HK1129298B - Dihydrodiazepines useful as inhibitors of protein kinases - Google Patents

Description

Dihydrodiazepines useful as inhibitors of protein kinases

Field of the invention

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. The invention also relates to processes for preparing the compounds of the invention.

Background

In recent years, better understanding of the structure of enzymes and other biomolecules associated with disease has greatly facilitated the search for new therapeutic agents. One important class of enzymes that has been the subject of extensive research is protein kinases.

Protein kinases constitute a large family of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells (see Hardie, G and Hanks, S.the protein kinase products Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are thought to have evolved from a common genetic gene by preserving their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into several families according to the substrates they phosphorylate (e.g. protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that generally correspond to each kinase family have been identified (see, e.g., Hanks, s.k., Hunter, t., FASEB j.1995, 9, 576-596; Knighton et al, Science1991, 253, 407-414; Hiles et al, Cell 1992, 70, 419-429; Kunz et al, Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO J1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by affecting the transfer of phosphoryl groups from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular switches, capable of modulating or regulating the biological function of the target protein. These phosphorylation events are ultimately stimulated in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress response signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H₂O₂) Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), and growth factors such as granulocyte macrophage colony stimulating factor (GM-CSF) and Fibroblast Growth Factor (FGF). Extracellular stimuli can affect one or more cellular responses involving cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, carbohydrate metabolism, protein synthesis control, and cell cycle regulation.

Many diseases are associated with abnormal cellular responses triggered by the aforementioned protein kinase-mediated events. These diseases include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergy and asthma, alzheimer's disease, and hormone-related diseases. Accordingly, there is a continuing effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

Polo-like kinases (Plk) belong to the serine/threonine kinase family, which are highly conserved between different species from yeast to humans (see Lowery DM et al, Oncogene2005, 24; 248-. Plk kinases play multiple roles in the cell cycle, including entry into and control of progression through mitosis.

Plk1 was the most well identified of the Plk family members. Plk1 is widely expressed and is most abundant in tissues with high mitotic indices. The protein levels of Plk1 rise and peak in mitosis (Hamamaka, R et al, J Biol Chem1995, 270, 21086-21091). The reported Plk1 substrates are all molecules known to regulate entry into and progression through mitosis, including CDC25C, cyclin B, p53, APC, BRCA2, and proteasomes. Plk1 is upregulated in a variety of cancer types, with expression levels correlated with disease severity (Macmillan, JC et al, Ann Surg Oncol 2001, 8, 729-. Plk1 is an oncogene capable of transforming NIH-3T3 cells (Smith, MR et al, Biochem Biophys Res Commun 1997, 234, 397-405). Plk1 reduces tumor Cell proliferation and viability in vitro due to deletion or inhibition of s iRNA (antisense, microinjected antibody) or transfection of a dominant negative component of Plk1 into cells (Guan, R et al, Cancer Res 2005, 65, 2698-containing 2704; Liu, X et al, Proc Natl Acad Sci USA 2003, 100, 5789-5794, Fan, Y et al, World J Gastroenterol 2005, 11, 4596-containing 4599; Lane, HA et al, J Cell Biol 1996, 135, 1701-containing 1713). Tumor cells deficient in Plk1 have spindle checkpoints activated as well as defects in spindle production, chromosome alignment and segregation, and cytokinesis. Loss of viability has been reported to be the result of induction of apoptosis. In contrast, normal cells were reported to maintain viability following the absence of Plk 1. In vivo Plk1 knockdown by siRNA or the use of a dominant negative component would cause growth inhibition or regression of tumors in xenograft models.

Plk2 is expressed primarily during the G1 phase of the cell cycle, and is localized to centrosomes in interphase cells. Plk2 knockout mice develop normally, are fertile, and have normal survival rates, but are about 20% lower than wild-type mice. Cells from the knockout animals progress more slowly through the Cell cycle than normal mice (Ma, S et al, Mol Cell Biol 2003, 23, 6936-one 6943). Plk2 blocked centromere replication due to siRNA deletion or transfection of kinase-inactive mutants into cells. Down-regulation of Plk2 also sensitizes tumor cells to paclitaxel, promoting mitotic catastrophe, in part by inhibition of the p53 response (Burns TF et al, Mol Cell Biol 2003, 23, 5556-.

