), 7.95 (s, 1H), 7.66 - 7.24 (m, 6H), 7.08 (s, 1H) , 6.84 (s, 1H), 6.20 (s, 1H), 5.52 - 5.35 (m, 1H), 4.74 - 4.58 (m, 4H), 3.65 (s , 3H), 2.30 (s, 3H). 171 LL LL Z=\ ϊ> о )==^ ^x Z- ^Z / 539.1 'NMR (400 MHz, DMSSMb)δ 8.90 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 6.22 (d, J = 2.0 Hz, 1H), 4 .82 (t, J = 13.2 Hz, 2H), 4.48 (t, J = 12.8 Hz, 2H), 3.64 (s, 3H), 2.91 - 2.73 (m, 4H), 2.21 - 2.09 (m, 1H), 2.04 - 1.93 (m, 1H). 172 /= ^s: \-o O\ ?=< ^z _v z I ~r Cn ¹ 'z' ^z / 539.2 'NMR (400 MHz, DMSSMb) δ 8.56 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.71 - 7.68 (m, 2H), 7.64 - 7.56 (m, 2H), 7.32 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 1.3 Hz, 1H) , 6.84 (s, 1H), 6.22 (d, J= 1.7 Hz, 1H), 5.50 5.44 (m, 1H), 4.78 - 4.60 (m, 4H) , 3.67 (s, 3H), 2.32 (s, 3H). 173 jx^HxP ' / \ ^<R> cc Cl №* \ ^FF F 540,0 'NMR (400 MHz, DMSSMb) δ 9.54 (s, 1H), 8.06 (s, 1H), 7.96 - 7.81 (m, 2H), 7.78 - 7.46 (m, 5H), 7.08 (s, 1H), 5.54 - 5.36 (m, 1H), 4.84 - 4.54 (m, 4H), 3.71 (s, 3H), 2.34 (s, 3H). 174 ^N > / ^X ---CiR) /Y Cl 14= ⁷ 7 ^FF F 540,0 'NMR (400 MHz, DMSSMb) δ 8.65 (dd, J = 4.6, 1.3 Hz, 1H), 8.53 (s, 1H), 8.21 (dd, J = 8.2, 1.3 Hz, 1H), 7.96 (s, 1H), 7.73 (dd, J = 8.2, 4.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 6.20 (d, J = 1.9 Hz, 1H), 5.37 - 5.27 (m, 1H), 4.74 - 4.65 (m, 2H), 4.62 - 4.53 (m, 2H), 3.65 (s, 3H), 2.30 (s, 3H).

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175 N=/ ) ^FF F 540,0 Ή NMR (400 MHz, DMSO-ab) δ 8.85 (s, 1H), 8.43 (d, J = 3.7 Hz, 1H), 8.14 (s, 1H), 7.88 (d , J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.61 - 7.47 (m, 1H), 7.33 7.30 (m, 1H), 7.15 (s , 1H), 6.97 (s, 1H), 6.24 - 6.21 (m, 1H), 5.33 - 5.10 (m, 1H), 4.76 - 4.46 (m, 4H ), 3.64 (s, 3H), 2.45 - 2.43 (m, 3H). 176 / Z' ^Z \ I f 540.2 Ή NMR (400 MHz, DMSO-de) δ 9.15 (s, 1H), 8.27 (s, 1H), 7.94 - 7.86 (m, 2H), 7.69 - 7.66 ( m, 2H), 7.64 - 7.57 (m, 1H), 7.36 - 7.34 (m, 2H), 6.29 (d, J= 1.7 Hz, 1H), 5.51 - 5.45 (m, 1H), 4.87 - 4.62 (m, 4H), 3.69 (s, 3H), 2.36 (s, 3H). 177 / z'\ i ъ _=/ o Jra 1 -И >ζ' Όλ 540.2 Ή NMR (400 MHz, DMSO-de) δ 8.93 (s, 1H), 8.66 (d, J= 4.1 Hz, 1H), 8.14 (s, 1H), 8.02 (d , J= 8.0 Hz, 1H), 7.84 (d, J= 1.7 Hz, 1H), 7.43 (t, J= 8.0 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.01 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H), 5.44 - 5.41 (m, 1H), 4.75 - 4.59 (m, 4H), 3.65 (s, 3H), 2.42 (s, 3H). 178 A o U ³¹ ' Υ. ^τ ζ' ^ζ / 541,0 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.89 - 7.84 (m, 2H), 7.68 - 7.65 ( m, 2H), 7.61 - 7.55 (m, 1H), 7.33 (d, J= 1.9 Hz, 1H), 7.18 (d, J= 1.7 Hz, 1H), 6.98 (s, 1H), 6.24 (d, J = 1.9 Hz, 1H), 5.30 - 5.16 (m, 1H), 4.53 - 4.48 (m, 2H) , 3.66 (s, 3H), 1.33 (d, 7=6.7 Hz, 3H). 179 / Ζ'\ I Jra 7 Η'ΐΥ'τ αΟ 541,1 Ή NMR (400 MHz, DMSSMb) δ 8.54 (s, 1H), 7.94 (s, 1H), 7.76 - 7.66 (m, 2H), 7.59 (d, J= 1, 6 Hz, 1H), 7.46 7.36 (m, 2H), 7.29 (d, J= 1.9 Hz, 1H), 7.06 (d, J= 1.6 Hz, 1H), 6.82 (s, 1H), 6.57 - 6.25 (m, 1H), 6.19 (d, J = 1.9 Hz, 1H), 5.67 - 5.54 (m, 1H) , 4.88 - 4.78 (m, 1H), 4.73 - 4.62 (m, 1H), 3.64 (s, 3H), 2.28 (s, 3H).

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180 'd F 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.53 (s, 1H), 7.96 (s, 1H), 7.84 - 7.74 (m, 1H), 7.62 - 7.54 ( m, 2H), 7.49 - 7.41 (m, 1H), 7.32 - 7.28 (m, 1H), 7.06 (s, 1H), 6.83 (s, 1H), 6 .23 - 6.18 (m, 1H), 5.51 - 5.36 (m, 1H), 4.79 - 4.55 (m, 4H), 3.65 (s, 3H), 2.29 (s, 3H). 181 F 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.91 - 7.78 (m, 1H), 7.71 - 7.51 ( m, 3H), 7.30 (a, J = 1.8 Hz, 1H), 7.05 (a, J = 1.5 Hz, 1H), 6.82 (s, 1H), 6.20 ( a, J = 1.8 Hz, 1H), 5.41 - 5.31 (m, 1H), 4.76 - 4.51 (m, 4H), 3.64 (s, 3H), 2.29 (s, 3H). 182 F 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.63 - 7.52 (m, 2H), 7.50 - 7.46 ( m, 2H), 7.30 (a, J = 1.9 Hz, 1H), 7.05 (a, J = 1.6 Hz, 1H), 6.82 (s, 1H), 6.20 ( a, J= 1.9 Hz, 1H), 5.43 - 5.33 (m, 1H), 4.74 - 4.51 (m, 4H), 3.64 (s, 3H), 2.29 (s, 3H). 183 F 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.69 - 7.47 (m, 4H), 7.29 (a, J= 1.9 Hz, 1H), 7.05 (a, J= 1.6 Hz, 1H), 6.82 (s, 1H), 6.20 (a, J= 1.9 Hz, 1H), 5 .51 - 5.35 (m, 1H), 4.74.4.57 ( _m , 4H), 3.64 (s, 3H), 2.29 (s, 3H). 184 -ώ % F 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.91 - 7.78 (m, 1H), 7.61 - 7.47 ( m, 2H), 7.37 - 7.27 (m, 2H), 7.09 (a, J= 1.2 Hz, 1H), 6.85 (s, 1H), 6.22 (a, J = 1.8 Hz, 1H), 5.52 - 5.34 (m, 1H), 4.78 - 4.59 (m, 4H), 3.66 (s, 3H), 2.30 (s, 3H). 185 ^x 'z' ^z / 541.2 Ή NMR (400 MHz, DMSO-ab) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.86 - 7.68 (m, 1H), 7.57 (s, 1H) , 7.45 - 7.28 (m, 3H), 7.10 (s, 1H), 6.85 (s, 1H), 6.23 - 6.20 (m, 1H), 5.52 - 5 .35 (m, 1H), 4.91 4.56 (m, 4H), 3.66 (s, 3H), 2.30 (s, 3H).

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186 N=/ F ^F F 542,0 Ή NMR (400 MHz, DMSO-ab) δ 9.12 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.77 - 7.67 (m, 2H) , 7.46 - 7.38 (m, 2H), 7.36 - 7.31 (m, 2H), 6.58 - 6.23 (m, 2H), 5.70 - 5.56 (m, 1H), 4.98 - 4.88 (m, 1H), 4.76 - 4.65 (m, 1H), 3.67 (s, 3H), 2.33 (s, 3H). 187 ΤΊ =T f :¾ 542.1 Ή NMR (400 MHz, DMSO-ab) δ 9.64 (s, 1H), 8.30 (s, 1H), 7.88 - 7.85 (m, 1H), 7.78 - 7.63 ( m, 3H), 7.61-7.17 (m, 4H), 6.46 (s, 1H), 5.30 - 5.10 (m, 1H), 4.52 (yinnp.s, 2H) , 2.35 (s, 3H), 1.29 (d, 7=5.1 Hz, 3H). 188 -i F 542.2 Ή NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.25 (s, 1H), 7.96 - 7.76 (m, 2H), 7.59 - 7.45 ( m, 1H), 7.43 - 7.22 (m, 3H), 6.30 - 6.26 (m, 1H), 5.53 5.36 (m, 1H), 4.87 - 4.59 (m, 4H), 3.69 (s, 3H), 2.34 (s, 3H). 189 ) ^F FF F 542.2 Ή NMR (400 MHz, dmso-de) δ 9.11 (s, 1H), 8.25 (s, 1H), 7.91 - 7.70 (m, 2H), 7.56 - 7.22 ( m, 4H), 6.31 - 6.25 (m, 1H), 5.54 - 5.37 (m, 1H), 4.89 4.51 (m, 4H), 3.67 (s, 3H ), 2.34 (s, 3H). 190 AviO F 543.1 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 1.0 Hz, 1H), 7.85 - 7 .69 (m, 2H), 7.48 - 7.42 (m, 2H), 7.35 (d, J= 1.6 Hz, 1H), 7.20 (s, 1H), 6.99 ( s, 1H), 6.26 (d, J = 1.6 Hz, 1H), 5.48 - 5.42 (m, 1H), 4.85 - 4.57 (m, 4H), 3.68 (s, 3H). 191 h/UwiCK '•5 F 543.2 Ή NMR (400 MHz, DMSO-de) δ 8.89 (s, 1H), 8.15 (s, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.68 - 7 .59 (m, 1H), 7.57 - 7.49 (m, 3H), 7.33 (d, J= 1.9 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 6.99 (s, 1H), 6.24 (d, J= 1.9 Hz, 1H), 5.42 - 5.36 (m, 1H), 4.79 - 4.54 (m , 4H), 3.66 (s, 3H).

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192 / ^Z ' ^Z \_ ^T J b A ^ζ ^ζ ^ζ jTb Q^X-ss/ 543.2 Ή NMR (400 MHz, DMSO-ab) δ 8.67 (s, 1H), 8.09 (d, J= 2.9 Hz, 1H), 7.88 (d, J= 7.4 Hz, 1H ), 7.77 (s, 1H), 7.70 - 7.52 (m, 3H), 7.31 (d, J = 1.8 Hz, 1H), 7.17 (s, 1H), 7 .03 (d, J= 5.5 Hz, 1H), 6.21 (d, J= 1.8 Hz, 1H), 5.49 5.43 (m, 1H), 4.82 - 4.61 (m, 4H), 3.65 (s, 3H). 193 / ^Z ' ^Z \_ ^T I Q^X-ss/ 544.2 Ή NMR (400 MHz, DMSSMb) δ 9.36 (s, 1H), 8.47 (d, J= 3.3 Hz, 1H), 7.94 (d, J= 1.7 Hz, 1H), 7.88 (d, J= 7.4 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.61 - 7.56 (m, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.27 (s, 1H), 6.27 (d, 7= 1.9 Hz, 1H), 5.515.45 (m, 1H), 4.93-4.58 ( m, 4H), 3.68 (s, 3H). 194 F 544.2 Ή NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.53 (d, J = 4.6 Hz, 1H), 8.14 (s, 1H), 8.08 - 7 .98 (m, 1H), 7.88 7.74 (m, 2H), 7.32 (d, 7= 1.8 Hz, 1H), 7.17 (d, 7= 1.3 Hz, 1H ), 6.97 (s, 1H), 6.22 (d, 7= 1.8 Hz, 1H), 5.52 - 5.18 (m, 1H), 4.80 - 4.53 (m, 4H), 3.65 (s, 3H). 195 / z- ^z \ I Й -JKa _z . K' ω 544.9 Ή NMR (400 MHz, DMSO-de) δ 8.53 (s, 1H), 8.01 (d, 7= 5.3 Hz, 1H), 7.96 (s, 1H), 7.56 (d , 7= 1.6 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.07 (d, 7 = 1.6 Hz, 1H), 6.83 (s, 1H), 6 .20 (d, 7= 1.9 Hz, 1H), 5.44 - 5.22 (m, 1H), 4.74 - 4.53 (m, 4H), 3.65 (s, 3H), 2.29(s,3H). 196 / A A A 545,0 Ή NMR (400 MHz, DMSSMb) δ 8.72 (s, 1H), 8.07 (d, 7= 2.9 Hz, 1H), 7.77 (s, 1H), 7.74 - 7.64 (m, 2H), 7.44 7.36 (m, 2H), 7.29 (d, 7= 1.9 Hz, 1H), 7.22 (s, 1H), 7.01 (d, 7 = 5.5 Hz, 1H), 6.54-6.26 (m, 1H), 6.19 (d, 7= 1.9 Hz, 1H), 5.67 - 5.55 (m, 1H) , 4.92 - 4.87 (m, 1H), 4.71 - 4.59 (m, 1H), 3.63 (s, 3H).

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197 GA A. nA/x \> g/A \_w d \=/ N=/ > ^FF F 546.1 Ή NMR (400 MHz, DMSO-ab) δ 8.53 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.84 - 7.80 (m, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.53 - 5.42 (m, 1H), 4.80 - 4.56 (m, 4H), 3.65 (s, 3H), 2.30 (s, 3H). 198 O Z ^Z u AS £ T Az / 547,0 Ή NMR (400 MHz, DMSO-de) δ 8.78 (s, 1H), 8.55 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.60 (d, J= 1.6 Hz, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.13 (d, J= 1.6 Hz, 1H), 6.84 (s , 1H), 6.52 - 6.25 (m, 1H), 6.22 (d, J= 1.9 Hz, 1H), 5.45 - 5.32 (m, 1H), 4.88 - 4.77 (m, 1H), 4.64 4.51 (m, 1H), 3.67 (s, 3H), 2.31 (s, 3H). 199 JL JL Nn NA ^H N^Xf-yy kJ/Λ -A ^L, O N=/ 7\ FF 547.4 Ή NMR (400 MHz, DMSO-de) δ 8.89 (s, 1H), 8.15 (s, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.86 (d , J = 1.6 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.47 - 7.41 (m, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.20 7.14 (m, 1H), 7.12 (d, J= 2.0 Hz, 1H), 6.96 (s, 1H), 6.23 (d, J= 2, 0 Hz, 1H), 5.98 (s, 2H), 4.79 - 4.70 (m, 4H), 3.65 (s, 3H). 200 / Z'\ I b r=<(5 -P 3=z n^z-z V o 549.1 Ή NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.80 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 6.96 (s , 1H), 6.22 (d, J= 1.9 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.75 - 4.40 (m, 4H), 3.65 ( s, 3H). 201 N=/ ) ^FF °\ 551.2 Ή NMR (400 MHz, DMSO-de) δ 8.51 (s, 1H), 7.94 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.66-7 .63 (m, 2H), 7.577.54 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 1.2 Hz, 1H), 6 .82 (s, 1H), 6.18 (d, /= 2.0 Hz, 1H), 5.23-5.18 (m, 1H), 4.67 - 4.39 (m, 2H), 3.63 (s, 3H), 3.49-3.41 ( _m , 2H), 3.20 (s, 3H), 2.28 (s, 3H).

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202 / ^z ' ^z \ ^t to A 552.2 'NMR (400 MHz, DMSO-ab) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.88-7.84 (m, 2H), 7.66-7.62 ( m, 2H), 7.59 - 7.53 (m, 1H), 7.34 - 7.26 (m, 2H), 6.25 (d, J = 2.0 Hz, 1H), 5.23 -5.19 (m, 1H), 4.76 - 4.42 (m, 2H), 3.66 (s, 3H), 3.50 - 3.41 (m, 2H), 3.18 (s , 3H), 2.32 (s, 3H). 203 / Z- ^Z \ I Й Π 553.1 'NMR (400 MHz, DMSODb) δ 8.89 (s, 1H), 8.14 (s, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.25-7.22 (m, 3H), 7.07 (d, 7= 1.6 Hz, 1H), 6.99 (s, 1H), 6.92 -6.89 (m, 2H), 6.24 (d, 7= 2.0 Hz, 1H), 5.01 - 4.89 (m, 1H), 4.59 (d, 7= 14 Hz, 1H), 4.344.25 (m, 1H), 3.66 (s, 3H), 3.00-2.96 (m, 2H), 2.66-2.56 (m, 2H), 2.36 2.24 (m, 2H). 204 / Ζ' ^Ζ 4 I Й π /=ζ 557,0 'NMR (400 MHz, DMSODb) δ 8.54 (s, 1H), 7.95 (s, 1H), 7.92 - 7.83 (m, 1H), 7.68 - 7.52 (m, 4H), 7.29 (d, 7 = 1.8 Hz, 1H), 7.06 (d, 7 = 1.4 Hz, 1H), 6.81 (s, 1H), 6.57 - 6, 19 (m, 1H), 6.19 (d, J = 1.8 Hz, 1H), 5.71 - 5.58 (m, 1H), 4.89 - 4.77 (m, 1H), 4 .74 - 4.60 (m, 1H), 3.64 (s, 3H), 2.28 (s, 3H). 205 ca I ΞΕ ' _Z -Z / 557.9 'NMR (400 MHz, DMSODb) δ 9.12 (s, 1H), 8.25 (s, 1H), 7.97 - 7.82 (m, 2H), 7.70 - 7.53 (m, 3H), 7.37 - 7.28 (m, 2H), 6.59 - 6.23 (m, 2H), 5.75 5.59 (m, 1H), 5.01 - 4.87 (m , 1H), 4.76 - 4.63 (m, 1H), 3.68 (s, 3H), 2.34 (s, 3H). 206 / z-\ I ъ i=\ - m S I A 559,0 'NMR (400 MHz, DMSODb) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.90 - 7.84 (m, 2H), 7.69 - 7.50 (m, 3H), 7.33 (d, 7 = 1.9 Hz, 1H), 7.17 (d, 7 = 1.6 Hz, 1H), 6.97 (s, 1H), 6.24 (d, 7= 1.9 Hz, 1H), 5.51 - 5.41 (m, 1H), 4.82 - 4.60 (m, 4H), 3.66 (s, 3H).