Plk3 is expressed throughout the cell cycle, increasing from G1 to mitosis. Expression is upregulated in hyperproliferative ovarian and breast cancers and is associated with poor prognosis (Weichert, W et al, BrJcancer2004, 90, 815-. In addition to regulation of mitosis, Plk3 is believed to be involved in golgi fission and DNA-damage responses during the cell cycle. Inhibition of dominant negative expression of Plk3 was reported to promote p 53-independent apoptosis after DNA damage, inhibiting tumor cell colony formation (Li, Z et al, J Biol Chem 2005, 280, 16843-.

Plk4 is structurally more distinct from other Plk family members. The deletion of this kinase leads to apoptosis of cancer cells (Li, J et al, Neoplasia2005, 7, 312-. Mice with Plk4 knockout stopped at E7.5, most cells were mitotic, and chromosomes were partially sequestered (Hudson, JW et al, Current Biology 2001, 11, 441-.

Molecules of the protein kinase family have been implicated in the growth, proliferation and survival of tumor cells. Therefore, there is an urgent need to develop compounds useful as protein kinase inhibitors. There is substantial evidence that P lk kinase is essential for cell differentiation. Cell cycle arrest is a clinically proven means of inhibiting tumor cell proliferation and viability. Therefore, there is a need to develop compounds useful as inhibitors of P lk family protein kinases (e.g., Plk1, Plk2, Plk3, and Plk4) that will inhibit proliferation, reduce tumor cell viability, and in particular there is a strong medical need to develop new cancer treatments, including treatments that will be administered orally.

Summary of The Invention

The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as inhibitors of protein kinases. In some embodiments, these compounds are useful as inhibitors of Plk protein kinases; in some embodiments, an inhibitor of PLK1 protein kinase. These compounds have formula I as defined herein or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions, including but not limited to autoimmune, inflammatory, proliferative or hyperproliferative diseases, neurodegenerative diseases, or immunologically-mediated diseases. The compounds provided by the invention are also useful in kinase studies in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of novel kinase inhibitors.

Detailed description of the invention

The present invention provides compounds of formula I:

wherein

X¹Is a valence bond, O, NR⁸S, SO or SO₂；

Y¹Is O or NR⁹；

R¹Is H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; wherein said R¹Optionally substituted with 0-5J 1; with the proviso that when X¹When it is a valence bond, R¹Is not H;

R²is H, C_1-10Aliphatic radical, - (C)_1-10Aliphatic radical) - (C_3-10Cycloaliphatic radical), C_3-8Cycloaliphatic radicals, halogen C_1-4An aliphatic group; wherein said R²Optionally by 0-4J²Substitution;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl or 5-10 membered heteroaryl; wherein each R³、R⁴、R⁵And R⁶Optionally and independently by 0-5J, respectively³、J⁴、J⁵And J⁶Substitution; and

R⁷is H, C (O) R, C (O) OR OR C (O) NRR', C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, - (C)_1-6Aliphatic radical) - (C_3-10Cycloaliphatic group), - (C)_1-6Aliphatic radical) - (C_6-10Aryl) or- (C)_1-6Aliphatic group) - (5-10 membered heteroaryl); wherein said R⁷Optionally by 0-5J⁷Substitution; or

R³And R⁴Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the carbon atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁴The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁴Substitution;

R⁵and R⁶Optionally together with the carbon atom to which they are attachedA 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R⁵And R⁶The rings constituting the monocyclic ring are optionally substituted by 0-4J⁵⁶Substitution;

R³and R⁵Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the carbon atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁵The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁵Substitution;

R³and R⁷Optionally forming a 4-8 membered saturated or partially unsaturated monocyclic ring together with the atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁷The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁷Substitution;

R⁵and R⁷Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R⁵And R⁷The rings constituting the monocyclic ring are optionally substituted by 0-4J⁵⁷Substitution;

R⁸is H, C_1-6Aliphatic radical, C_3-8Cycloaliphatic, C (O) R, C (O) OR OR C (O) NRR';

R⁹is H or unsubstituted C_1-6An aliphatic group; or

R²And R⁹Optionally forming a 5-8 membered aromatic or non-aromatic monocyclic ring together with the atoms to which they are attached, containing 2-4 heteroatoms independently selected from O, N and S; said is prepared from R²And R⁹The rings constituting the monocyclic ring are optionally substituted by 0-4J²⁹Substitution;

each J¹Independently is C_1-6Haloalkyl, halo, NO₂CN, Q or-Z-Q; or, two J¹Together may optionally constitute 0;

z is C_1-6Aliphatic radicals, optionally substituted by 0 to 3 occurrences of-NR-, -O-, -S-, -C (O) -, -C (═ NR) -, -C (═ NOR) -, -SO-or-SO₂-substitution; each Z is optionally substituted by 0-2J^ZSubstitution;

q is H; c_1-6An aliphatic group; a 3-8 membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N and S; or an 8-12 membered aromatic or non-aromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N and S; each Q is optionally substituted with 0-5J^Q；

Each J²Is halo or halo C_1-4An aliphatic group;

each J³、J⁴、J⁵And J⁶Independently is C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical or- (C)_1-4Alkyl radical)_n-V¹(ii) a Wherein

n is 0 or 1;

V¹is halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), halogeno group, NO₂、CN、OH、OR”、SH、SR”、NH₂、NHR”、N(R”)₂、COH、COR”、CO₂H、CO₂R”、CONH₂、CONHR”、CONR”₂、OCOR”、OCONH₂、OCONHR”、OCON(R”)₂、NHCOR”、NR”COR”、NHCO₂R”、NR”CO₂R”、NHCO₂H、NR”CO₂H、NHCONH₂、NHCONHR”、NHCON(R”)₂、SO₂NH₂、SO₂NHR”、SO₂N(R”)₂、NHSO₂R”、NR”SO₂R”；

Or V¹Is a bicyclic radical selected from C_3-6A cycloaliphatic, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl; wherein the cyclic group is optionally substituted with 0-3J^VSubstitution;

r' is unsubstitutedC_1-4An aliphatic group;

or two identical J's bound to the same atom³、J⁴、J⁵Or J⁶Together may optionally constitute 0;

each J^ZAnd J^VIndependently is halo, C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical, NO₂、CN、-NH₂、-NH(C_1-4Aliphatic group), -N (C)_1-4Aliphatic radical)₂、-OH、-O(C_1-4Aliphatic group), -CO₂H、-CO₂(C_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group) or halo (C)_1-4Aliphatic groups);

each J^Q、J⁷、J²⁹、J³⁴、J⁵⁶、J³⁵、J³⁷And J⁵⁷Independently is M or-Y-M;

each Y is independently unsubstituted C_1-6Aliphatic radicals, optionally substituted by 0 to 3 occurrences of-NR-, -O-, -S-, -C (O) -, -SO-or-SO₂-substitution;

each M is independently H, C_1-6Aliphatic radical, C_3-6Cycloaliphatic, halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), 3-6 membered heterocyclic group, halogeno group, NO₂、CN、OH、OR’、SH、SR’、NH₂、NHR’、N(R’)₂、COH、COR’、CO₂H、CO₂R’、CONH₂、CONHR’、CONR’₂、OCOR’、OCONH₂、OCONHR’、OCON(R’)₂、NHCOR’、NR’COR’、NHCO₂R’、NR’CO₂R’、NHCO₂H、NR’CO₂H、NHCONH₂、NHCONHR’、NHCON(R’)₂、SO₂NH₂、SO₂NHR’、SO₂N(R’)₂、NHSO₂R 'or NR' SO₂R’；

R is H or unsubstituted C_1-6An aliphatic group;

r' is unsubstituted C_1-6An aliphatic group; or two R' groups together with the atoms to which they are bonded form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N and S.