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207 nXtJvA O F 559.9 Ή NMR (400 MHz, DMSO-ab) δ 8.86 (s, 1H), 8.64 (dd, J = 4.6, 1.2 Hz, 1H), 8.20 (dd, J = 8.2, 1.2 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.74 7.70 (m, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 1.7 Hz), 6.97 (s, 1H), 6.22 (d, J = 1.9 Hz, 1H), 5.39 - 5.25 (m, 1H), 4.81 - 4.72 (m, 1H), 4.72 - 4.64 (m, 1H), 4.63 - 4.52 (m, 2H), 3.65 (s, 3H). 208 RAM» N=/ Y-,? F ^F F 561,0 Ή NMR (400 MHz, DMSSMb) δ 8.90 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.77 - 7.65 (m, 2H), 7 .48 - 7.37 (m, 2H), 7.33 (d, J= 1.8 Hz, 1H), 7.19 (d, J = 1.4 Hz, 1H), 6.99 (s, 1H), 6.57 - 6.29 (m, 1H), 6.24 (d, J= 1.8 Hz, 1H), 5.70 - 5.56 (m, 1H), 4.96 - 4 .85 (m, 1H), 4.75 - 4.64 (m, 1H), 3.66 (s, 3H). 209 O 0 u. ΑΧ o / 567,0 Ή NMR (400 MHz, DMSSMb) δ 8.89 (s, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.88 (s , 1H), 7.35 (d, J = 1.3 Hz, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.57 - 6.18 (m, 2H) , 5.48 - 5.33 (m, 1H), 4.96 - 4.82 (m, 1H), 4.66 - 4.52 (m, 1H), 3.68 (s, 3H). 210 / /==\ Ω Ου? ^ζ γ 579,1 Ή NMR (400 MHz, DMSSMb) δ 8.91 (s, 1H), 8.17 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.33 - 7.25 (m, 3H), 7.11 (d, J = 2.0 Hz, 1H), 7.06 - 7.02 (m, 2H) , 7.01 (s, 1H), 6.26 (d, J= 1.6 Hz, 1H), 4.76 4.71 (m, 1H), 4.25 (d, J= 2.4 Hz , 2H), 3.68 (s, 3H), 3.03 - 2.93 (m, 2H), 2.93 - 2.70 (m, 3H), 2.65 - 2.51 (m, 1H), 2.24 - 2.12 (m, 1H), 2.04 - 1.93 (m, 1H ).

Example 8: Synthesis of compounds 211-214.

Connection 211.

5-chloro-4-(3-((2-fluorophenoxy)methyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepin-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine.

(A) 8-(2,5-dichloropyrimidin-4-yl)-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

A mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one (2.70 g, 9.78 mmol), Pd(dppf) _{Cl2 - CH2Cl2} (799 mg, 0.98 mmol), 2,4,5-trichloropyrimidine (1.97 g, 10.76 mmol), and cesium carbonate (9.56 g, 29.33 mmol) in 1,4-dioxane/water (120 mL/30 mL) was degassed and then stirred at 80 °C for 3 h under nitrogen. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in EA, stirred for 30 min, then filtered and the precipitate was dried in vacuo to give the title compound as a yellow solid (2.85 g). MS (m/z): 296.9 (M+H)+.

(B) 8-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one.

A mixture of 8-(2,5-dichloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-one (2.80 g, 9.46 mmol), 1-methyl-1H-pyrazol-5-amine (4.59 g, 47.28 mmol), Pd ₂ dba ₃ (0.87 g, 0.95 mmol), Xantphos (1.09 g, 1.89 mmol), and cesium carbonate (9.24 g, 28.36 mmol) in 1,4-dioxane (140 mL) was degassed and stirred at 100 °C for 6 h under nitrogen. The mixture was filtered and the filtrate was extracted with EA and water. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on an ISCO system (eluiro

- 117 047819 was washed with methanol in water 0%~100%) to give the title compound as a yellow solid (1.52 g, yield 45.0%). MS (m/z): 358.0 (M+H)+.

(C) 5-chloro-4-(3-((2-fluorophenoxy)methyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepine-1 0-πλ)-Ν-(1-methyl-1 H-pyrazol-5-yl)pyrimidin-2-amine.

The title compound was prepared according to the method described in Example 1 using the appropriate intermediates and reagents. MS (m/z): 506.2 (M+H).

¹ H NMR (400 MHz, DMSO-06) δ 9.48 (s, 1H), 8.43 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.60 ( d, J=2.0 Hz, 1H), 7.44-7.39 (m, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.25-7.20 (m , 1H), 7.19-7.13 (m, 1H), 7.04-6.96 (m, 1H), 6.26 (d, J=1.9 Hz, 1H), 5.40 ( s, 2H), 4.50-4.41 (m, 2H), 4.37-4.30 (m, 2H), 3.68 (s, 3H), 2.40-2.30 (m, 2H).

The following compounds were prepared according to the method for preparing compound 211 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (Μ+Η) ⁺ ‘N NMR 212 pg ^C| -A Ν=> 447.9 Ή NMR (400 MHz, DMSO-ab) δ 9.59 (s, IH), 8.55 - 8.53 (m, 2H), 8.10 (a, J= 6.0 Hz, IH), 7 .91 (a, J = 6.0 Hz, IH), 7.64 (s, IH), 7.38 (4, J = 1.9 Hz, IH), 6.28 (a, J = 1, 9 Hz, IH), 4.38 (q, J= 10.8 Hz, 2H), 3.69 (s, 3H). 213 .01 JL 1 - ν-ν । f HN N TiV—< Ο· % Ά vra Ν=/ 534.1 Ή NMR (400 MHz, DMSO-ab) δ 9.45 (s, IH), 8.42 (s, IH), 7.95 (4, J = 1.9 Hz, IH), 7.58 (4 , J= 1.9 Hz, IH), 7.35 (a, J= 1.8 Hz, IH), 6.25 (a, J= 1.8 Hz, IH), 4.83 (s, 2H ), 4.47-4.38 (m, 2H), 4.30-4.21 (m, 2H), 3.67 (s, 3H), 2.59 - 2.50 (m, 2H), 2.37 - 2.25 (m, 4H), 1.94-1.82 (m, IH), 1.81-1.67 (m, IH). 214 jL JL - ν-ν f ΗΝ^4 ύ A ^F -A ^Χ Ό <> ^F №* FF 535,1 Ή NMR (400 MHz, DMSO-ab) δ 8.44 (s, IH), 7.90 (s, IH), 7.82 (s, IH), 7.26 (s, IH), 7.10 (s, IH), 7.02 (s, IH), 6.19 (s, IH), 4.79 (t, J = 13.2 Hz, 2H), 4.45 (t, J = 12, 4 Hz, 2H), 3.87 (s, 3H), 3.64 (s, 3H), 2.91 -2.83 (m, 2H), 2.80-2.74 (m, 2H), 2.18-2.11 (m, IH), 2.04 - 1.93 (m, IH).

Example 9: Synthesis of compounds 215-216.

Connection 215.

(S)-10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-ol.

OAs

OH OH(A) (R)-8-6pom-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-4-yl-acetate .

To a solution of ((3)-8-bromo-4-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one (1.5 g, 0.006 mol) and Ac ₂ O (0.7 g, 0.006 mol) in THF (50 mL) were added Et ₃ N (1.3 g, 0.012 mol) and N,N-dimethylpyridin-4-amine (40 mg, 0.300 mmol). After stirring at 50 °C for 1 h, the mixture was concentrated and the residue was dissolved in DCM. The organic layer was then washed with saturated NaHCO ₃ solution and water and concentrated to give the title compound as a yellow oily substance (1.5 g, yield 88.2%). MS (m/z): 287.0/289.0 (M+H) ⁺ .

- 118 047819 (B) ^)-1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-III -pyrrolo[1,2a][1,4]diazepin-4-yl-acetate.

A mixture of (D)-8-bromo-1-oxo-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepin-4-yl acetate (200 mg, 0.669 mmol), Pd ₂ (dba) ₃ (32 mg, 0.035 mmol), tricyclohexylphosphine (10 mg, 0.035 mmol), BPIN (178 mg, 0.669 mmol), and KOAc (137 mg, 1.398 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 16 h under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a white solid (150 mg, 64.2% yield). MS (m/z): 335.1 (M+H)+.

(C) ^)-8-(5-chloro-2-((1-methyl-III-pyrazol-5-yl)amino)pyridin-4-yl)-4-hydroxy-2,3,4,5-tetrahydro1 H-pyrrolo[1 ,2-a] [ 1,4]diazepin-1 -one.

A mixture of (1)-1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1/3-pyrrolo[1,2-a][1,4]diazepin-4-yl acetate (150 mg, 0.449 mmol), Pd(dppf)Cl ₂ was stirred.

(16 mg, 0.023 mmol), N2CO3 (95 mg, 0.898 mmol) and 5-chloro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (150 mg, 0.449 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at 80 °C for 2 h under nitrogen atmosphere. The mixture was diluted with water and extracted with DCM. The organic layer was concentrated and the residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a white solid (100 mg, 59.9% yield). MS (m/z): 373.1 (M+H) ⁺ .

(D) (S)-10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-ol.

A mixture of ((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-4-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one (100 mg, 0.269 mmol), 1(trifluoromethyl)cyclobutane-1-carbohydrazide (49 mg, 0.269 mmol) in _POCl3 (5 mL) was stirred at 80 °C for 2 h. The mixture was concentrated and the residue was dissolved in DCM and MeOH. Then the organic layer was washed with saturated _NaHCO3 solution and water, concentrated and the residue was dissolved in NMP (5 mL). A drop of HOAc was added and the mixture was stirred at 130 °C under microwave irradiation for 30 min. The reaction mixture was then purified directly on an ISCO system (eluted with methanol in water 0%~100%) to afford the title compound as a light yellow solid (20 mg, 14.4% yield). MS (m/z): 519.0 (M+H) ⁺ .

^1H NMR (400 MHz, DMSODb) δ 8.85 (s, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.31 (s, 1H), 7.07 ( s, 1H), 6.96 (s, 1H), 6.21 (s, 1H), 4.45-4.28 (m, 2H), 4.14-4.01 (m, 2H), 3 .82-3.7 (m, 1H), 3.03-2.86 (m, 2H), 2.73-2.69 (m, 2H), 2.16-2.12 (m, 1H) , 2.03-2.00 (m, 1H).

The following compound was prepared according to the method for preparing compound 215 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure lx-ms (m/z) (M+H) ⁺ 'N NMR 216 JL JL nn f -N-Ч ϊ Λ ^{F Ν} . 7 VW V OH 519,0 'H NMR (400 MHz, DMSO-ab) δ 8.88 (s, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7. 09 (s, 1H), 6.97 (s, 1H), 6.23 (s, 1H), 4.47 - 4.29 (m, 2H), 4.16 - 4.02 (m, 2H) , 3.83-3.80 (m, 1H), 3.66 (s, 3H), 3.04 - 2.89 (m, 2H), 2.74-2.71 (m, 2H), 2 .18-2.15 (m, 1H), 2.04-2.01 (m, 1H).

Example 10: Synthesis of compounds 217-219.

Connection 217.

-((10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-6,6-difluoro-6,7-dihydro-5Hpyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-3-yl)methyl)-1H-pyrrole-2-carbonitrile.

(A) 8-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-4,4-difluoro-2,3,4,5-tetrahydro-1Hpyrrolo[1,2-a][1,4]diazepin-1-one.

The title intermediate was prepared according to the method described in Example 1 using the appropriate intermediates and reagents.

(B) 2-((4-methoxybenzyl)oxy)acetohydrazide.

- 119 047819

To a solution of ethyl 2-hydroxyacetate (3.1 g, 30 mmol) in anhydrous DMF (50 mL) was added NaH (1.5 mg, 36 mmol, 60% dispersion in liquid paraffin) portionwise at 5 °C under nitrogen atmosphere. The mixture was stirred for 1 h. 1-(Chloromethyl)-4-methoxybenzene (5.6 g, 36 mmol) was added dropwise and the mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated ammonium chloride solution and then concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EA = 4:1) to give a yellow oily substance. The oily substance was dissolved in ethanol (100 mL) and hydrazine hydrate (4.5 mL, 85%) was added. The solution was heated under reflux for 2 h. The solvent was removed on a rotary evaporator and the residue was purified on an ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow oily substance (3.7 g, yield 59%). MS (m/z): 121.1 (M+H)+.

(C) 5-chloro-4-(3-(chloromethyl)-6,6-difluoro-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepine-1 0-a)-\'-(1 -methyl-1 H-pyrazol-5-yl)pyridin-2-amine.

A mixture of 8-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one (784 mg, 2 mmol) and 2-((4-methoxybenzyl)oxy)acetohydrazide (841 mg, 4 mmol) in _POCl3 (10 mL) was stirred at 100°C for 2 h under nitrogen. The solvent was removed on a rotary evaporator and the residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was dissolved in a solution of acetic acid (2 drops) in n-BuOH (20 mL). The solution was stirred at 130 °C for 2 h and then concentrated in vacuo. The residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (380 mg, 41% yield). MS (m/z): 465.1, 467.1 (M+H) ⁺ .

(D) 1-((10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-6,6-difluoro-6,7-dihydro-5Hpyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-3-yl)methyl)-1H-pyrrole-2-carbonitrile.

A mixture of 5-chloro-4-(3-(chloromethyl)-6,6-difluoro-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4-c][1,4]diazepine-10-a)-\'-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (80 mg, 0.17 mmol), 1H-pyrrole-2-carbonitrile (19 mg, 0.21 mmol), and cesium carbonate (166 mg, 0.51 mmol) in acetonitrile (10 mL) was stirred at room temperature under nitrogen overnight. The reaction was quenched with dilute aqueous HCl and then neutralized with saturated aqueous sodium bicarbonate to pH 8. The mixture was extracted with DCM/MeOH (10:1). The organic phases were combined and then concentrated in vacuo. The residue was purified by ISCO (eluted with methanol in water 0%~100%) and by pTLC (DCM/MeOH=10:1) to afford the title compound as a light yellow solid (19.1 mg, 22% yield). MS (m/z): 521.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-ab) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.31 ( d, J=1.9 Hz, 1H), 7.25 (dd, J=2.7, 1.6 Hz, 1H), 7.13 (d, J=1.9 Hz, 1H), 6, 98 (dd, J=4.0, 1.6 Hz, 1H), 6.96 (s, 1H), 6.23 (dd, J=4.0, 2.7 Hz, 1H), 6.21 (d, J=1.9 Hz, 1H), 5.60 (s, 2H), 4.80-4.69 (m, 4H), 3.64 (s, 3H).

The following compounds were prepared according to the method for preparing compound 217 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 218 |№ ^С1 А О 1 N=/ N FF 539,0 Ή NMR (400 MHz, DMSO-ab) δ 9.02 (s, 1H), 8.13 (s, 1H), 7.87 (d, J= 1.7 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.23 (dd, J= 5.0, 3.3 Hz, 1H), 7.13 (d, J= 1.8 Hz, 1H), 7.04 (s, 1H), 6.22-6.21 (m, 2H), 5.57 (s, 2H), 4.81 - 4.69 (m, 4H), 3.65 (s, 3H). 219 _____Cl F -6 l N=/ N F F 539,0 Ή NMR (400 MHz, DMSO-de) δ 8.85 (s, 1H), 8.14 (s, 1H), 7.87 (d,7= 1.7 Hz, 1H), 7.31 (d,7 = 1.8 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.13 (d,7 = 1.8 Hz, 1H), 6.97 (d,7= 2.0 Hz, 1H), 6.95 (s, 1H), 6.21 (d,7= 1.8 Hz, 1H), 5.55 (s, 2H), 4.83 - 4.67 (m, 4H), 3.64 (s, 3H).

Example 11: Synthesis of compounds 220-228.

Connection 220.

^)-4-(3-((2-chlorophenyl)difluoromethyl)-5-(methoxymethyl)-5,6-dihydroimidazo[1,2-a][1,2,4]triazo.1o|3,4- c|pyrazin-9-yl)-5-methyl-\'-(1-methyl-111-11irazol-5-yl)pyrimidin-2-amine.

- 120 047819

(A) Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate.

To a solution of methyl 1H-imidazole-2-carboxylate (10 g, 79.3 mmol) and K ₂ CO ₃ in acetone (300 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (14.3 g, 85.6 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (PE:EA=2:1) to give the title compound as a yellow oily substance (11.9 g, yield 58.5%). MS (m/z): 257.0 (M+H) ⁺ .

(B) Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate.

To a mixture of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (16.6 g, 64.7 mmol), BPIN (32.8 g, 129.2 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (2.2 g, 3.3 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (1.5 g, 6.5 mmol) was added anhydrous THF (110 mL) and the resulting mixture was degassed three times with nitrogen. The mixture was then refluxed overnight under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DMF (400 mL), and Pd( _PPh3 ) ₄ (3.8 g, 3.3 mmol), CuI (1.3 g, 6.5 mmol), _Cs2CO3 ( _15.8 g, 97.0 mmol), and 2,4-dichloro-5-methylpyrimidine (15.8 g, 97.0 mmol) were added. The resulting mixture was degassed three times with nitrogen. The mixture was then stirred at 90 °C overnight under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in TFA (100 mL) and heated under reflux for 2 h. The volatiles were removed, and the residue was neutralized with saturated _NaHCO3 solution and extracted with DCM/MeOH (10:1). The combined organic layers were concentrated and the residue was purified by silica gel chromatography (DCM:MeOH=10:1) to give the title compound as an off-white solid (15.2 g, 92.9% yield). MS (m/z): 253.0 (M+H) ⁺ .