In one embodiment, R¹Is H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; wherein said R¹Optionally by 0-5J¹Substitution; with the proviso that when X¹When it is a valence bond, R¹Is not H; other variables are as defined herein.

In another embodiment, R⁷Is H, C (O) R, C (O) OR OR C (O) NRR', C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, - (C)_1-6Aliphatic radical) - (C_3-10Cycloaliphatic group), - (C)_1-6Aliphatic radical) - (C_6-10Aryl), - (C)_1-6Aliphatic group) - (5-10 membered heteroaryl) or- (C_1-6Aliphatic group) - (3-6 membered heterocyclic group); wherein said R⁷Optionally by 0-5J⁷Substitution; other variables are as defined herein.

In another embodiment, Q is H; c_1-6An aliphatic group; a 3-8 membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N and S; or a 7-12 membered aromatic or non-aromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N and S; each Q is optionally substituted by 0-5J^QSubstitution; other variables are as defined herein.

In another embodiment, each M is independently H, C_1-6Aliphatic radical, C_3-6Cycloaliphatic, halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), 3-6 membered heterocyclic group, C_6-10Aryl, halo, NO₂、CN、OH、OR’、SH、SR’、NH₂、NHR’、N(R’)₂、COH、COR’、CO₂H、CO₂R’、CONH₂、CONHR’、CONR’₂、OCOR’、OCONH₂、OCONHR’、OCON(R’)₂、NHCOR’、NR’COR’、NHCO₂R’、NR’CO₂R’、NHCO₂H、NR’CO₂H、NHCONH₂、NHCONHR’、NHCON(R’)₂、SO₂NH₂、SO₂NHR’、SO₂N(R’)₂、NHSO₂R 'or NR' SO₂R', or two M together may optionally form ═ 0; other variables are as defined herein.

The compounds of the present invention include those generally described above, and the classes, subclasses, and species disclosed herein are further illustrated. Unless otherwise indicated, the following definitions should apply. For the purposes of the present invention, the chemical elements will be according to the CAS version of the Handbook of chemistry and Physics, 75^thAnd Ed is identified. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999 and "March's Advanced Organic Chemistry", 5^th Ed.，Ed.：Smith，M.B.and March，J.，John Wiley &Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the designated range of atomic numbers includes any integer therein. For example, a group having 1-4 atoms may have 1, 2, 3, or 4 atoms.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as those set forth generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted. In general, the term "substituted," whether preceded by the term "optionally," means that a hydrogen radical in a given structure is replaced with a radical that is designated as a substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds.

The term "stable" as used herein means compounds that are substantially unchanged when subjected to the conditions used for their preparation, detection, preferably recovery, purification, and for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that remains substantially unchanged in the absence of moisture or other chemically reactive conditions at a temperature of 40 ℃ or less for at least one week.

The term "aliphatic group" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, which has a single point of attachment to the rest of the molecule.

Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

The term "cycloaliphatic" (alternatively "carbocycle" or "carbocyclyl" or "cycloalkyl", etc.) denotes a monocyclic C₃-C₈Hydrocarbons or bicyclic radicals C₈-C₁₂Hydrocarbons or bicyclic radicals C₇-C₁₂Hydrocarbons, which are fully saturated or contain one or more units of unsaturation, but are not aromatic, having a single andthe point of attachment of the remainder of the molecule, wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" and the like as used herein, denote non-aromatic monocyclic, bicyclic or tricyclic ring systems in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members. In some embodiments, 1 to 4 heteroatoms are present in the ring system.

Suitable heterocycles include, but are not limited to, 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyrazinyl, 2-tetrahydropyrazinyl, 3-tetrahydropyrazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiophenyl, benzodithiane, and 1, 3-dihydro-imidazol-2-one.

Cyclic groups (e.g., cycloaliphatic and heterocyclic) can be linearly fused, bridged, or spiro.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized forms of any basic nitrogen or heterocyclic ring substitutable nitrogen, e.g. N (as in 3, 4-dihydro)-2H-pyrrolyl), NH (e.g. in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

The term "non-aromatic" as used herein describes a saturated or partially unsaturated ring.