(C) Methyl-B)-1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin4-yl)-1 H-imidαzol-2-carboxylate.

To a solution of methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate (2.5 g, 9.9 mmol), tert-butyl (1-hydroxy-3-methoxypropan-2-yl)carbamate (2.3 g, 12.0 mmol) and _PPh3 (5.3 g, 20.0 mmol) in anhydrous THF (100 mL) was added dropwise DIAD (4.6 g, 20.0 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel chromatography (PE:EA=2:1) to give the title compound as a yellow viscous substance (2.5 g, yield 57.4%). MS (m/z): 440.0 (M+H) ⁺ .

(D) (CH)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin8(5H)-one.

A mixture of methyl (1H)-1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate (2.5 g, 5.7 mmol) and TFA (15 mL) in DCM (20 mL) was stirred at room temperature for 3 h. The mixture was concentrated and the residue was dissolved in MeOH (10 mL) and a solution of ammonia in MeOH (30 mL, 7 M) was added. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow solid (1.21 g, yield 69.2%). MS (m/z): 308.0 (M+H) ⁺ .

(E) (R)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.

To a solution of 1-methyl-1H-pyrazol-5-amine (0.12 g, 1.24 mmol) in THF (10 mL) was added NaHMDS (0.5 mL, 1.0 mmol, 2 M in THF) at room temperature and the resulting mixture was stirred for an additional 20 min under nitrogen atmosphere. (N)-2-(2-chloro-5-methylpyrimidin-4-yl)-6(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (0.12 g, 0.39 mmol) was added and the mixture was refluxed overnight. The reaction was quenched with 4 N HCl. The volatiles were removed and the residue was neutralized with saturated NaHCO ₃ solution. The solvent was removed and the residue was purified by silica gel chromatography (DCM:MeOH=10:1) to give the title compound as a yellow solid (0.118 g, 82.1% yield). MS (m/z): 369.2 (M+H) ⁺ .

(F) U)-4-(3-((2-chlorophenyl)difluoromethyl)-5-(methoxymethyl)-5,6-dihydroimidazo[1,2-a] [1,2,4]triazolo[3,4 -c|pyrazin-9-yl)-5-methyl-\-(1-methyl-111-11irazol-5-yl)pyrimidin-2-amine.

- 121 047819

The title compound was prepared according to the method described in Example 7 using the appropriate intermediates and reagents. MS (m/z): 553.0 (M+H)+.

1H NMR (400 MHz, DMSO^b) δ 9.22 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.89 (d, J=7.5 Hz , 1H), 7.70-7.64 (m, 2H), 7.62-7.54 (m, 1H), 7.32 (d, J=1.8 Hz, 1H), 6.30 ( d, J=1.8 Hz, 1H), 5.38-5.32 (m, 1H), 4.87 (d, J=14.0 Hz, 1H), 4.69 (dd, J=14 ,0, 5.1 Hz, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 2H), 3.13 (s, 3H), 2.52 (s, 3H).

The following compounds were prepared according to the method for preparing compound 220 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure lx-ms (m/z) (M+H) ⁺ Ή NMR 221 / L Όα 523,0 Ή NMR (400 MHz, DMSO-ab) δ 9.22 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 7.5 Hz , 1H), 7.69 - 7.64 (m, 2H), 7.63 7.55 (m, 1H), 7.32 (d, J = 1.9 Hz, 1H), 6.30 (d , J= 1.9 Hz, 1H), 5.42 - 5.26 (m, 1H), 4.75 - 4.60 (m, 2H), 3.69 (s, 3H), 2.53 ( s, 3H), 1.34 (d, J= 6.7 Hz, 3H). 222 W z fЧ-ζι т 523.2 Ή NMR (400 MHz, DMSO-de) δ 9.21 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 7.7 Hz , 1H), 7.76 - 7.64 (m, 2H), 7.63 7.53 (m, 1H), 7.37 - 7.26 (m, 1H), 6.30 (s, 1H) , 5.44 - 5.24 (m, 1H), 4.78 - 4.56 (m, 2H), 3.69 (s, 3H), 2.54 (s, 3H), 1.35 (d , J = 6.7 Hz, 3H).

- 122 047819

223 |AG u AX ^F °\ 537,1 'H NMR (400 MHz, DMSO-ab) δ 9.20 (s, 1H), 8.32 (a, J= 0.6 Hz, 1H), 8.12 (s, 1H), 7.81 - 7.67 (m, 2H), 7.50 - 7.38 (m, 2H), 7.32 (a, j = 1.9 Hz, iH), 6.30 (a, j = 1.9 Hz, IH), 5.32 (aa, J = 10.3, 4.8 Hz, iH), 4.86 (a, j = 14.0 Hz, iH), 4.69 (aa, j = 14.0, 5.1 Hz, IH), 3.69 (s, 3H), 3.58 3.51 (m, 2H), 3.12 (s, 3H), 2.53 (a, J = 0.5 Hz, 3H). 224 / Ζ-\ I fi- uX -n /=Z 541,0 'NMR (400 MHz, DMSO-ab) δ 9.22 (s, IH), 8.32 (s, IH), 8.10 (s, IH), 7.90 (a, J = 7.4 Hz , IH), 7.69 - 7.65 (m, 2H), 7.63 7.56 (m, IH), 7.33 (a, J = 1.8 Hz, IH), 6.30 (a , J= 1.8 Hz, IH), 5.62 - 5.53 (m, IH), 4.98 (4, J= 14.2 Hz, IH), 4.87 - 4.62 (m, 3H), 3.69 (s, 3H), 2.52 (s, 3H). 225 ϊ^ΊΓ -A N=/ > ^FF F 541,0 'NMR (400 MHz, DMSO-ab) δ 9.22 (s, IH), 8.32 (s, IH), 8.10 (s, IH), 7.90 (a, J = 7.3 Hz , IH), 7.70 - 7.58 (m, 2H), 7.61 7.51 (m, IH), 7.32 (s, IH), 6.30 (s, IH), 5.60 - 5.54 (m, IH), 4.98 (a, J = 14.4 Hz, IH), 4.87 - 4.62 (m, 3H), 3.68 (s, 3H), 2, 52 (s, 3H). 226 _F HN k A kAA ^F FF ^F 543,0 'NMR (400 MHz, DMSO-ab) δ 9.76 (s, IH), 8.39 (s, IH), 8.16 (s, IH), 7.92 - 7.58 (m, 4H), 7.49 - 7.39 (m, 2H), 6.53 (s, IH), 5.37 - 5.23 (m, IH), 4.73 - 4.63 (m, 2H), 2.55 (s, 3H), 1.33 (a, J= 6.7 Hz, 3H). 227 z-aT I xi -n /=Z 545,0 ΉNMR (400 MHz, DMSO-ab) δ 8.39 (a, J = 5.2 Hz, 1H), 8.12 (s, 1H), 7.92 - 7.85 (m, 2H), 7.76 (s, 1H), 7.69 - 7.65 (m, 2H), 7.64 - 7.55 (m, 2H), 7.23 - 7.13 (m, 1H), 6.48 (s, 1H), 5.37 - 5.32 (m, 1H), 4.71 4.61 (m, 2H), 1.35 (4, J = 6.7 Hz, 3H). 228 |AT _F HN k A AW ^F Y FF ^Cl 559,0 Ή NMR (400 MHz, DMSO-ab) δ 9.76 (s, IH), 8.39 (s, IH), 8.17 (s, IH), 7.91-7.87 (m, IH) , 7.78 - 7.70 (m, 2H), 7.68 - 7.66 (m, 2H), 7.62 - 7.57 (m, IH), 6.54 (a, J= 1, 6 Hz, IH), 5.39 - 5.31 (m, IH), 4.74 4.63 (m, 2H), 2.56 (s, 3H), 1.35 (a, J = 6, 7 Hz, 3H).

Example 12: Synthesis of compounds 229-274, 322.

Connection 229.

^)-2-((5-chloro-4-(3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)pyridin-2-yl)amino)propan-1-ol.

(A) 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro5H-pyPPROlo[1, 2-a][1,2,4]triazolo[3,4-c][1,4]diazepine.

The title intermediate was prepared according to the method described in Example 1 using the appropriate intermediates and reagents. MS (m/z): 423.1 (M+H)+.

(B) (S)-2-((5-chloro-4-(3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)pyridin-2-yl)amino)propan-1-ol.

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A mixture of 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine (85 mg, 0.2 mmol), (S)-2((5-chloro-4-iodopyridin-2-yl)amino)propan-1-ol (94 mg, 0.3 mmol), Pd(PPh ₃ ) ₄ (23 mg, 0.02 mmol) and Na ₂ CO ₃ (63 mg, 0.6 mmol) in a mixture of 1,4-dioxane/water (10 mL, 4:1) was stirred at 80°C under nitrogen atmosphere for 2 h. The solvent was removed on a rotary evaporator and the residue was purified by ISCO (eluted with methanol in water 0%~100%) and by pTLC (DCM:MeOH=10:1) to give the title compound as a light yellow solid (39 mg, 41% yield). MS (m/z): 481.1 (M+H).

¹ H NMR (400 MHz, DMSO-ab) δ 7.95 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 6.71 (s, 1H), 6.32 (d, J=7.8 Hz, 1H), 4.69 (t, J=5.5 Hz, 1H), 4.32 (t, J=6.0 Hz, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.92-3.86 (m, 1H), 3.49-3.43 (m, 1H), 3.30-3.24 (m, 1H), 2.95-2.87 (m, 2H), 2.79-2.68 (m, 2H), 2.35-2.26 (m, 2H), 2.23-2.10 (m, 1H), 2.05-1.96 (m, 1H), 1.11 (d, J=6.6 Hz, 3H).

The following compounds were prepared according to the method for preparing compound 229 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 230 N |G /X , ^N ~NF _ HN K A A ^F 465,1 'NMR (400 MHz, DMSO-ab) δ 7.95 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H ), 6.64 (s, 1H), 6.38 (d, J = 7.7 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.07 4.04 (m, 2H ), 4.01 - 3.89 (m, 1H), 2.90 (dd, J= 21.1, 9.9 Hz, 2H), 2.74 - 2.69 (m, 2H), 2, 34 - 2.22 (m, 2H), 2.19 - 2.12 (m, 1H), 2.04 - 1.95 (m, 1H), 1.12 (d, J = 6.4 Hz, 6H). 231 A -A/x n^ _{m with} HN Ν J ^{1 F} \,F —. Αχ ^N '>z'' ^{F N} .j A №* \Z 468,1 'NMR (400 MHz, DMSO-de) δ 9.21 (s, 1H), 8.32 (s, 1H), 8.26 (d, J= 1.6 Hz, 1H), 7.97 (d , J = 6.0 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.46 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.68 (s, 3H), 2.96 - 2.89 (m, 2H), 2.86 - 2.79 (m, 2H), 2.39 (s, 3H), 2.21 - 2.14 (m, 1H), 2.05 - 1.96 (m, 1H). 232 ϊΠ AA^/xn _{hi c H} N nA^/ NF _F Y M> 468,1 'NMR (400 MHz, DMSSMb) δ 9.33 (s, 1H), 8.41 (d, J= 5.2 Hz, 1H), 8.12 (d, J= 1.6 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.35-7.32 (m, 2H), 6.29 (d, J = 1.9 Hz , 1H), 3.69 (d, J = 1.7 Hz, 3H), 3.20-3.16 (m, 2H), 2.83-2.79 (m, 2H), 2.41 ( s, 3H), 2.16-2.12 (m, 1H), 1.96-1.92 (m, 1H). 233 N^ Al ,N~NF _c i ja A N=/ 469.2 'NMR (400 MHz, DMSSMb) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.38 (s, 1H), 7.29 - 7.26 (m, 1H), 7 .11 (s, 1H), 6.84 (s, 1H), 6.20 6.17 (m, 1H), 4.38 - 4.32 (m, 2H), 4.31 4.20 (m , 2H), 3.64 (s, 3H), 2.38 - 2.22 (m, 5H), 1.63 - 1.47 (m, 2H), 1.48 - 1.32 (m, 2H ). 234 ϊΠΓ As Jk^x N^., _c HN - NF __ A ^-N nALf N А У / X N=/ FF 475.2 'NMR (400 MHz, DMSSMb) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.49 - 7.08 (m, 4H), 6.83 (s, 1H), 6 .20 - 6.18 (m, 1H), 4.38 (s, 2H), 3.64 (s, 3H), 2.29 (s, 3H), 1.56 (s, 6H).

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235 —Λ.Ν F 1 ft '' JI to N p V_Z X N=/ 4> ^FF 477.2 Ή NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.12 (d, J= 2.4 Hz, 1H), 7.67 (s, 1H), 7.38-7.23 (m, 3H), 7.09 (d, J= 4.2 Hz, 1H), 6.24 (d, J= 1.6 Hz, 1H), 4.45 (s, 2H), 3.68 (s, 3H), 1.62-1.52 (m, 2H), 1.41-1.32 (m, 2H). 236 zP Az-λ N'M _{c H} N Ν^γγ^ζ NF _F U CT 482.1 Ή NMR (400 MHz, DMSODb) 9.20 (s, 1H), 8.31 (s, 1H), 8.09 (d, 7= 1.5 Hz, 1H), 7.81 (s, 1H) , 7.53 (d, 7= 1.5 Hz, 1H), 7.34 (d, 7= 1.9 Hz, 1H), 6.28 (d, 7 = 1.9 Hz, 1H), 3 .68 (s, 3H), 3.25 - 3.20 (m, 2H), 2.85-2.80 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H ), 2.20 - 2.13 (m, 1H), 1.98-1.94 (m, 1H). 237 Pl NN F _c -A ^T O <> ^F 483.2 'NMR (400 MHz, DMSODb) δ 8.51 (s, 1H), 7.94 (s, 1H), 7.40 (d, 7= 2.0 Hz, 1H), 7.29 (d, 7 = 1.9 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.84 (s, 1H), 6.20 (d, J = 1.9 Hz, 1H), 4.37 - 4.27 (m, 2H), 4.11 3.99 (m, 2H), 3.65 (s, 3H), 2.96 - 2.84 (m, 2H), 2.79 - 2.66 (m, 2H), 2.32 - 2.27 (m, 5H), 2.21-2.11 (m, 1H), 2.04-1.95 (m, 1H). 238 ϊΠΓ zk Az-λ ^N 'M c _H NFF -i W 484.1 Ή NMR (400 MHz, DMSODb) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.79 (s, 1H), 7.34 - 7.32 (m, 1H), 7 .28 (s, 1H), 6.27 - 6.25 (m, 1H), 4.82 - 4.73 (m, 1H), 4.46 - 4.39 (m, 1H), 4.35 - 4.28 (m, 1H), 3.67 (s, 2H), 2.98 2.84 (m, 2H), 2.79 - 2.63 (m, 2H), 2.33 (s, 3H), 2.22 - 2.10 (m, 1H), 2.07 - 1.92 (m, 1H), 1.18 (d, 7= 6.4 Hz, 3H). 239 ϊΠΓ zk Az-λ ^N 'M c HN Ν NF _F р J \ ^/ ^N ~pp ^F N=/ 4 \z 484.1 Ή NMR (400 MHz, DMSODb) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.79 (s, 1H), 7.33 (d, J = 1.8 Hz, 1H ), 7.28 (s, 1H), 6.27 (d, 7 = 1.8 Hz, 1H), 4.81 - 4.75 (m, 1H), 4.45 4.41 (m, 1H ), 4.34 - 4.30 (m, 1H), 3.68 (s, 3H), 2.98 - 2.82 (m, 2H), 2.81 - 2.63 (m, 2H), 2.33 (s, 3H), 2.16-2.12 (m, 1H), 2.02 - 1.98 (m, 1H), 1.19 (d, 7= 6.9 Hz, 3H).

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240 ъ ^Q X _Q Q ^Q 486.1 Ή NMR (400 MHz, DMSO-ab) δ 8.53 (s, 1H), 7.93 (s, 1H), 7.40 (a, J= 2.0 Hz, 1H), 7.29 (a, J = 1.9 Hz, 1H), 7.08 (a, J = 2.1 Hz, 1H), 6.85 (s, 1H), 6.20 (a, J = 1.9 Hz, 1H), 4.35 - 4.29 (m, 2H), 4.08 4.02 (m, 2H), 2.94 - 2.87 (m, 2H), 2.77 2.67 (m, 2H), 2.32 - 2.27 (m, 2H), 2.29 (s, 3H), 2.19 - 2.12 (m, 1H), 2.02 - 1.95 (m, 1H). 241 Ϊ if JL 1 - nn f _ HN Ti\s—ft. P ^F -Λ OO ^F N=/ 487,1 'NMR (400 MHz, DMSO-ab) δ 8.67 (s, 1H), 8.07 (a, J = 3.0 Hz, 1H), 7.59 (t, J = 2.3 Hz, 1H), 7.30 (a, J = 1.9 Hz, 1H), 7.19 (a, j = 1.1 Hz, iH), 7.04 (a, j = 5.5 _Hz , 1H), 6.22 (a, J = 1.9 Hz, iH), 4.36 - 4.32 (m, 2H), 4.07 - 4.03 (m, 2H), 3.66 (s, 3H), 2.95 - 2.87 (m, 2H), 2.77 - 2.67 (m, 2H), 2.34 - 2.24 (m, 2H), 2.19-2.12 (m, IH), 2.03 - 1.95 (m, IH). 242 / ^Z ' ^Z \ ^T 'j ¥ 487.2 'NMR (400 MHz, DMSO-ab) δ 8.51 (s, IH), 7.95 (s, IH), 7.54 (s, IH), 7.47 - 7.13 (m, 2H) , 7.06 (s, IH), 6.82 (s, IH), 6.19 6.17 (m, IH), 4.47 (s, 2H), 3.63 (s, 3H), 2 .79 - 2.65 (m, 2H), 2.29 (s, 3H), 2.25 2.17 (m, 2H), 2.12 - 1.87 (m, 2H). 243 Ν^ϊ] F to 1 1 nn f _ HN N TV-// ft U ^F -A ^T O <> ^F 488,1 Ή NMR (400 MHz, CD ₃ OD) δ 8.35 (a, J = 5.2 Hz, IH), 7.55 (a, J = 4.8 Hz, IH), 7.43 (δ, J = 2.0 Hz, IH), 7.14 (δ, J = 4.8 Hz, IH), 6.33 (δ, J= 2.4 Hz, IH), 4.254.22 (m, 2H), 4.13 - 4.09 (m, 2H), 3.75 (s, ZN), 3.02-2.94 (m, 2H ), 2.88-2.81 (m, 2H), 2.43 - 2.38 (m, 2H), 2.32-2.25 (m, IH), 2.17-2.08 (m, IH). 244 νλ/ JL JL n-n 'i hn^YM ft η λ A CHE M 489.1 'NMR (400 MHz, DMSO-δό) δ 8.66 (s, IH), 8.06 (δ, J = 3.0 Hz, IH), 7.56 (t, J = 2.2 Hz, IH ), 7.40 (ΐδ, J= 8.5, 1.5 Hz, IH), 7.30 (δ, J = 1.9 Hz, IH), 7.24 (δ, J = 1.7 Hz , IH), 7.23 - 7.12 (m, 2H), 7.03 6.96 (m, 2H), 6.21 (δ, J = 1.9 Hz, IH), 5.38 (s , 2H), 4.41 (t, J= 5.2 Hz, 2H), 4.33 (t, J= 5.6 Hz, 2H), 3.65 (s, 3H), 2.36 - 2.31 (m, 2H).

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245 / I Tsa cf _m Ul 490,1 Ή NMR (400 MHz, DMSO-ab) δ 9.28 (s, 1H), 8.41 (δ, J= 5.2 Hz, 1H), 7.69 (s, 1H), 7.36 - 7.29 (m, 3H), 7.29 - 7.13 (m, 3H), 6.27 (a, J= 1.8 Hz, 1H), 4.24 (s, 2H), 4.10 (t, J= 6.3 Hz, 2H), 3.98 (t, J= 6.6 Hz, 2H), 3.67 (s, 3H), 2.16 - 2.06 (m, 2H). 246 N^i] F JL 11 1 n-n i HN N Ji -L 43 Ό N=/ 490.2 Ή NMR (400 MHz, CD ₃ 0D) δ 8.32 (a, J = 5.2 Hz, 1H), 7.46 (δ, J = 4.8 Hz, 1H), 7.42 (a, J = 2.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.14-7.10 (m, 3H), 7.03-6.98 (m, 1H), 6.32-6.31 (m, 1H), 5.39 (s, 2H), 4.42 - 4.39 (m , 2H), 4.32 - 4.29 (m, 2H), 3.74 (s, 3H), 2.49 - 2.43 (m, 2H). 247 z^ about ξΌ / ^z 491,1 'NMR (400 MHz, DMSO-ab) δ 8.82 (s, 1H), 8.13 (s, 1H), 7.66 (s, 1H), 7.33 - 7.30 (m, 1H) , 7.02 - 6.96 (m, 2H), 6.23 - 6.21 (m, 1H), 4.25 (s, 2H), 3.65 (s, 3H), 3.16 3, 12 (m, 2H), 2.90 - 2.86 (m, 2H), 1.53 (s, 6H). 248 JL JI , ^N ~NF _c HN ^yvT'> ^F -A ΌΑ N=/ 494.1 Ή NMR (400 MHz, DMSO-ab) δ 9.47 (yiniip.s, 1H), 8.50 (s, 1H), 7.69 (a, J = 2.0 Hz, 1H), 7.37 (a, J = 1.8 Hz, 1H), 7.31 (a, J = 2.0 Hz, 1H), 6.92 (s, 1H), 6.27 (a, J = 1.9 Hz, 1H), 4.34 (t, J = 6.0 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.66 (s, 3H), 2.94 - 2.87 (m, 2H), 2.77 - 2.68 (m, 2H), 2.34 - 2.26 (m, 2H), 2.19 - 2.12 (m, 1H), 2.03 - 1.95 (m, 1H). 249 .Cl I tt _Λ ^F \ 1 in / \ J Y __As. n\/f n > \_/ x N=/ T ^FF 495,1 'NMR (400 MHz, DMSO-ab) δ 8.88 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.44-7.16 (m, 3H) , 7.02 (s, 1H), 6.26 (a, J = 2.0 Hz, 1H), 4.45 (s, 2H), 3.68 (s, 3H), 1.60 (s, 6H). 250 |4T N-... _with AW 496.2 Ή NMR (400 MHz, DMSO-ab) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.67 (s, 1H), 7.36 - 7.24 (m, 2H) , 6.26 (s, 1H), 4.37 - 4.21 (m, 2H), 3.67 (s, 3H), 2.96 - 2.81 (m, 2H), 2.80 2, 70 (m, 2H), 2.33 (s, 3H), 2.09 - 1.90 (m, 2H), 1.35-1.19 (m, 4H).

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251 N=/ 498.2 Ή NMR (400 MHz, DMSO-ab) δ 9.08 (s, 1H), 8.22 (a, J= 0.4 Hz, 1H), 7.68 (a, J = 2.0 Hz, 1H ), 7.40 (a, J= 2.0 Hz, 1H), 7.31 (a, j = 2.0 Hz, iH), 6.26 (a, j = 2.0 _gc , 1H), 4.43 - 4.26 (m, 2H), 3.67 (s, 3H), 2.44 - 2.41 ( m, IH), 2.36 - 2.31 (m, IH), 2.32 (s, 3H), 1.71-1.60 (m, 4H), 1.62 (s, 3H), 1.58 (s, 3H). 252 l>-\_ A o c5 ^m 499,1 'NMR (400 MHz, DMSO-ab) δ 8.28 (s, IH), 7.44 (a, J = 2.5 Hz, IH), 7.43 - 7.35 (m, IH), 7 .26 (a, J = 1.9 Hz, IH), 7.25 7.16 (m, IH), 7.16-7.10 (m, IH), 7.07 (a, 7= 1, 7 Hz, IH), 7.02 - 6.95 (m, IH), 6.61 (s, IH), 5.38 (s, 2H), 4.41 - 4.37 (m, 2H), 4.34 - 4.31 (m, 2H), 2.59 (yinnp.s, IH), 2.38 - 2.28 (m, 2H), 0.74 - 0.68 (m, 2H), 0.48 - 0.42 (m, 2H). 253 / z-\ I \ / ⁼⁼ \ ^A ~ 503,0 'NMR (400 MHz, DMSO-ab) δ 8.81 (s, IH), 8.14 (s, IH), 7.74 (a, 7= 1.7 Hz, IH), 7.33 (a , J = 2.0 Hz, IH), 7.01 (a, J = 1.7 Hz, IH), 6.96 (s, IH), 6.23 (a, J = 2.0 Hz, IH ), 4.53 (s, 2H), 3.65 (s, 3H), 3.33 - 3.32 (m, 2H), 2.96 - 2.83 (m, 2H), 2.80 - 2.67 (m, 2H), 2.20 - 2.08 (m, 2H), 2.04-1.91 (m, 2H). 254 .Cl iT to 1 . NN HN k /--/ ^F - A Ά kF ^N ! /\JF N=/ 503,1 'NMR (400 MHz, DMSO-ab) δ 8.80 (s, IH), 8.11 (s, IH), 7.51 (a, 7= 2.0 Hz, IH), 7.32 (a , J = 2.0 Hz, IH), 7.24 (a, J = 2.0 Hz, IH), 6.99 (s, IH), 6.23 (a, J = 2.0 Hz, IH ), 4.29 (s, 2H), 4.07 (s, 2H), 3.65 (s, 3H), 2.95 - 2.91 (m, 2H), 2.83 2.73 (m , 2H), 0.79 - 0.77 (m, 2H), 0.71 0.66 (m, 2H). 255 T p O 4-n / 503,1 'NMR (400 MHz, DMSO-ab) δ 8.83 (s, IH), 8.12 (s, IH), 7.77 (a, 7= 1.8 Hz, IH), 7.32 (a, 7= 1.7 Hz, IH), 6.99 (s, IH), 6.90 (a, 7 = 1.8 Hz, IH), 6.22 (a, 7 = 1.7 Hz, IH), 4.09 (t, 7= 6.7 Hz, 2H), 3.65 (s, 3H), 3.08 - 3.04 (m, 2H), 2.86 - 2.79 (m, 2H), 2.21 (t, 7= 6.7 Hz, 2H), 0.98-0.93 (m, 2H), 0.83-0.79 (m, 2H).

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256 XI ϊΠΤ _H nVA^^;sj f _f -ft -Ά 503.2 'NMR (400 MHz, DMSO-ab) δ 8.84 (s, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 7.32 (d, J = 1.8 Hz , 1H), 7.10 (d, J = 1.3 Hz, 1H), 6.99 (s, 1H), 6.23 (d, J = 1.8 Hz, 1H), 4.83 - 4 .72 (m, 1H), 4.43 - 4.37 (m, 1H), 4.33 - 4.26 (m, 1H), 3.66 (s, 2H), 2.98 - 2.83 (m, 2H), 2.79 - 2.61 (m, 2H), 2.21-2.10 (m, 1H), 2.07 - 1.92 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H). 257 / Z'\ I b 07 r o c5 ^m 506,0 Ή NMR (400 MHz, DMSO-de) δ 9.31 (s, 1H), 8.43 (m, 1H), 7.74 (s, 1H), 7.47 7.37 (m, 1H), 7.37 - 7.29 (m, 2H), 7.30 7.10 (m, 2H), 7.05 - 6.95 (m, 1H), 6.30 6.27 (m, 1H), 5.45 (s, 2H), 4.25 - 4.09 (m, 4H), 3.68 (s, 3H), 2.35 - 2.26 (m, 2H). 258 / Z' ^z I 509,1 'NMR (400 MHz, DMSO-de) δ 8.54 (s, 1H), 7.92 (s, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.27 (d , J = 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.85 (s, 1H), 6.20 (d, J = 2.0 Hz, 1H ), 4.25 (s, 2H), 3.98 (s, 2H), 3.64 (s, 3H), 2.85 - 2.77 (m, 2H), 2.72 2.65 (m , 2H), 2.27 (s, 3H), 2.16 - 2.09 (m, 1H), 2.01 - 1.92 (m, 1H), 0.74 - 0.72 (m, 4H). 259 / z- ^z \ I Г \\ 1=( - A /\/ ^z 515.2 'NMR (400 MHz, DMSO-de) δ 8.83 (s, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.32 (d, J = 1.7 Hz , 1H), 7.13 (d, J = 1.3 Hz, 1H), 6.99 (s, 1H), 6.23 (d, J = 1.7 Hz, 1H), 4.32 - 4 .22 (m, 2H), 3.66 (s, 3H), 3.00 - 2.82 (m, 2H), 2.78 - 2.70 (m, 2H), 2.12 - 2.00 (m, 1H), 2.00 - 1.89 (m, 1H), 1.33 - 1.16 (m, 4H). 260 / z- ^z \ I \ y n =/ Q Y 517,1 'NMR (400 MHz, DMSO-de) δ 8.87 (s, 1H), 8.18 (s, 1H), 7.87 (d, 7= 1.6 Hz, 1H), 7.35 (d , 7=1.6 Hz, 1H), 7.31 - 6.94 (m, 3H), 6.61-6.30 (m, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.64-5.50 (m, 1H), 4.92 4.87 (m, 1H), 4.78-4.61 (m, 1H), 3.68 (s, 3H).

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261 x? XI ιΓ JL JL . nn f _f -л Any N=/ ' 517,1 'NMR (400 MHz, DMSO-ab) δ 8.81 (s, 1H), 8.11 (s, 1H), 7.71 (a, 7= 2.0 Hz, 1H), 7.31 (a , J= 1.9 Hz, 1H), 6.91 (s, 1H), 6.81 (a, j = 2.0 Hz, iH), 6.20 (a, j = 1.9 _Hz , 1H), 4.03 - 3.95 (m, 2H), 3.82 - 3.72 (m, 2H), 3, 63 (s, 3H), 2.98 -2.88 (m, 2H), 2.76 - 2.67 (m, 2H), 2.21-2.11 (m, IH), 2.05 - 1.98 (m, IH), 1.94 - 1.88 (m, 2H), 1.85 - 1.80 (m, 2H). 262 XI ΐ lT to JL N-n F _ HN ft. Jc -a \A> N=/ 517.2 'NMR (400 MHz, DMSO-ab) δ 8.96 (s, IH), 8.13 (s, IH), 7.73 (s, IH), 7.33 - 7.30 (m, IH) , 7.09 (s, IH), 6.98 (s, IH), 6.24 6.22 (m, IH), 4.52 - 4.43 (m, 2H), 4.224.21 (m, IH), 3.65 (s, 3H), 2.93 - 2.84 (m, 2H), 2.75 - 2.74 (m, 2H), 2.33 - 2.31 (m, 2H) , 2.17 - 2.15 (m, IH), 2.05-2.03 (m, IH), 1.10 (a, 7=6.3 Hz, 3H). 263 to to - N—N _{F F} 4 L/C to X ^L 'i Ϊ <><Ό ο ^v N= 519,1 'NMR (400 MHz, DMSO-ab) δ 9.10 (s, IH), 7.98 (s, IH), 7.71 (t, 7= 57.2 Hz, IH), 7.64 (s , IH), 7.43 (a, 7= 1.9 Hz, IH), 7.12 (a, J = 2.0 Hz, IH), 7.02 (s, IH), 6.45 6, 41 (m, IH), 4.38 - 4.29 (m, 2H), 4.10 4.01 (m, 2H), 2.95 - 2.87 (m, 2H), 2.77 2, 68 (m, 2H), 2.32 (s, 3H), 2.30 - 2.74 (m, 2H), 2.22 - 2.10 (m, IH), 2.05 - 1.95 (m, IH). 264 to X Nn F HN N VV-Il ft. k ^F Ά ^T O <> ^F 14= ⁷ 7\ FF 520,1 'NMR (400 MHz, DMSO-ab) δ 9.13 (s, IH), 8.26 (a, 7= 0.8 Hz, IH), 7.89 (a, 7 = 2.0 Hz, IH), 7.32 (a, 7= 2.0 Hz, IH), 7.28 (a, j = 2.0 Hz, iH), 6.26 (a, j = 2.0 _Hz , IH), 4.84 (t, 7= 13.2 Hz, 2H), 4.47 (t, 7 = 12.8 Hz, 2H), 3.67 (s, 3H), 2.97 - 2.84 (m, 2H), 2.82 - 2.75 (m, 2H), 2.33 (s, 3H), 2.20 - 2.13 (m, IH), 2.04 - 1.95 (m, IH). 265 _H AAq-λ a -Λ ХЛп n=/ ; ^FF 520.3 Ή NMR (400 MHz, DMSO-ab) δ 9.13 (s, IH), 8.25 (s, IH), 7.91 (s, IH), 7.81 - 7.65 (m, 2H) , 7.46-7.40 (m, 2H), 7.33 (s, 2H), 6.27 (s, IH), 5.02 - 4.89 (m, IH), 4.74 (a , 7= 13.6 Hz, IH), 4.48-4.42 (m, IH), 3.67 (s, 3H), 2.34 (s, 3H), 1.70 - 1.44 ( m, 2H), 0.90 (t, 7= 7.4 Hz, 3H).

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266 xfx XI ΐ if to JI N-N F hn^ YVJ' ύ 1 Ά ΌΤ N=/ F F 521,0 'NMR (400 MHz, DMSO-ab) δ 8.87 (s, 1H), 8.15 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 6.47 (t, J = 56.0 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H), 4.80 (t, J = 13.2 Hz, 2H), 4.45 (t, J = 12.8 Hz, 2H), 3.65 (s, 3H), 2.73 - 2.56 (m, 4H), 2.16 - 2.09 (m, 1H), 1.98 - 1.90 (m, 1H). 267 xjx XI ΐ if JL JL . nn f HN ^-^ liXs—Z ⁷ P ^F -A ^X O <> ^F _N =/ (S)^S? 529,1 'H NMR (400 MHz, DMSO-de) δ 8.84 (s, 1H), 8.12 (s, 1H), 7.71 (d, J= 2.1Hz, 1H), 7.31 (d , J= 1.9 Hz, 2H), 7.00 (s, 1H), 6.23 (d, J = 1.9 Hz, 1H), 5.14 - 5.10 (m, 1H), 4 .76 - 4.71 (m, 1H), 3.65 (s, 3H), 2.95 2.80 (m, 2H), 2.79 - 2.67 (m, 2H), 2.52 2 .48 (m, 1H), 2.34 - 2.27 (m, 2H), 2.18 2.14 (m, 2H), 2.00 - 1.94 (m, 2H), 1.90 1.77 (m, 1H). 268 .^x XI ΐ if JL JL nn f _c HN ^^ γΧ —& ύ Jc ^F -Λ ^L O <> ^F kA 2\ 529,1 'NMR (400 MHz, DMSO-de) δ 8.86 (s, 1H), 8.12 (s, 1H), 7.56 (d, J= 1.2 Hz, 1H), 7.34 - 7 .28 (m, 2H), 7.00 (s, 1H), 6.23 (d, J= 1.6 Hz, 1H), 4.28 (s, 2H), 3.99 (s, 2H) , 3.65 (s, 3H), 2.86 - 2.78 (m, 2H), 2.72 2.65 (m, 2H), 2.16 - 2.09 (m, 1H), 1, 99 1.93 (m, 1H), 0.75 - 0.72 (m, 4H). 269 ^x XI N |f Jx JL .N~NF hn ύ P ^F 0— 533,1 'NMR (400 MHz, DMSO-de) δ 8.89 (s, 1H), 8.13 (s, 1H), 7.68 (d, 7= 2.0 Hz, 1H), 7.20 (d , 7= 2.0 Hz, 1H), 7.01 (s, 1H), 5.71 (s, 1H), 4.38 - 4.27 (m, 2H), 4.08 - 3.99 ( m, 2H), 3.70 (s, 3H), 3.51 (s, 3H), 2.91 2.87 (m, 2H), 2.76 - 2.65 (m, 2H), 2, 31 2.25 (m, 2H), 2.16 - 2.12 (m, 1H), 1.99 1.95 (m, 1H). 270 >x XI lUf —Λ F 1 IL '' A A A^ ^N N'X/'-F ^N 7 \j X N=/ _F _/ FF FF 535,0 'NMR (400 MHz, DMSO-de) δ 8.88 (s, 1H), 8.15 (s, 1H), 7.93 (d,7= 1.5 Hz, 1H), 7.31 (d , 7= 1.9 Hz, 1H), 7.29 - 7.03 (m, 1H), 7.26 (d, 7= 1.5 Hz, 1H), 6.97 (s, 1H), 6 .23 - 6.20 (m, 2H), 5.05 (d, 7= 14.9 Hz, 1H), 4.79 (d, 7= 11.7 Hz, 1H), 3.64 (s, 3H).