The term "alkoxy" or "thioalkyl" as used herein means an alkyl group, as defined above, attached to the bulk carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy groups, as the case may be, substituted with one or more halogen atoms. The term "halogen" denotes F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", denotes monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heteroaryl", used alone or as part of a larger portion of "heteroaralkyl" or "heteroarylalkoxy", denotes monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, there are 1-4 heteroatoms in the ring system. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Suitable heteroaryl rings include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, purinyl, pyrazinyl, 1, 3, 5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

The terms "protecting group" and "protecting group" as used herein refer to an ingredient used to temporarily block one or more desired reactive sites in a polyfunctional compound. In certain embodiments, the protecting group has one or more, or preferably all, of the following characteristics: a) selective reaction in good yield to give a protected substrate, b) it is stable to reactions taking place at one or more other reactive sites; and c) is selectively removed in good yield by a reagent that does not attack the deprotected functional groups being regenerated. One skilled in the art will appreciate that in some cases, the reagent does not attack other reactive groups in the compound. In other cases, the reagent may also react with other reactive groups in the compound. Exemplary protecting Groups are found in Greene, t.w., Wuts, P.G in "Protective Groups in organic synthesis", Third Edition, John Wiley & Sons, New York: 1999 and other versions of this document, the entire contents of which are incorporated herein by reference. The term "nitrogen" is used herein. Protecting group "means a moiety used to temporarily block one or more desired nitrogen-reactive sites in a polyfunctional compound. Preferred nitrogen protecting groups also have the above characteristics, and certain exemplary nitrogen protecting groups are also described in Chapter 7 in Greene, T.W., Wuts, P.G in "protective groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference.

In some embodiments, the alkyl or aliphatic chain may optionally be replaced by another atom or group. This means that the methylene units of the alkyl or aliphatic chain are optionally replaced by said other atoms or groups. Examples of such atoms or groups would include, but are not limited to, -NR-, -O-, -C (O) -, -C (═ N-CN) -, -C (═ NR) -, -C (═ NOR) -, -S-, -SO-, or-SO₂-. These atoms or groups may combine to form larger groups. Examples of such groups include, but are not limited to, -OC (O) -, -C (O) CO-, -CO₂-、-C(O)NR-、-C(＝N-CN)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-, -NRC (O) NR-, -OC (O) NR-and-NRSO₂NR-, wherein R is as defined herein.

Alternative substitutions, unless otherwise specified, produce chemically stable compounds. Alternative substitutions may occur within the strand, as well as at the end of the strand; i.e. at the connection point and/or also at the end. The two alternative substitutions may also be adjacent to each other within the chain, as long as a chemically stable compound results. Alternative substitutions may also completely replace all carbon atoms in the chain. E.g. C₃The aliphatic group may optionally be replaced by-NR-, -C (O) -and-NR-to produce-NRC (O) NR- (urea).

Unless otherwise specified, if a substitution occurs at a terminus, the substitute atom is bonded to the terminal H. For example, if-CH₂CH₂CH₃Optionally interrupted by-O-, the resulting compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂OH。

Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure. For example, the R and S configuration of each asymmetric center, the (Z) and (E) double bond isomersAnd conformational isomers of (Z) and (E). As will be appreciated by those skilled in the art, substituents may be free to rotate about any rotatable bond. For example, is depicted asThe substituents also represent

Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational or rotational mixtures of these compounds are within the scope of the invention.

Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise specified, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by¹³C-or¹⁴C-enriched carbon instead of compounds having the structure of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

The compounds of the invention may be present in free form for use in therapy, or as pharmaceutically acceptable salts as appropriate.

The term "pharmaceutically acceptable salt" as used herein, means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences, 1977, 66, 1-19, by s.m.berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. These salts may be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared as follows: 1) reacting the free base form of the purified compound with a suitable organic or inorganic acid, and 2) isolating the salt formed.

Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, salts of lactic acid, salts of malonic acid, methanesulfonic acid, salts of 2-naphthalenesulfonates, Pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, salicylate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The invention also encompasses quaternization of any basic nitrogen-containing group of the compounds as disclosed herein. By means of such quaternization, products which are soluble or dispersible in water or oil can be obtained.

Base addition salts can be prepared as follows: 1) reacting the acid form of the purified compound with a suitable organic or inorganic base, and 2) isolating the salt formed. Base addition salts include alkali metal or alkaline earth metal salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations, generated using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. Other acids and bases, although not pharmaceutically acceptable per se, may be used to prepare salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid or base addition salts.

The following writing was used:

LG leaving group

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

DMSO dimethyl sulfoxide

DMA dimethyl acetamide

TCA trichloroacetic acid

ATP adenosine triphosphate

DEAD azodicarboxylic acid diethyl ester

HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

BSA bovine serum albumin

DTT dithiothreitol

MOPS 4-Morpholpropanesulfonic acid

NMR nuclear magnetic resonance

HPLC high performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

TLC thin layer chromatography

Rt Retention time

In one aspect of the invention, X¹Is O, NR⁸Or S. In some embodiments, X¹Is NR⁸. In other aspects, Y¹Is O.

In another aspect of the invention, R¹Is optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl.

In one embodiment, R¹Is optionally substituted C_6-10Aryl radicals, for example phenyl.

In one embodiment, R¹Optionally J is¹Is substituted, wherein J¹is-H, -O-C_1-6Alkyl, halo, or-C (O) N (R) (Q), wherein R is-H.

In one embodiment, R¹Optionally J is¹Is substituted, wherein J¹is-H, -OCH₃Halo, or-C (O) N (R) (Q), wherein R is-H.

In one embodiment, J¹is-OCH₃or-C (O) N (R) ZQ, wherein Z is C_1-6Aliphatic, Q is a 3-8 membered aromatic or non-aromatic monocyclic ring having 1-3 heteroatoms independently selected from O, N and S; or an 8-12 membered aromatic or non-aromatic bicyclic ring system having 1-5 heteroatoms independently selected from O, N and S; q is optionally substituted by 0-5J^QAnd (4) substitution. In certain embodiments, Z is C_1-6Alkyl, and in a more particular embodiment, Z is-CH₂-。

In one embodiment, J¹is-OCH₃or-C (O) N (R) ZQ, wherein Z is C_1-6Aliphatic radical, Q is a 5-6 membered aromatic radical having 1 heteroatom selected from O and N (e.g. pyridine); wherein Q is optionally substituted by 0-5J^QAnd (4) substitution. In certain embodiments, Z is C_1-6Alkyl, and in a more particular embodiment, Z is-CH₂-。

In certain embodiments, Z is C_1-6Alkyl radicalIn a more specific embodiment, Z is-CH₂-。

In one embodiment, J¹is-OCH₃or-C (O) N (R) (Q), wherein R is-H and Q is C_1-6Alkyl, 3-6 membered cycloalkyl, 7-12 membered non-aromatic bicyclic ring system or 8-12 membered non-aromatic bicyclic ring system wherein each Q is substituted with 0-5J^QAnd (4) substitution.

In one embodiment, J¹is-OCH₃or-C (O) N (R) (Q), wherein R is-H and Q is 3-6 membered cycloalkyl, wherein each Q is substituted with 0-5J^QAnd (4) substitution.

In one embodiment, J¹is-OCH₃or-C (O) N (R) (Q), wherein R is-H and Q is cyclohexyl, wherein each Q is substituted with 0-5J^QAnd (4) substitution.

In one embodiment, J¹is-OCH₃or-C (O) N (R) (Q), wherein R is-H and Q is C_6-10Aryl or 5-10 membered heteroaryl having 0-5 heteroatoms independently selected from O, N and S; wherein each Q is substituted by 0-5J^QAnd (4) substitution.

In one embodiment, J¹is-OCH₃or-C (O) N (R) (Q), wherein R is-H, Q is a 3-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from O, N and S; wherein each Q is substituted by 0-5J^QAnd (4) substitution.

In one embodiment, J¹Is Q, and Q is:

wherein Q is 0-5J^QAnd (4) substitution.

In one embodiment, Q is substituted with 0, 1 or 2J^QAnd (4) substitution.

In one embodiment, each J is^QIndependently F, -OH, -OR 'OR-OC (O) R'.

In one embodiment, each R' is independently C_1-6Aliphatic groups, wherein aliphatic groups are straight chain.

[006₇]In one embodiment, each R' is independently C_1-6Alkyl, wherein alkyl is linear.

In one embodiment, R' is CH₃。

In another aspect, R²Is optionally substituted C_1-10Aliphatic radical or optionally substituted C_3-10A cycloaliphatic group.

In some embodiments, R³And R⁴Together with the carbon atoms to which they are attached form an optionally substituted 3-6 membered monocyclic ring.

In other embodiments, R³And R⁵Together with the carbon atoms to which they are attached form an optionally substituted 3-6 membered monocyclic ring.

In other embodiments, R³、R⁴、R⁵And R⁶Independently is an optionally substituted group selected from H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl or 5-10 membered heteroaryl. In some embodiments, each R is³And R⁴Independently is H, C_1-6Aliphatic radicals or C_3-8A cycloaliphatic group. In some embodiments, R³And R⁴One is H and the other is C_1-6Aliphatic radicals or C_3-8A cycloaliphatic group.

In one embodiment, each R is³And R⁴Independently is H or C_1-3Alkyl, or R³And R⁴Together with the carbon atoms to which they are attached form an optionally substituted 3-4 membered monocyclic ring.

In one embodiment, R³And R⁴One is H and the other is ethyl or (S) -methyl.

In one embodiment, R³And R⁴One is H, the other isIs (R) -methyl.

In one embodiment, each R is³And R⁴Is methyl.

In one embodiment, R³And R⁴Together with the carbon atoms to which they are attached form an unsubstituted 3-4 membered monocyclic ring.

In one embodiment, R³And R⁴Together with the carbon atoms to which they are attached form an unsubstituted 3 membered monocyclic ring.

In one embodiment, R⁵Is H.

In one embodiment, R⁶Is H.

In some embodiments, J³And J⁴Independently a halo group.

In other embodiments, R⁵And R⁷Together with the atoms to which they are attached form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring.

In one aspect of the invention, R⁷Is an optionally substituted group selected from C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. In some aspects, R⁷Is an optionally substituted group selected from C_1-10Aliphatic radical, C_3-8Cycloaliphatic, phenyl, 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 5-pyridazinyl, 3, 5-pyrimidinyl, and 3-8 membered heterocyclyl. In other aspects, R⁷Is not 3-amino-2, 4-pyrimidine.

In one embodiment, R⁸Is H.

One aspect of the invention provides a compound of formula II:

wherein

R¹Is optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R²is H or an optionally substituted group selected from C_1-10Aliphatic radical and C_3-10A cycloaliphatic group;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radicals or C_3-10A cycloaliphatic group; wherein each R³、R⁴、R⁵And R⁶Optionally respectively 0-5J³、J⁴、J⁵And J⁶Substitution; or

R³And R⁴May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R³and R⁵May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R⁵and R⁷May form, together with the atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R²and R⁹Together with the atoms to which they are attached may form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.

Another aspect of the invention provides a compound of formula III:

wherein

R¹Is optionally substituted C_6-10Aryl or optionally substituted 5-to 10-memberedA heteroaryl group;

R²is H or an optionally substituted group selected from C_1-10Aliphatic radical and C_3-10A cycloaliphatic group;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radicals or C_3-10A cycloaliphatic group; wherein each R³、R⁴、R⁵And R⁶Optionally respectively 0-5J³、J⁴、J⁵And J⁶Substitution; or

R³And R⁴May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R³and R⁵May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R⁵and R⁷May form, together with