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271 / What ^{do you} _mean ?' 537,1 'H NMR (400 MHz, DMSSMb) δ 9.31 (ymiip.s, 1H), 8.43 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 ( d, J= 1.9 Hz, 1H), 7.04 (d, J= 1.8 Hz, 1H), 6.83 (s, 1H), 6.27 (d, J= 1.9 Hz, 1H), 4.33 (t, J= 5.6 Hz, 2H), 4.05 (t, J= 5.6 Hz, 2H), 3.66 (s, 3H), 2.93 - 2, 86 (m, 2H), 2.76 - 2.66 (m, 2H), 2.30 - 2.26 (m, 2H), 2.16 - 2.10 (m, 1H), 2.03 - 1.95 (m, 1H). 272 F J.F νΑΑέ JL JL N-N ’i -A M 539.1 'H NMR (400 MHz, DMSO-de) δ 9.28 (s, 1H), 8.43 (s, 1H), 7.40 (td, J= 8.5, 1.5 Hz, 1H), 7.36 (d, J= 1.9 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.14 (t , J= 11.1 Hz, 1H), 7.09 (d, J= 1.7 Hz, 1H), 7.02 - 7.69 (m, 1H), 6.82 (s, 1H), 6 .27 (d, J = 1.9 Hz, 1H), 5.39 (s, 2H), 4.42 - 4.32 (m, 4H), 3.66 (s, 3H), 2.36 - 2.32 (m, 2H). 273 jfl -Λ p D ~A AA N=/ F ^F FF 546,0 'H NMR (400 MHz, DMSO-de) δ 9.28 (s, 1H), 8.37 (d, J= 5.2 Hz, 1H), 7.99 (d, J = 0.9 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.49 7.38 (m, 3H), 7.34 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 6.36 - 6.27 (m, 2H), 5.10 - 5.05 (m, 1H), 4.88 - 4.76 (m, 1H), 3 .68 (s, 3H). 274 Heat F 548,0 ‘HNMR (400 MHz, DMSO-de) δ 8.03 (s, 1H), 7.83 (d, J= 1.6 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.57 (s, 1H), 7.47 - 7.39 (m, 2H), 7.22 (d, J= 1.6 Hz, 1H), 7.02 (s, 1H), 5.50 - 5.36 (m, 1H), 4.83 - 4.57 (m, 4H), 3.67 (br, 4H), 2.74 (br, 4H). 322 J? _D N^Af' ⁰ JL JL nn f xS ^X O <> ^F N=/ 486.3 'NMR (400 MHz, DMSSMb) δ 8.53 (s, 1H), 7.92 (s, 1H), 7.40 (d, J= 2.0 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.84 (s, 1H), 6.19 (d, J = 1.9 Hz, 1H), 4.34 - 4.28 (m, 2H), 4.06 4.01 (m, 2H), 3.64 (s, 3H), 2.93 - 2.86 (m, 2H), 2.75 - 2.67 (m, 2H), 2.33 - 2.25 (m, 2H), 2.21 - 2.09 (m, 1H), 2.01 - 1.96 (m, 1H).

Example 13: Synthesis of compounds 275-280.

Connection 275.

^)-2-((5-methyl-4-(3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)pyrimidin-2-yl)amino)propan-1-ol.

(A) 10-(2-chloro-5-methylpyrimidin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine.

A mixture of 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine (2.0 g, 4.7 mmol), 2,4-dichloro-5-methylpyrimidine (620 mg, 3.8 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (300 mg, 0.40 mmol), and Na ₂ CO ₃ (1.0 g, 9.4 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 90°C for 4 h. The resulting mixture was concentrated and purified using ISCO (eluted with methanol in water 0%~100%) to give the title compound as a white solid (500 mg, 25.0% yield). MS (m/z): 423.0.

(B) (S)-2-((5-methyl-4-(3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-α][1,2,4]triα

- 132 047819 zolo[3,4-c][1,4]diazepin-10-yl)pyrimidin-2-yl)amino)propan-1-ol.

A mixture of 10-(2-chloro-5-methylpyrimidin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine (50 mg, 0.12 mmol), (N)-2-aminopropan-1ol (44 mg, 0.59 mmol), and DIPEA (76 mg, 0.59 mmol) in NMP (2 mL) was stirred at 180°C for 2.5 h under microwave irradiation. The resulting mixture was purified directly on an ISCO system (eluted with methanol in water 0%~100%) and by pTLC (DCM:MeOH=15:1) to afford the title compound as a white solid (8.0 mg, yield 14.7%). MS (m/z): 462.1 (M+H)+.

^1H NMR (400 MHz, DMSO^6) δ 8.03 (s, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 6.15 (d, J=8.1 Hz, 1H), 4.58 (s, 1H), 4.37-4.29 (m, 2H), 4.09-3.95 (m, 3H), 3.53-3.45 (m, 1H), 3.40-3.32 (m, 2H), 2,972.86 (m , 2H), 2.74-2.71 (m, 2H), 2.35-2.28 (m, 2H), 2.25 (s, 3H), 2.21-2.11 (m, 1H), 2.04-1.94 (m, 1H), 1.14 (d, J=6.6 Hz, 3H).

The following compounds were prepared according to the method for preparing compound 275 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 276 N Jk JL NN F HN N 4 jL J< ^F 'Ln J ^F oh ^v ' 482.1 Ή NMR (400 MHz, DMSO-ab) δ 8.22 (s, 1H), 7.96 (d, J= 2.0 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.75 (br, 1H), 4.37 - 4.31 (m, 2H), 4.08 - 4.02 (m, 2H), 4.02 - 3.96 (m, 1H), 3.51-3.44 (m, 1H), 3.39-3.36 (m, 1H), 2.95 - 2.86 (m, 2H), 2.76 - 2.65 (m, 2H), 2.33 2.25 (m, 2H), 2.22 - 2.09 (m, 1H), 2.02 - 1.94 (m, 1H), 1.13 (d, 7= 6.6 Hz, 3H). 277 AA , ^N ~NF HN N ΤίΆ-Υ L J< ^F ή w- 0 488.2 Ή NMR (400 MHz, DMSO-de) δ 8.04 (s, 1H), 7.63 (d, 7= 1.9 Hz, 1H), 7.40 (d, 7= 1.9 Hz, 1H), 6.51 (d, 7= 7.6 Hz, 1H), 4.38-4.28 (m, 2H), 4.08 - 3.82 (m, 5H), 3.43 - 3.37 (m, 2H), 2.93 - 2.89 (m, 2H), 2.79 - 2.66 (m, 2H), 2.33 - 2.30 (m, 2H), 2.25 (s, 3H), 2.18 - 2.14 (m, 1H), 2.00 - 1.93 (m, 1H), 1.88 - 1.82 (m, 2H), 1.53 - 1.49 (m, 2H). 278 Jk 1 nn F HN N YV7 i > ^F 4 A FF 494.1 Ή NMR (400 MHz, DMSO-de) δ 8.08 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.23 (d, J = 6.3 Hz , 1H), 4.36 - 4.31 (m, 2H), 4.23 - 4.16 (m, 1H), 4.09 - 3.98 (m, 2H), 2.97 - 2.85 (m, 4H), 2.76 2.67 (m, 2H), 2.66 - 2.57 (m, 2H), 2.33 - 2.27 (m, 2H), 2.25 (s, 3H), 2.20 - 2.11 (m, 1H), 2.02 1.94 (m, 1H). 279 Jk JL nn f _c HN N Ii\s—7 <> ^f 518.2 Ή NMR (400 MHz, DMSO-de) δ 8.04 (s, 1H), 7.62 (d, 7= 1.9 Hz, 1H), 7.41 (d, 7= 1.9 Hz, 1H ), 6.63 (d, 7= 8.0 Hz, 1H), 4.36 - 4.29 (m, 2H), 4.08 -3.92 (m, 4H), 3.83 - 3, 74 (m, 1H), 3.42 - 3.29 (m, 5H), 3.19 - 3.07 (m, 1H), 2.93 - 2.89 (m, 2H), 2.75 - 2.71 (m, 2H), 2.35 - 2.23 (m, 5H), 2.22 2.10 (m, 1H), 2.04 - 1.99 (m, 2H), 1.55 - 1.41 (m, 1H). 280 ϊΑΓ /k D N... / ⁵⁵ ^ HN N Ν £ \ 7s. '-N G 1 ^x A _F \ff Y-/ 547,0 Ή NMR (400 MHz, DMSO-de) δ 8.13 (s, 1H), 7.86 (s, 1H), 7.84 (d, 7= 1.4 Hz, 1H), 7.77 - 7 .66 (m, 2H), 7.46 - 7.37 (m, 3H), 7.07 (d, 7= 6.6 Hz, 1H), 5.26 - 5.14 (m, 1H), 4.57 - 4.45 (m, 3H), 4.45 -4.35 (m, 1H), 4.16-4.01 (m, 1H), 3.11 2.96 (m, 1H) , 2.94 - 2.83 (m, 1H), 2.29 (s, 3H), 2.22 - 1.96 (m, 2H), 1.30 (d, 7= 6.6 Hz, 3H).

Example 14: Synthesis of compounds 281-298.

Compound 281.

5-methyl-N-(2-methylpyridin-4-yl)-4-(3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)pyrimidin-2-amine.

- 133 047819

A mixture of 10-(2-chloro-5-methylpyrimidin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine (30 mg, 0.07 mmol), 2-methylpyridin-4-amine (15 mg, 0.14 mmol), Pd ₂ (dba) ₃ (16 mg, 0.007 mmol), Xantphos (4.1 mg, 0.007 mmol) and Cs ₂ CO ₃ (69 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was stirred at 150°C for 30 min under microwave irradiation. The mixture was concentrated and partitioned between water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were concentrated and purified by pTLC (DCM:MeOH = 15:1) to give the title compound as a white solid (8.5 mg, 24.2% yield). MS (m/z): 495.1 (M+H)+.

^1H NMR (400 MHz, DMSO^b) δ 9.63 (s, 1H), 8.34 (s, 1H), 8.19 (d, J=5.7 Hz, 1H), 7.73 ( d, J=6.0 Hz, 2H), 7.59-7.54 (m, 1H), 7.55-7.52 (m, 1H), 4.42-4.35 (m, 2H), 4.11-4.05 (m, 2H), 2.98-2.89 (m, 2H), 2.76-2.72 ( m, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 2.34-2.30 (m, 2H), 2.23-2.12 (m, 1H), 2.05-1.95 (m, 1H).

The following compounds were prepared according to the method for preparing compound 281 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

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Conn. Structure LC-MS (m/z) (M+H) ⁺ Ή NMR 282 / Z- ^Z \ X ь of 440,0 Ή NMR (400 MHz, DMSOAB) δ 9.33 (s, 1H), 8.42 (d, J= 5.1 Hz, 1H), 8.20 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.59 (s, 1H), 7.39 - 7.30 (m, 3H), 7.22 - 7.02 (m, 3H), 6.32 - 6.27 (m, 1H), 4.46 (s, 2H), 3.69 (s, 3H). 283 / Z'\ ZE Gx of Λά 454.1 Ή NMR (400 MHz, DMSO-de) δ 9.20 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 6.0 Hz , 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.41 - 7.30 (m, 2H), 7.22 6.99 (m , 3H), 6.28 (d, J = 1.5 Hz, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.38 (s, 3H). 284 k 1 n-n F HN N A SjA 485.1 Ή NMR (400 MHz, DMSO-de) δ 8.33 (s, 1H), 7.76 (d, J= 1.8 Hz, 1H), 7.47 (d, J= 1.8 Hz, 1H), 6.20 (s, 1H), 4.41 - 4.33 (m, 2H), 4.10 - 4.01 (m, 2H), 2.96 - 2.85 (m, 2H), 2.76 - 2.68 (m, 2H), 2.36 (s, 3H), 2.34 - 2.29 (m, 2H), 2.20 - 2.11 (m, 4H), 2.03 - 1.95 (m, 1H). 285 ΐ if k JL . n-n f HN N YV< k Ja -a Ό v №* 488,1 Ή NMR (400 MHz, DMSO-de) δ 9.33 (s, 1H), 8.43 (d, J= 3.3 Hz, 1H), 7.76 (s, 1H), 7.40 - 7 .32 (m, 2H), 6.26 (d, J= 1.8 Hz, 1H), 4.40 - 4.31 (m, 2H), 4.07 - 4.01 (m, 2H), 3.68 (s, 3H), 2.93 - 2.89 (m, 2H), 2.79 - 2.67 (m, 2H), 2.36 - 2.24 (m, 2H), 2, 21 - 1.98 (m, 2H). 286 k 1 N-n F HN N YVS k k Ϋ) ChLR N 495.2 Ή NMR (400 MHz, DMSO-de) δ 8.46 (s, 1H), 8.33 (s, 1H), 8.28 - 8.22 (m, 2H), 8.14 (d, J= 5.7 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 4.41 - 4.31 (m, 2H), 4.09 - 4.02 (m, 2H), 2.97 - 2.85 (m, 2H), 2.78 - 2.68 (m, 2H), 2.37 (s, 3H) , 2.34 - 2.29 (m, 2H), 2.29 (s, 3H), 2.20 - 2.11 (m, 1H), 2.02 - 1.96 (m, 1H). 287 NS \_12У AF N=/ \ ^FF 510,0 Ή NMR (400 MHz, DMSO-de) δ 11.84 (yiniip.s, 1H), 9.03 (s, 1H), 8.43 (s, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.80 - 7.67 (m, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.47 - 7.39 (m, 2H), 5.30 - 5.20 (m, 1H), 4.62 - 4.53 (m, 2H), 2.42 (s, 3H), 1.32 (d, J= 6.7 Hz, 3H).

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288 N=< \ ^FF 520,1 Ή NMR (400 MHz, DMSO-ab) δ 9.02 (s, 1H), 8.22 (s, 1H), 7.84 (d, J= 1.2 Hz, 1H), 7.76 - 7 .65 (m, 2H), 7.46 - 7.37 (m, 2H), 7.34 (d, J= 1.2 Hz, 1H), 6.02 (s, 1H), 5.26 - 5.15 (m, 1H), 4.56 - 4.47 (m, 2H), 3.57 (s, 3H), 2.32 (s, 3H), 2.08 (s, 3H), 1 .29 (d, J =6.6 Hz, 3H). 289 and AO /D W N=/ \ ^FFF 520,1 Ή NMR (400 MHz, DMSO-de) δ 9.04 (s, 1H), 8.23 (s, 1H), 7.84 (d, J= 1.5 Hz, 1H), 7.77 - 7 .65 (m, 2H), 7.48 - 7.37 (m, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 6.25 (d, J= 1.8 Hz, 1H), 5.28 - 5.13 (m, 1H), 4.57 - 4.46 (m, 2H), 4.05 - 4 .00 (m, 2H), 2.33 (s, 3H), 1.33 - 1.23 (m, 6H). 290 ⁿ /nVi O -nA-f N=/ \ ^FF 524.1 Ή NMR (400 MHz, DMSO-de) δ 8.92 (s, 1H), 8.20 (s, 1H), 7.81 (d, J= 1.4 Hz, 1H), 7.77 - 7 .67 (m, 2H), 7.46 - 7.37 (m, 3H), 7.26 (s, 1H), 5.25 - 5.12 (m, 1H), 4.55 4.45 ( m, 2H), 3.58 (s, 3H), 2.32 (s, 3H), 1.28 (d, J =6.7 Hz, 3H). 291 ⁿ A\ul o ^N xA Af A\FF ^F 534.1 Ή NMR (400 MHz, DMSO-de) δ 9.06 (s, 1H), 8.23 (s, 1H), 7.84 (d, J= 1.4 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.47 - 7.37 (m, 2H), 7.35 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 6.27 (d, J= 1.8 Hz, 1H), 5.26 - 5.13 (m, 1H), 4.59 - 4.46 (m, 2H), 3.97 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.74 1.63 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H), 0.78 (t, ./=7.4 Hz, 3H). 292 YES 'n=/ \ FF ^F 534.1 Ή NMR (400 MHz, DMSSMb) δ 8.93 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.77 - 7.66 (m, 2H), 7 .47 - 7.35 (m, 3H), 7.32 (d, J= 1.1 Hz, 1H), 6.18 (d, 7= 1.6 Hz, 1H), 5.22 - 5, 17 (m, H), 4.57 - 4.45 (m, 3H), 2.32 (s, 3H), 1.34 - 1.26 (m, 9H). 293 “DuLP NO-/-D ^N vA Af N=/ \ FF ^F 536,0 Ή NMR (400 MHz, DMSO-de) δ 8.22 (s, 1H), 7.86 (d, J= 1.2 Hz, 1H), 7.77 - 7.66 (m, 2H), 7 .47 - 7.37 (m, 2H), 7.35 (d, J= 1.6 Hz, 1H), 7.32 (d, 7= 1.2 Hz, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.25 - 5.15 (m, 1H), 4.54 - 4.49 (m, 2H), 4.10 (t, J = 5.8 Hz, 2H ), 3.69 (t, J= 5.8 Hz, 2H), 2.33 (s, 3H), 1.29 (d, 7= 6.7 Hz, 3H).

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294 dAnhr Y 1 FF ^F N't/ 547,0 Ή NMR (400 MHz, DMSO-ab) δ 8.38 (s, 1H), 8.30 (s, 1H), 7.93 (d, J= 1.3 Hz, 1H), 7.83 (s , 1H), 7.78 - 7.68 (m, 3H), 7.49 7.39 (m, 3H), 5.31 - 5.12 (m, 1H), 4.61 4.43 (m , 2H), 3.79 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H), 1.32 (d, J= 6.6 Hz, 3H). 295 —ζ/ ^Ν 'ν AL 'Ο-Λ Ν=/ \ FF ^F 548,0 Ή NMR (400 MHz, DMSO-de) δ 9.14 (s, 1H), 8.21 (s, 1H), 7.82 (d, J= 1.4 Hz, 1H), 7.77 - 7 .65 (m, 2H), 7.54 (d, J= 1.7 Hz, 1H), 7.47 - 7.35 (m, 2H), 7.29 (d, J = 1.4 Hz, 1H), 6.24 (d, J= 1.7 Hz, 1H), 5.54 - 5.42 (m, 1H), 5.25 - 5.14 (m, 1H), 4.94 - 4 .85 (m, 2H), 4.81 - 4.71 (m, 2H), 4.56 - 4.46 (m, 2H), 2.32 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H). 296 550,1 Ή NMR (400 MHz, DMSO-de) δ 8.98 (s, 1H), 8.24 (s, 1H), 7.86 (s, 1H), 7.81 - 7.61 (m, 2H) , 7.50 - 7.25 (m, 4H), 6.32 (s, 1H), 5.29 - 5.09 (m, 1H), 4.61 - 4.41 (m, 2H), 4 .30 - 4.10 (m, 2H), 3.72 - 3.56 (m, 2H), 3.19 (s, 3H), 2.34 (s, 3H), 1.29 (d, J = 5.9 Hz, 3H). 297 Aaau? but ' _N =/ v ^FF 550,1 Ή NMR (400 MHz, DMSO-de) δ 9.04 (s, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.77 - 7.65 (m, 2H) , 7.48 - 7.31 (m, 4H), 6.28 (d, J= 1.7 Hz, 1H), 5.26 - 5.12 (m, 1H), 4.81 4.63 ( m, 1H), 4.58 - 4.44 (m, 2H), 4.06 (t, J= 7.0 Hz, 2H), 3.37 - 3.33 (m, 2H), 2.33 (s, 3H), 1.90 - 1.77 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H). 298 ΐΎ _H NN £ \ r-/-А , ^Ν ·γί ' _F №* \ ^FF 556.1 Ή NMR (400 MHz, DMSO-de) δ 9.30 (s, 1H), 8.26 (s, 1H), 7.87 (d, J= 1.5 Hz, 1H), 7.78 - 7 .66 (m, 2H), 7.46 - 7.38 (m, 3H), 7.36 (d, J= 1.5 Hz, 1H), 6.45 - 6.11 (m, 2H), 5.25 - 5.15 (m, 1H), 4.63 - 4.49 (m, 4H), 2.34 (s, 3H), 1.29 (d, J= 6.6 Hz, 3H) .

Example 15: Synthesis of compound 299.

Connection 299.

(10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methanol.

(A) 8-bromo-1-oxo-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepine-4-carboxylic acid.

To a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (5.0 g, 24.5 mmol) in DMF (100 mL) was slowly added NaH (3.43 g, 85.7 mmol, 60% dispersion in liquid paraffin) at 0 °C. The reaction mixture was stirred for 0.5 h, and then 3-bromo-2-(bromomethyl)propanoic acid was added. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction was then quenched with saturated ammonium chloride solution, the mixture was adjusted to pH < 4 with dilute HCl, and the mixture was ex

- 137 047819 was extracted with EA. The organic layer was washed with brine, dried and concentrated. Ammonium hydroxide (50 mL) was added to the residue and the resulting mixture was stirred at 100 °C overnight. The mixture was concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (1.30 g, 16.1% yield). MS (m/z): 273.0/275.0 (M+H)+.

(B) 8-bromo-4-(hydroxymethyl)-2,3,4,5-tetrahydro-III-pyrrolo[1,2-a][1,4]diazepin-1-one.

To a mixture of 8-bromo-1-oxo-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepine-4-carboxylic acid (800 mg, 2.93 mmol) in THF (10 mL) was added BH ₃ -Me ₂ S (4.5 mL, 9.0 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 3 h under nitrogen atmosphere. The reaction was then quenched with MeOH, concentrated and purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (250 mg, 32.8% yield). MS (m/z): 259.0/261.0 (M+H)+.

(C) (10-bromo-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4c][1,4]diazepin-6-yl)methyl acetate.

To a mixture of 8-bromo-4-(hydroxymethyl)-2,3,4,5-tetrahydro-N-pyrrolo[1,2-a][1,4]diazepin-1-one (250 mg, 0.96 mmol) in DCM (10 mL) were added _Et3N (194.3 mg, 1.92 mmol), _Ac2O (148 mg, 1.44 mmol), and YN-dimethylpyridin-4-amine (12 mg, 0.096 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction was then quenched with water and the mixture was extracted with DCM. The organic layer was washed with brine, dried, and concentrated. The residue was mixed with 1-(trifluoromethyl)cyclobutane-1-carbohydrazide (210 mg, 1.15 mmol) and _POCl3 (5 mL). The resulting mixture was stirred at 70 °C for 2 h. The volatiles were removed and the residue was dissolved in DCM and MeOH. The organic layer was then washed with saturated _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The residue was dissolved in NMP (5 mL) and 2 drops of HOAc were added. The resulting mixture was stirred at 130 °C for 0.5 h under microwave irradiation. Then the reaction system was purified directly on an ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a yellow solid (220 mg, yield 51.0%). MS (m/z): 447.0/449.0 (M+H)+.

(D) (10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-di-hydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methyl acetate.

A mixture of (10-bromo-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methyl acetate (80 mg, 0.18 mmol), BPIN (91 mg, 0.36 mmol), Pd ₂ (dba) ₃ (16 mg, 0.018 mmol), tricyclohexylphosphine (10 mg, 0.036 mmol), and potassium acetate (53 mg, 0.54 mmol) in 1,4-dioxane (8 mL) was stirred at 100 °C for 5 h under nitrogen. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified on an ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a white solid (10 mg, 11.1% yield). MS (m/z): 495.1 (M+H)+.

(E) (10-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrin-4-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methanol.

A mixture of (10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methyl acetate (10 mg, 0.02 mmol), 5-chloro-4-iodo-N-(1-methyl-N-pyrazol-5-yl)pyridin-2-amine (9 mg, 0.024 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (2 mg, 0.002 mmol) and sodium carbonate (6.4 mg, 0.06 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed. The mixture was stirred at 80°C for 1 h under nitrogen atmosphere. The mixture was then concentrated and the residue was purified by ISCO system (eluted with methanol in water 0%~100%) to give the title compound as a light yellow solid (3.0 mg, yield 28.0%). MS (m/z): 533.0 (M+H)+.

^1H NMR (400 MHz, DMSOD6) δ 8.86 (s, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 7.33 (s, 1H), 7.14 ( s, 1H), 6.98 (s, 1H), 6.24 (s, 1H), 5.06 (t, J=5.0 Hz, 1H), 4.32-4.17 (m, 2H), 4.14-4.09 (m, 1H), 3.75-3.69 (m, 1H), 3 .67 (s, 3H), 3.50-3.36 (m, 3H), 2.97-2.89 (m, 2H), 2.77-2.72 (m, 2H), 2.19-2.14 (m, 1H), 2.08-1.94 (m, 1H).

Example 16: Synthesis of compounds 300-303.

Connection 300.

5-chloro-4-(6-(methoxymethyl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4-c][1,4]diazepin-10-yl)-N(1-methyl-III-pyrazol-5-yl)pyridin-2-amine.

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(A) 10-bromo-6-(methoxymethyl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4 -c][1,4]diazepine.

A mixture of (10-bromo-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4-c][1,4]diazepin-6-yl)methyl acetate (140 mg, 0.31 mmol) and Na ₂ CO ₃ (99 mg, 0.93 mmol) in THF (3 mL) and water (3 mL) was stirred at room temperature for 0.5 h. The mixture was then diluted with water and extracted with DCM. The organic layer was washed with brine, dried and concentrated. The residue was dissolved in THF (10 mL) and cooled to 0 °C. NaH (20 mg, 0.50 mmol, 60% dispersion in liquid paraffin) was added and the mixture was stirred for another 20 min. Iodomethane was added and the reaction mixture was stirred at room temperature for 0.5 h. The reaction was then quenched with saturated ammonium chloride and the mixture was extracted with DCM. The organic layer was concentrated and purified by ISCO (eluted with methanol in water 0%~100%) to give the title compound as a white solid (110 mg, 83.8% yield). MS (m/z): 419.0/421.0 (M+H)+.

(B) 5-chloro-4-(6-(methoxymethyl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2a][1,2,4]triazolo[3,4-c][1,4]diazepine-10-ide)-\'-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine.

The title compound was prepared according to the method described in Example 15 using the appropriate intermediates and reagents. MS (m/z): 547.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO^b) δ 8.83 (s, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.31 (s, 1H), 7, 12 (s, 1H), 6.96 (s, 1H), 6.21 (s, 1H), 4.23 (d, J=4.3 Hz, 2H), 4.08-4.05 (m, 1H), 3.82-3.72 (m, 1H), 3.64 (s, 3H), 3.36-3 .30 (m, 2H), 3.24 (s, 3H), 2.93-2.85 (m, 2H), 2.75-2.68 (m, 3H), 2.18-2.13 (m, 1H), 2.03-1.97 (m, 1H).

The following compounds were prepared according to the method for preparing compound 300 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

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Conn. Structure lx-ms (m/z) (M+H) ⁺ Ή NMR 301 / z-\ I 511,1 Ή NMR (400 MHz, DMSO-ab) δ 8.84 (s, 1H), 8.14 (s, 1H), 7.82 (d, J= 1.6 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.19 (a, J = 1.6 Hz, 1H), 6.96 (s, 1H), 6.22 (a, ./=1.6 Hz, 1H), 5.20-5.12 (m, 1H), 4.64 (a, J = 13.2 Hz, 1H), 4.51-4.46 (m, 1H), 3.64 (s, 3H), 3.48-3.44 (m, 1H), 3.37 - 3.31 (m, 2H), 3.16 (s, 3H). 302 Ί ¹ ιΓ k JI N—NF HN — yfXs-—·# i A ^F -nA ^l » iK ^{F N} , / \z 14= ⁷ ό 533.3 Ή NMR (400 MHz, DMSO-ab) δ 8.88 (s, 1H), 8.13 (s, 1H), 7.75 (a, J= 1.8 Hz, 1H), 7.32 (a , J = 1.9 Hz, 1H), 7.09 (a, J= 1.8 Hz, 1H), 6.96 (s, 1H), 6.23 (a, J= 1.9 Hz, 1H ), 4.46-4.42 (m, 1H), 4.32 - 4.22 (m, 1H), 4.16-4.12 (m, 2H), 3.93 3.83 (m, 1H), 3.65 (s, 3H), 3.41 (s, 3H), 2.992.96 (m, 1H), 2.83-2.79 (m, 3H), 2.17-2.13 (m, 1H), 2.01 -1.98 (m, 1H). 303 £ / 535.3 Ή NMR (400 MHz, DMSO-ab) δ 8.53 (s, 1H), 7.95 (s, 1H), 7.75-7.67 (m, 2H), 7.59 (a, J = 1.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.29 (a, J = 1.6 Hz, 1H), 7.03 (a, J= 1.2 Hz, 1H), 6.83 (s, 1H), 6.20 (a, J= 1.6 Hz, 1H), 5.23 - 5.13 (m, 1H), 4.68 - 4.44 (m, 2H), 3.64 (s, 3H), 3.48 3.40 (m, 2H), 3.20 (s, 3H), 2.29 (s, 3H).

Example 17: Synthesis of compounds 304-321.

Connection 304.

5-chloro-N-(1-methyl-1H-pyrazol-5-yl)-4-(3'-(1,1,2,2-tetrafluoroethyl)-5Ή,7Ή-spiro[oxetane-3,6' pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine]-10'-yl)pyridin-2-amine.

(A) 10'-bromo-3'-(1,1,2,2-tetrafluoroethyl)-5'H,7'H-spiro[oxetane-3,6'-pyrrolo[1,2-a] [1 ,2,4]triazolo[3,4-c][1,4]diazepine].

To a solution of 8'-bromo-2',3'-dihydro-1'H,5'H-spiro[oxetane-3,4'-pyrrolo[1,2-a][1,4]diazepine]-1'-one (400 mg, 1.48 mmol) in DCM (30 mL) was added CF ₃ SO ₃ Me (291 mg, 1.77 mmol) and the mixture was stirred overnight at reflux temperature under nitrogen. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in propan-2-ol (20 mg), and 2,2,3,3-tetrafluoropropanehydrazide (283 mg, 1.77 mmol) and HOAc (2 drops) were added. The mixture was then flushed with nitrogen gas and stirred at 70°C for 3 h and then at 90°C for 3 h. The mixture was concentrated and the residue was purified by ISCO purification (eluted with methanol in water 0%~100%) to give an off-white solid (203 mg, 34.7% yield). MS (m/z): 394.9/396.9 (M+H)+.

(B) 5-chloro-N-(1-methyl-1H-pyrazol-5-yl)-4-(3'-(1,1,2,2-tetrafluoroethyl)-5Ή,7H-spiro[oxetane-3 ,6'-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diazepine]-10'-yl)pyridin-2-amine.

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The title compound was prepared according to the method described in Example 15 using the appropriate intermediates and reagents. MS (m/z): 523.0 (M+H)+.

^1H NMR (400 MHz, DMSO-46) δ 8.83 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.62-7.14 (m, 3H ), 6.98 (s, 1H), 6.23 (s, 1H), 4.73 (s, 2H), 4.66 (s, 2H), 4.51-4.42 (m, 2H), 4.41-4.31 (m, 2H), 3.64 (s, 3H).

The following compounds were prepared according to the method for preparing compound 304 using appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Conn. Structure LC-MS (m/z) (Μ+Η) ⁺ Ή NMR 305 ✓X ✓Cl 1 if Η N н ι L r ' JI i a l 505,1 Ή NMR (400 MHz, DMSO-ab) δ 8.83 (s, IH), 8.13 (s, IH), 7.72 (δ, 7= 1.6 Hz, IH), 7.32 (a , J = 1.9 Hz, IH), 7.02 (a, 7= 1.6 Hz, IH), 6.94 (s, IH), 6.22 (a, 7= 1.9 Hz, IH ), 5.03 - 4.99 (m, 2H), 4.83 - 4.70 (m, 4H), 3.65 (s, 3H), 3.49 3.40 (m, 2H), 3 .05 - 2.89 (m, 2H). 306 k JL , ^Ν 'Ν F Ά ^X OV ^F Ν=/ ο 525,1 'NMR (400 MHz, DMSO-46) δ 8.56 (s, IH), 7.95 (s, IH), 7.60 (a, 7= 1.4 Hz, IH), 7.30 (4 , J = 1.5 Hz, IH), 7.04 (4, 7= 1.4 Hz, IH), 6.85 (s, IH), 6.21 (4, 7= 1.5 Hz, IH ), 4.65 (s, 2H), 4.47 (4.7= 6.5 Hz, 2H), 4.39 - 4.29 (m, 4H), 3.66 (s, 3H), 2 .98 - 2.87 (m, 2H), 2.86 - 2.76 (m, 2H), 2.31 (s, 3H), 2.25 - 2.14 (m, IH), 2.07 - 1.93 (m, IH). 307 / ζ-\ X 7 ysz 545.1 Ή NMR (400 MHz, DMSO-46) δ 8.90 (s, IH), 8.14 (s, IH), 7.86 (4, 7= 1.5 Hz, IH), 7.33 (4 , J = 1.5 Hz, IH), 7.18 (4, 7= 1.5 Hz, IH), 6.98 (s, IH), 6.23 (4, 7= 1.5 Hz, IH ), 4.67 (s, 2H), 4.45 (4.7= 6.4 Hz, 2H), 4.39 - 4.26 (m, 4H), 3.66 (s, 3H), 3 .00 - 2.85 (m, 2H), 2.86 - 2.72 (m, 2H), 2.26-2.12 (m, IH), 2.07-1.91 (m, IH).

The following compounds were prepared according to the preparation methods described in the examples above, using the appropriate intermediates and reagents under appropriate conditions, which may be known to one skilled in the art.

Connection Structure LC-MS (m/z) (M+H) ⁺ 308 k JL nn ^f , f hnC KAf -A Ά v N=/ 484.1

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309 / z'\ x ιλ\ _ζ <> 485.1 310 / ^z ' ^z \ ¹ \ >r> 483.1 311 -AW N=/ 484.1 312 N^jA to JL nn ^f , f hn nAA ύ Xp 1 WnW OW <> N=/ 483.1 313 / z'\ x Э 484.1 314 / Z'\ ¹ th 484.1 315 n^a to JL . nn ^f . f ^HN A / F A HN-A NyX O vk v N=/ 483.1 316 / ^Z ' ^Z \ ^z 9Ζγ _ζ \ > 483.1 317 to IL m nn ^f . f Asa 484.1 318 AJAn ,ν-n ^f , F -A °~O<> N=/ 485.1 319 N^iA L !L Μ N—N ^F . F -.Aw 501,1 320 / ^Z ' ^Z \ ¹ ° 485.1 321 n^JA JL JL c nn ^f > f -A ^γ Ό o N=/ 501,1

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Example 18: ERK2 Z-lyte kinase assay 1. Materials and reagents:

Supplier Cat.№ Z-lyte Ser/Thr3 Assay Kit Invitrogen PV3176 Peptide Z-LYTE Ser/Thr3 Invitrogen PV3200 Phospho-peptide Z-LYTE Ser/Thr3 Invitrogen PV3215 5X kinase buffer Invitrogen PV3189 10 mM ATP Invitrogen PV3227 Developing reagent A Invitrogen PV3295 Developing buffer Invitrogen P3127 Stop reagent Invitrogen P3094 MAPK1(ERK2) enzyme Invitrogen PV3313 3 84-well plate (black) Corning 3575 Victor3 PerkinElmer™

2. Reaction stages: Tablet diagram.

1 Conc. comp. (µM) Conc. comp. 1 (μM) Conc. comp. 2 (μM) .......... Conc. comp. N (µM) Cl 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3,ZZE-01 3,ZZE-01 3,ZZE-01 3,ZZE-01 3,ZZE-01 3,ZZE-01 3,ZZE-O1 3,ZZE-01 C2 1,11E-01 1,11E-01 1,11E-01 1,11E-01 1,11E-01 1,11E-01 1,11E-01 1,11E-01 3,70E-02 3,70E-02 3,70E-02 3,70E-02 3,70E-02 3,70E-02 3,70E-02 3,70E-02 C3 1,23E-02 1,23E-02 1,23E-02 1,23E-02 1,23E-02 1,23E-02 1,23E-02 1,23E-02 4,12E-03 4D2E-03 4,12E-03 4,12E-03 4,12E-03 4D2E-03 4,12E-03 4,12E-03 1,37E-03 1,37E-03 1,37E-03 1,37E-03 1,37E-03 1,37E-03 1,37E-03 1,37E-03 4,57E-04 4,57E-04 4,57E-04 4,57E-04 4,57E-04 4,57E-04 4,57E-04 4,57E-04

3. Obtaining the solution.

1) 1.33X kinase buffer: 5X kinase buffer was diluted to 1.33X with distilled deionized water ( _ddH2O ).

2) 4X test compounds: The test compounds were serially diluted to 4-fold the desired concentration, maintaining the DMSO concentration at 8%. The final concentrations were 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014, 0.00046 μM, and the final DMSO concentration was 2%.

3) Kinase/peptide mixture (P/K solution): The kinase/peptide mixture was prepared by diluting kinase to 0.6 µg/mL and Z-LYTE™ Ser/Thr3 peptide to 4 µM in 1.33X kinase buffer. Mixed gently by pipetting.

4) Phospho-peptide solution (PP solution): 0.4 µl of Z-LYTE™ Ser/Thr3 phospho-peptide was added to 99.6 µl of 1.33X kinase buffer.

5) ATP solution: ATP solution was prepared by diluting 10 mM ATP in 1.33X kinase buffer to 100 µM.

6) Developing solution: Developing reagent A was diluted in developing buffer 1:1024.

4. Reaction.

1) Kinase reaction (in a volume of 10 µl).

a. In a 384-well plate, 2.5 μl of 4X test compounds were added to each well except wells C1, C2, C3. 2.5 μl of 8% DMSO was added to wells C1, C2, C3.

b. Place the tablet in ice.

c. Add 5 µl of the P/K mixture to each well with the test compound and to wells C1 and C2.

d. Add 5 µl of PP solution to well C3.

e. Add 2.5 µl of 1.33X kinase buffer to wells C1 and C3.

f. Add 2.5 µl of 4X ATP solution to each well containing the test compound and to the well

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C2, respectively. The plate was shaken for 30 seconds and centrifuged (1500 rpm, 1 min).

g. Cover the plate to protect from light and incubate the plate for 1 hour at RT (2530°C).

2) Manifesting reaction.

a. Add 5 µl of developing solution to all wells.

b. The plate was shaken for 30 seconds and centrifuged (1500 rpm, 1 min).

c. Cover the plate to protect from light and incubate the plate for 1 hour at RT (2530°C).

3) Stop the reaction and read.

a. Add 5 µl of stop reagent to all wells.

b. The plate was shaken for 30 seconds and centrifuged (1500 rpm, 1 min).

c. The signals of coumarin (exc. 400 nm, isp. 445 nm) and fluorescein (exc. 400 nm, isp. 520 nm) were measured, respectively.

5. Data analysis.

Emission ratio (ER) = coumarin emission (445 nm)/fluorescein emission (520 nm). Phosphorylation, % = 1-[ER X C3520 nm - C3445 nm] / [(C1445 nm - C3445 nm) + ER X (C3520 nm - C1520 nm)] Inhibition rate (IR) = 1- %Phos _C2 /% _{Phos C2} .

6. IC ₅₀ value: IC ₅₀ was determined using additional Microsoft Excel software, XLfit™ (version 2.0) from ID Business Solutions (Guildford, UK).

Example 19: Study of p-RSK (Thr359) Acumen in colo205 cells.

1. Cell line.

colo205 (SIBS).

2. Materials and reagents.

Rabbit mAb phospho-p90RSK (Thr359) (D1E9): Cell Signal, # 8753.

Alexa Fluor® 488 Donkey Anti-Rabbit IgG: Invitrogen, #A-21206.

Propidium iodide: Sigma, #p4170.

4% paraformaldehyde: SCRC, #DF021.

10% Triton X-100: PIERCE, #28314.

96-well plate (black with clear well bottom): BD, #354640.

Acumen® eX3 (Multi-laser cytometer for multi-parameter microplate screening): TTP LabTech.

3. Acumen study protocol.

4000 cells were seeded in 100 µl 10% FBS/well in a 96-well plate and incubated at 37°C, 5% _CO2 , overnight.

The compound was diluted to 3, 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.001 μM, maintaining the DMSO concentration at 5%. 10 μl of the diluted compound were added to each well and incubated at 37°C, 5% CO ₂ , for 1 hour.

100 μl of 4% pre-warmed paraformaldehyde (2% final concentration) was added and incubated for 45 min at room temperature.

Paraformaldehyde solutions were removed. 100 μl of ice-cold 0.1% Triton were added to fixed cells at room temperature for 30 min.

Washed twice with 150 µl PBS and incubated with 100 µl blocking buffer (1% BSA in PBS) for 2~3 hours at room temperature, and covered the plate.

The plates were washed once with PBS and incubated with 35 µl p-RSK (Thr359) (1:1000 dilution) overnight at 4°C. The plate was covered.

The plates were washed twice with PBS and incubated for 1.5 h at room temperature with 35 µl Alexa Fluor® 488 anti-rabbit IgG diluted 1:1000 in antibody dilution buffer (0.1% BSA in PBS). The plate was covered with foil to prevent exposure to light.

The plates were washed twice with 150 μl of PBS. 35 μl of 1.5 μM propidium iodide stock solution were added to each well to determine the cell number, and the plate was covered.

Incubated at room temperature for 30 minutes. Placed the plate in Acumen Explorer and scanned using the appropriate instrument settings.

4. Data analysis.

.. . , _η/λ Percentage _{of wells} with connection '- Percentage of _wells with min signal . „ „

Inhibition (%) = 100-------------------------------------x 100

Percentage _hole with max signal ' - Percentage _hole with min signal

Note:

The percentage _{of wells with compound} corresponds to the proportion of cells with a positive result out of the number of cells that were treated with the compound.

The percentage of wells _{with min signal} corresponds to the proportion of cells with a positive result among cells treated with 3 μM GDC0994.

- 144 047819

The percentage of _wells with a max _signal corresponds to the proportion of cells with a positive result among the cells that were not treated with the compound.

5. IC ₅₀ value: IC ₅₀ was determined using additional Microsoft Excel software, XLfit™ (version 2.0) from ID Business Solutions (Guildford, UK).

Results:

Connection Example 18 Example 19 Connection Example 18 Example 19 Connection Example 18 Example 19 IC ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) 1 A E 104 A D 207 A D 2 A D 105 IN D 208 WITH D 3 A D 106 A D 209 IN D 4 A E 107 A E 210 WITH E 5 A E 108 A D 211 V D 6 IN D 109 A E 212 A D 7 A D 110 A E 213 A D 8 A E 111 A E 214 IN E 9 A D 112 IN D 215 A D 10 A E FROM IN E 216 A D AND A D 114 A E 217 A D 12 A D 115 IN E 218 IN D 13 A E 116 IN E 219 A E 14 A D 117 A D 220 A D 15 IN D 118 WITH D 221 A D 16 A D 119 IN E 222 A D 17 A D 120 A D 223 A D 18 IN E 121 A D 224 A D 19 A D 122 A D 225 A D 20 A D 123 A D 226 A D 21 A E 124 A D 227 A D 22 A E 125 IN D 228 A D 23 IN D 126 IN D 229 A D 24 IN E 127 IN D 230 IN E 25 A E 128 V D 231 A D 26 A D 129 A D 232 A D 27 A D 130 IN E 233 A D 28 A D 131 A D 234 A E

- 145 047819

29 A D 132 IN D 235 IN D 30 A D 133 A D 236 A D 31 IN D 134 IN D 237 A D 32 A D 135 IN D 238 A E 33 C D 136 WITH D 239 A E 34 C E 137 With D 240 A D 35 c D 138 V D 241 A E 36 A E 139 A D 242 IN E 37 A D 140 A D 243 A E 38 C D 141 A D 244 IN D 39 IN D 142 IN D 245 A D 40 A D 143 WITH D 246 A D 41 A E 144 A D 247 A D 42 A E 145 A D 248 IN E 43 IN D 146 A D 249 IN D 44 c E 147 A E 250 A D 45 A D 148 IN D 251 A D 46 A D 149 A D 252 WITH E 47 A D 150 A D 253 A D 48 A E 151 A D 254 A D 49 A D 152 A D 255 A E 50 A E 153 A D 256 A D 51 A D 154 A D 257 IN D 52 A D 155 IN D 258 A D 53 IN E 156 A D 259 IN D 54 IN D 157 IN D 260 IN E 55 IN D 158 IN D 261 WITH D 56 A D 159 IN D 262 V D 57 A E 160 A D 263 A D 58 A D 161 A D 264 A E 59 A D 162 IN D 265 WITH E 60 A D 163 A D 266 A D 61 A D 164 A D 267 WITH E 62 A D 165 IN D 268 A D 63 A D 166 A D 269 IN E 64 A E 167 A D 270 WITH D 65 A D 168 IN E 271 IN D 66 A D 169 A D 272 With D 67 A D 170 WITH E 273 V E 68 IN E 171 WITH D 274 With D

- 146 047819

69 A E 172 IN D 275 A D 70 A D 173 IN E 276 A D 71 A D 174 A D 277 A D 72 IN D 175 A E 278 A E 73 A E 176 IN D 279 A E 74 A D 177 WITH D 280 IN E 75 A E 178 With D 281 A D 76 A E 179 With D 282 A E 77 A D 180 With D 283 A D 78 A D 181 V E 284 A E 79 A D 182 V E 285 A E 80 A D 183 A D 286 IN D 81 A D 184 IN D 287 IN D 82 A D 185 With D 288 WITH D 83 WITH D 186 V D 289 WITH D 84 IN E 187 With D 290 IN E 85 A D 188 V D 291 WITH D 86 IN D 189 V D 292 WITH E 87 A D 190 With D 293 IN D 88 A D 191 V E 294 WITH E 89 A D 192 With D 295 IN D 90 IN D 193 V D 296 IN D 91 IN D 194 A D 297 WITH D 92 IN D 195 A D 298 WITH D 93 V D 196 IN D 299 A D 94 A D 197 V E 300 IN D 95 IN D 198 A D 301 A E 96 V D 199 IN E 302 A D 97 V D 200 V D 303 IN E 98 A D 201 With D 304 A D 99 A E 202 V D 305 A E 100 A D 203 V D 306 A D 101 A D 204 With D 307 A D 102 A D 205 With D 103 IN D 206 With D

Note: A<5, 5<B<10, C>10; D<100, E>100.

Claims (45)

1. Compound of formula (I): or its pharmaceutically acceptable salt, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein selected from: - 147 047819 where R ₁₀ and R11 are independently selected from hydrogen, halogen, -CN, C1.6 alkyl, C1.6 alkoxyl, _C1.6 haloalkyl; L is absent, or L is -NRc, O, or S; Rc is hydrogen or C^alkyl; Ar is heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -KH( _C1.6 alkyl), -Y( _C1.6 alkyl)2, -CN, mercapto, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 alkoxyl, C1.6 haloalkyl, -(C _1.6 alkyl)-OH, -(C _1.6 alkyl)-O-( _{C 1.6 alkyl} ), _C3.8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said C1.6 alkyl, C1.6 alkoxyl, C1.6 haloalkyl, C ₃ . ₈ cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl optionally substituted with one or more deuterium atoms; R1 is selected from hydrogen, C1.6 alkyl optionally substituted with one or more deuterium atoms, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, -( _C1.6 alkyl)-OH, -(C1.6 alkyl)-O-( _C1.6 alkyl), -( _C1.6 alkyl)-( _C3.8 cycloalkyl), -( _C1.6 alkyl)-( _3- to 8-membered heterocyclyl), -(C1.6 alkyl)phenyl, -( _C1.6 alkyl)heteroaryl, _C3.8 cycloalkyl, _3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said C2.6 alkenyl, C2.6 alkynyl, _C3 . ₈ -cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C1.6alkyl), -Y( _C1.6alkyl )2, -(C1.6alkyl)-OH, -( _C1.6alkyl )-O-( _C1.6alkyl ), _C3.8 -cycloalkyl, _3- to 8-membered heterocyclyl, phenyl, heteroaryl, C1.6alkyl optionally substituted with one or more deuterium atoms, C1.6alkoxyl and C1.6haloalkyl; R2 is selected from hydrogen, deuterium, halogen, hydroxy, amino, -KH(C1.6alkyl), -Y( _C1.6alkyl )2, -CN, mercapto, C1.6alkyl optionally substituted with one or more deuterium atoms, C2.6alkenyl, C2.6alkynyl, C1.6haloalkyl, -( _C1.6alkyl )-OH, -(C1.6alkyl)-O-( _C1.6alkyl ), -(C1.6alkyl)-( _{C3.8cycloalkyl} ), -(C1.6alkyl)-(3- _to 8-membered heterocyclyl), -(C1.6alkyl)phenyl, -(C1.6alkyl)heteroaryl, C3.8cycloalkyl, _3- to ₈ -membered heterocyclyl, phenyl and heteroaryl, wherein each of said C2.6alkenyl, C2.6alkynyl, _C3 . ₈ -cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C1.6alkyl), -( _C1.6alkyl )-OH, -(C1.6alkyl)-O-( _C1.6alkyl ), C1.6alkyl, C1.6alkoxyl, C1.6haloalkyl and oxo; Ra and Rb are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -KH(C1.6alkyl), -Y( _C1.6alkyl )2, -(C1.6alkyl)-OH, -( _C1.6alkyl )-O-( _C1.6alkyl ), -CN, mercapto, C1.6alkyl, C1.6alkoxyl and C1.6haloalkyl; or Ra and Rb together with the carbon atom to which they are attached form _{C3.6cycloalkyl} or 3- to 6-membered heterocyclyl, wherein each of said _C3 . ₆ -cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH( _C1.6 alkyl), -Y( _C1.6 alkyl)2, -( _C1.6 alkyl)-OH, -( _C1.6 alkyl)-O- _{( C1.6} alkyl), _{C1.6 alkyl, C1.6 alkoxyl} and _C1.6 haloalkyl; represents a double bond or a single bond, and if ------represents a double bond, then R ₃ and R5 are absent; _R3 , R4, R5, R6, _R7 and _R8 are independently selected from hydrogen, deuterium, halogen, hydroxy, -CN, mercapto, amino, -KH( _C1.6 alkyl), -Y( _C1.6 alkyl)2, -( _C1.6 alkyl)-OH, -( _C1.6 alkyl) _{-O-(C1.6 alkyl), C1.6 alkyl, -(C1.6 alkyl ) phenyl} , _C1.6 alkoxy and _C1.6 haloalkyl; or any two of _R3 , R4, R5, _R6 , _R7 and _R8 together with the carbon atom to which they are attached and Ring B form an 8- to ₁₃ -membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms, - 148 047 819 independently selected from N, O or S; wherein said spirocyclic, fused or bridged ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, _-CN , _{hydroxy ,} mercapto, amino, -NH(C _1-6 α-alkyl), -N( _{4 -} alkyl)- ... n is 0, 1 or 2; m is 0, 1, 2, 3, 4 or 5, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5, 6 or 7 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8-12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other; wherein said 3-8 membered heterocyclyl is a saturated or partially unsaturated ring containing 3-8 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and containing 1, 2 or 3 rings, wherein the N or S heteroatom is optionally oxidized to different oxidation states; wherein said 3-6 membered heterocyclyl is a saturated or partially unsaturated ring containing 3-6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and containing 1, 2 or 3 rings, wherein the N or S heteroatom is optionally oxidized to different oxidation states. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or its pharmaceutically acceptable ζ β ¹⁰ R11 ' an acceptable salt, characterized in that it is b ^a- 1) , and R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen and C _1-6 alkyl. 3. A compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is a monocyclic heteroaryl containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; each of which is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -CN, mercapto, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, -N-alkyl-OH, -(N-alkyl-O-alkyl), C _3-8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl, wherein each of said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl and heteroaryl is optionally substituted with one or more deuterium atoms. 4. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazolyl and thiazolyl (more preferably, Ar is selected from pyridyl, pyrimidinyl and 1,3,5-triazinyl), each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, P-alkyl optionally substituted with one or more deuterium atoms, P-alkoxyl and C _1-6 haloalkyl. 5. A compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. _R2qR23 R21 an acceptable salt, characterized in that Ar is ^or , where R ₂₀ , R ₂₁ , R22, R23 and R ₂₄ are independently selected from hydrogen, halogen, -CN, p^alkyl, optionally replaced by - 149 047819 containing one or more deuterium atoms, C _1-6 alkoxyl and C _1-6 haloalkyl. 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from C _1-6 alkyl, -(C _1-6 alkyl)-OH, saturated monocyclic C _3-8 cycloalkyl, saturated monocyclic 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms ring, wherein 1, 2, 3 or 4 atoms in the ring are ring heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said C _3-8 cycloalkyl, 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), 3-6-membered heterocyclyl, Aralkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl or _C1-6 haloalkyl. 7. A compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a heteroaryl selected from pyrazolyl, pyridyl, isoxazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 2,4,5,6-tetrahydrocyclopentadieno[c]pyrazolyl and 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridyl, wherein each said heteroaryl is optionally substituted with one or more substituents independently selected from Cl _-6 alkyl optionally substituted with one or more deuterium atoms, _C1-6 haloalkyl, Cl _-6 alkoxyl, halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl) and 3-6-membered heterocyclyl. 8. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₁ is pyrazolyl, which is optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 haloalkyl, C _1-6 alkoxyl, halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and oxetanyl. 9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₂ is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic C _3-8 cycloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining atoms in the ring are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said C _3-8 cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo. 10. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₂ is phenyl, said phenyl being optionally substituted with one or more substituents independently selected from halogen, -CN and C _1-6 alkoxyl. 11. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₂ is a heteroaryl selected from 1,2,5-oxadiazolyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, thiazolyl, isothiazolyl, benzo(isoxazolyl), thienyl, indazolyl and pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, halogen, oxo and -CN. 12. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₂ is a saturated monocyclic C _3-8 cycloalkyl optionally substituted with one or more substituents independently selected from - 150 047819 C _1-6 haloalkyl. 13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that m is 0, 1 or 2. 14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are independently selected from hydrogen, halogen, hydroxy and C _1-6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic N-cycloalkyl or a 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic p-cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen. 15. A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that L is absent or L is NH, O or S. 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from compounds 1-322, Compound Structure - 151 047819 - 152 047819 - 153 047819 - 154 047819 - 155 047819 - 156 047819 - 157 047819 - 158 047819 - 159 047819 - 160 047819 - 161 047819 - 162 047819 - 163 047819 - 164 047819 - 165 047819 - 166 047819 - 167 047819 - 168 047819 - 169 047819 - 170 047819 - 171 047819 - 172 047819 - 173 047819 - 174 047819 - 175 047819 - 176 047819 - 177 047819 - 178 047819 - 179 047819 - 180 047819 - 181 047819 - 182 047819 - 183 047819 - 184 047819 - 185 047819 - 186 047819 17. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that n is 0, ~~~~~~ is a double bond, R3 and R5 are absent, R4 and R6 are independently selected from hydrogen and C ₁ . ₆ alkyl. 18. A compound of formula (I) according to claim 17 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-1) - 187 047819 wherein R1 is heteroaryl optionally substituted with one or more substituents independently selected from _C1-6 alkyl optionally substituted with one or more deuterium atoms, _C1-6 haloalkyl, C1-6 alkoxyl, halogen, -N-( _4- alkylHOH, -N-(4-alkylO-(4-alkyl)- ... Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _-6 alkoxyl, and C _1-6 haloalkyl; R2 is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic Azcycloalkyl, phenyl and heteroaryl, wherein each of said saturated monocyclic Azcycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo; R ₄ and R ₆ are independently selected from hydrogen and C _1-6 alkyl; R ₁₀ and R11 are independently selected from hydrogen, halogen, C _1-6 alkyl, C _-6 alkoxy and C^haloalkyl; m is 0, 1 or 2; R _a and R b are independently selected from hydrogen, halogen, hydroxyl or C _1-6 alkyl; or R _a and R b together with the carbon atom to which they are attached form a saturated monocyclic N-cycloalkyl or 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic N-cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen; L is absent, or L is NH, O, or S; said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other. 19. A compound of formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R ₁ is pyrazolyl which is optionally substituted with one or more substituents independently selected from C _1-6 alkyl; Ar is pyrimidinyl which is optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, and halogen; R2 is selected from C^haloalkyl or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen; R ₁₀ and R _n represent hydrogen; m is 0 or 1; R _a and Rb are independently selected from hydrogen or C _1-6 alkyl; or R _a and Rb together with the carbon atom to which they are attached form a saturated monocyclic A _-6 cycloalkyl; and L is absent, or L is NH or O. 20. A compound of formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from the group consisting of: - 188 047819 Connection Structure 21. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that n is 0, ------ is a single bond, R3, _R4 , R5 and R6 are independently selected from hydrogen, _{-alkyl, C1.6haloalkyl ,} -( _C1.6alkyl )-O-( _C1.6alkyl ) and _- ( _{C1.6alkyl )} phenyl; or any pair of R3 and R4 or R5 and _R6 together with the carbon atom to which they are attached form a saturated monocyclic alkyl or saturated monocyclic 3- to 6-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring. - 189 047819 22. A compound of formula (I) according to claim 21 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-2) (1-2) where R ₁ is selected from C ₁ . ₆ αalkyl, -(C1. ₆ alkyl)-OH, saturated monocyclic C ₃ . ₈ cycloalkyl, a saturated 3- to 8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein each of said C _3-8 cycloalkyl, 3- to 8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl), saturated 3- to 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, C _1-6 αalkyl optionally substituted with one or more deuterium atoms, C _1-6 αlkoxyl and C _1-6 haloalkyl; Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -CN, C _1-6 alkyl optionally substituted with one or more deuterium atoms, C _1-6 alkoxyl, and C _1-6 haloalkyl; R2 is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic _C3-8 cycloalkyl, phenyl or heteroaryl, wherein each of said _C3-8 cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo; Z3 represents CR10 or N; _R3 , R4, R5 and _R6 are independently selected from hydrogen, _C1-6alkyl , _{C1-6haloalkyl} , -( _C1-6alkyl )-O-( _C1-6alkyl ) and -( _C1-6alkyl )phenyl; or any pair of R3 and _R4 or R5 and _R6 together with the carbon atom to which they are attached form a saturated monocyclic _{C3-6cycloalkyl} or a saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring; R ₁₀ and R11 are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxyl and C _1-6 haloalkyl; m is 0, 1 or 2; Ra and Rb are independently selected from hydrogen, halogen, hydroxy, or C _1-6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic C _3-6 cycloalkyl or 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic C _3-6 cycloalkyl or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen; L is absent, or L is NH, O, or S; said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other. 23. A compound of formula (I) according to claim 22 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from a saturated monocyclic 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and a heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, - 190 047819 and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _{1. 6} haloalkyl, halogen, -(C _1-6 alkyl)-OH, C _1-6 alkoxyl, -(C _{1. 6} alkyl)-O-(C _{1. 6} alkyl) and saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 heteroatoms in the ring independently selected from N, O and S; Ar is a heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C| _-6 alkyl optionally substituted with one or more deuterium atoms, and halogen; R2 is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other, and wherein each of said phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, _C1-6 alkyl, _C1-6 alkoxyl and oxo; Z ₃ represents CRio or N; _R3 , _R4 , R5 and _R6 are independently selected from hydrogen, _C1-6alkyl , _{C1-6haloalkyl} , -( _C1-6alkyl )-O-( _C1-6alkyl ) and -( _C1-6alkyl )phenyl; or any pair of _R3 and R4 or R5 and _R6 together with the carbon atom to which they are attached form a saturated monocyclic _{C3-6cycloalkyl} or a saturated monocyclic 3-6-membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring; m is equal to 1 or 2; Ra and Rb are independently selected from hydrogen and halogen; or Ra and _Rb together with the carbon atom to which they are attached form a saturated monocyclic _C3-6 cycloalkyl; R ₁₀ and R11 represent hydrogen; L is absent, or L is O. 24. A compound of formula (I) according to claim 23, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer or diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from morpholinyl, thiomorpholinyl and heteroaryl, wherein said heteroaryl is selected from pyrazolyl, 2,4,5,6-tetrahydrocyclopentadieno[c]pyrazolyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridyl, 1,3,4-thiadiazolyl and pyridyl, and each said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, -(C _1-6 alkyl)-OH, C _1-6 alkoxyl, -(C _1-6 alkyl)-O-(C _1-6 alkyl) and oxetanyl. 25. A compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is a heteroaryl selected from pyridyl, pyrimidinyl and 1,3,5-triazinyl; wherein each said heteroaryl is optionally substituted with one or more substituents selected from C _1-6 alkyl optionally substituted with one or more deuterium atoms, and halogen. 26. A compound of formula (I) according to claim 25 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. R ₂ i acceptable salt, characterized in that Ar is ^or , where R ₂₀ , R ₂₁ , R22, R ₂₃ and R ₂₄ are independently selected from hydrogen, halogen and C _1-6 alkyl optionally substituted with one or more deuterium atoms. 27. A compound of formula (I) according to claim 22 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. - 191 047819 an acceptable salt, characterized in that R2 is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, phenyl and heteroaryl, wherein said heteroaryl is selected from isoxazolyl, 1,2,5-oxadiazolyl, pyrazolyl, oxazolyl, pyridyl, thiazolyl, isothiazolyl, thienyl and benzo-2-isoxazolyl; wherein each of said phenyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxyl and oxo. 28. A compound of formula (I) according to claim 22 or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is selected from: - 192 047819 - 193 047819 - 194 047819 - 195 047819 - 196 047819 - 197 047819 - 198 047819 - 199 047819 - 200 047819 - 201 047819 - 202 047819 - 203 047819 - 204 047819 - 205 047819 - 206 047819 - 207 047819 - 208 047819 - 209 047819 - 210 047819 29. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that n is 1, ------ is a single bond, R3, R4, R5, R6, _R7 and _R8 are independently _selected from hydrogen, halogen, hydroxy, _C1.6 alkyl and _C1.6 alkoxy; wherein said _C1.6 alkyl is optionally substituted with _one or more substituents independently selected from hydroxy and C1.6 alkoxy; or any two of R3, R4, _R5 , R6, _R7 and _R8 together with the carbon atom to which they are attached and ring B form a 9-12 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms selected from _N , _O or S; wherein said spirocyclic, fused or bridged ring is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, _{C1.6 alkyl} and -CN. 30. A compound of formula (I) according to claim 29 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that said compound of formula (I) is a compound of formula (I-3) Rio ^R ''N' ^Ar Y<zz ^N 'N ⁿ JL JL Ri/ ^Ν \ / ^Ν ( ^CR aRb)m -LR ₂ ¹ 'ΊΊ ρ VJ ρ Γ<3 /—χ \ ^Κ 8 ^R 4 R ₅ R ₆ ^R7 (1-3) - 211 047819 wherein R1 is selected from _C1.6 alkyl, -( _C1.6 alkyl)-OH, saturated monocyclic _{C3.8 cycloalkyl} , saturated monocyclic 3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl; wherein each of said _{C3.8 cycloalkyl} , 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C1.6 alkoxyl and _C1.6 haloalkyl; Ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen, -CN, _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C1.6 alkoxyl, and _C1.6 haloalkyl; R2 is selected from halogen, -CN, _C1.6 alkyl, _C1.6 haloalkyl, saturated _{monocyclic C3-8} cycloalkyl, phenyl or heteroaryl, wherein _each of said saturated monocyclic _C3-8 cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1.6 alkyl, _C1.6 alkoxyl, _C1.6 haloalkyl and oxo; _R3 , R4, R5, _R6 , _R7 and _R8 are independently selected from hydrogen, halogen, hydroxy, _C1.6 alkyl and _C1.6 alkoxy; wherein said C1.6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy and _C1.6 alkoxy; or any two of _R3 , R4, R5, R6, _R7 and _R8 together with the carbon atom to which they are attached and ring B form Rd is halogen, t is 0, 1, 2 or 3; R ₁₀ and R11 are independently selected from hydrogen, halogen, _C1.6 alkyl, _C1.6 alkoxyl and _C1.6 haloalkyl; m is 0, 1 or 2; Ra and Rb are independently selected from hydrogen, halogen, hydroxy, or _C1.6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated _C3.6 cycloalkyl or _3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon; wherein each of said saturated _{C3-6 cycloalkyl} or 3-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen; L is absent, or L is NH, O, or S; said heteroaryl is a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other. 31. A compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from _C1.6 alkyl, -( _C1.6 alkyl)-OH, saturated monocyclic _{C3.8 cycloalkyl} , saturated monocyclic _{3-8-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl; wherein each of said C3-8 cycloalkyl} , 3-8-membered heterocyclyl and heteroaryl is optionally substituted with one or more substituents independently selected from halogen, _C1.6 alkoxyl, _C1.6 haloalkyl and _C1.6 alkyl optionally substituted with one or more deuterium atoms; Ar is a heteroaryl, said heteroaryl being a monocyclic aromatic hydrocarbon radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other; wherein said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _C1.6 alkyl optionally substituted with one or more deuterium atoms, _C1.6 alkoxyl and _C1.6 haloalkyl; R2 is selected from -CN, _C1.6 haloalkyl, saturated monocyclic _{C3.8 cycloalkyl} , phenyl or heteroaryl, wherein said heteroaryl is a monocyclic aromatic carbon - 212 047819 a hydrogen radical containing 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, or a bicyclic aromatic hydrocarbon radical containing 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein at least one of the rings is aromatic, and if the total number of S and O atoms in the heteroaryl group exceeds 1, then said S and O heteroatoms are not adjacent to each other; wherein each of said saturated monocyclic C ₃ . ₈ cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, C1_ ₆ alkyl and _C1 . ₆ haloalkyl; _R3 , R4, _R5 , _R6 , _R7 and R8 are independently selected from hydrogen, halogen, hydroxy, _{C1_6alkyl} and _{C1_6alkoxy} ; wherein said _{C1_6alkyl} is optionally substituted with one or more substituents independently selected from hydroxy and _{C1_6alkoxy} ; or any two of _R3 , _R4 , _R5 , _R6 , _R7 and R8 together with the carbon atom to which they are attached and ring B form Rd is halogen, t is 0, 1, 2 or 3; R ₁₀ and Rn are independently selected from hydrogen, halogen and C1_ ₆ alkyl; m is 0, 1 or 2; Ra and Rb _{are independently selected from hydrogen, halogen, hydroxy and C1_6 alkyl; or Ra and Rb together with the carbon atom to which they are attached form a saturated monocyclic C3-6 cycloalkyl or} 3-6-membered heterocyclyl, wherein said 3-6-membered heterocyclyl is a saturated monocyclic ring containing 3-6 ring atoms, wherein 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; wherein each of said saturated monocyclic _{C3-6 cycloalkyl} or 3-6-membered heterocyclyl is optionally substituted with one or more substituents selected from halogen; L is absent, or L is NH or O. 32. A compound of formula (I) according to claim 30, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer or diastereomer of _a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from: (1) _{C1_6} alkyl, (2) -( _{C1_6} alkyl)-OH, (3) saturated monocyclic _{C3_8} cycloalkyl which is optionally substituted with one or more substituents independently selected from halogen and _{C1_6} alkoxyl, (4) saturated monocyclic 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and (5) heteroaryl selected from pyrazolyl, pyridyl and isoxazolyl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from _{C1_6} alkoxyl, _{C1_6} haloalkyl and _{C1_6} alkyl optionally substituted by one or more deuterium atoms. 33. A compound of formula (I) according to claim 30, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that Ar is a heteroaryl selected from pyridyl and pyrimidinyl; wherein each said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, _{C1_6} alkyl optionally substituted with one or more deuterium atoms, _{C1_6} alkoxyl and _{C1_6} haloalkyl. 34. A compound of formula (I) according to claim 33 or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. R ₂ i acceptable salt, characterized in that Ar is ^or , where R ₂₀ , R21, R22, R23 and _R24 are independently selected from hydrogen, halogen, -CN, _{C1_6} alkyl optionally substituted with one or more deuterium atoms, _{C1_6} alkoxy and _{C1_6} haloalkyl. 35. A compound of formula (I) according to claim 30, or a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers or diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R2 is selected from: (1) -CN, ₍ 2) _{C1_6} haloalkyl, (3) saturated monocyclic _{C3_8} cycloalkyl which is optionally substituted with one or more substituents, - 213 047819 selected from C _1-6 haloalkyl, (4) phenyl which is optionally substituted with one or more substituents independently selected from halogen and -CN, and ( _{5) heteroaryl selected from 1,2,5-oxadiazolyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, pyrazolyl, indazolyl and pyrrolyl, wherein each said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN and C 1.6 alkyl} . 36. A compound of formula (I) according to claim 29 or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from: Compound 1 4 6 8 10 AND 12 Structure N*A| F JL 1 NN । -А , С N У L Л NN -А ^Х О о Ν=/ А» A-vAiL £j -А N=/ ' JU -A ^l Oa N=/ — X ¹ Π о 11 . nn N'° _n Ϊ iLm' ⁴ -N As ^N \ J ' N=/ A 1 nn -A <7 A JL nn f HN N W-ύ JA -A ^X O <> ^F N=/ - 214 047819 - 215 047819 - 216 047819 - 217 047819 - 218 047819 - 219 047819 - 220 047819 - 221 047819 - 222 047819 - 223 047819 - 224 047819 - 225 047819 - 226 047819 - 227 047819 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 38. A method for in vivo or in vitro inhibition of extracellular signal-regulated kinase (ERK) activity, comprising contacting an effective amount of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof with ERK. 39. Use of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a disease susceptible to ERK inhibition. 40. Use according to paragraph 39, characterized in that the said medicinal product is used for - 228 047819 treatment of cancer or autoimmune disease. 41. The use according to claim 40, wherein said cancer is a solid tumor or a hematological malignancy such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer such as non-small cell lung cancer, thyroid cancer such as papillary thyroid cancer, or ovarian cancer. 42. A method for treating or preventing a disease responsive to inhibition of extracellular signal-regulated kinase (ERK), comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. 43. Compound of formula (II): or racemic mixtures or enantiomers thereof, wherein R ₉ is a leaving group; R ₁₀ and Rn are independently selected from hydrogen, halogen, and _C1.6 alkyl; R ₃ , R4, R5, R6, R ₇ and R8 are independently selected from hydrogen, halogen, _C1.6 alkyl, _C1.6 alkoxy or _C1.6 haloalkyl; or any two of _{R 3} , R4, R5, R6, R ₇ and R8 together with the carbon atom to which they are attached and ring B form _/ or O( ^Rd )t, Rd is halogen, t is 0; provided that if _R10 and R11 are both hydrogen, then not all of _R3 , R4, R5, _R6 , _R7 and R8 are hydrogen, and if any one of _R3 , R4, R5, R6, _R7 and R8 is methyl, then not all of the remaining substituents are hydrogen; wherein said leaving group is selected from halogen, _C1.6 alkoxy and sulfonyloxy, and said sulfonyloxy is selected from _C1.6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and p-nitrophenylsulfonyloxy. 44. A compound selected from: or its racemic mixtures or enantiomers, where - 229 047819 R ₉ is a leaving group; R ₁₀ and R11 are independently selected from hydrogen; R3, R4, R5 and R6 are independently selected from hydrogen, C _1-6 haloalkyl or O-alkyl optionally substituted with phenyl; or any pair of R3 and R4 or R5 and R6 together with the carbon atom to which they are attached form a saturated C _3-6 cycloalkyl or a saturated 3-4 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from N, O and S and thereby together with ring B form a spirocyclic ring; provided that not all of R3, R4, R5 and R6 are hydrogen, and if one or two of _R3 , _R4 , R5 and R6 are C _1-6 alkyl then not all of the remaining substituents are hydrogen; wherein said leaving group is selected from halogen, C _1-6 alkoxy and sulfonyloxy, and said sulfonyloxy is selected from C _1-6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and p-nitrophenylsulfonyloxy. 46. A compound of formula (III) according to claim 45, selected from: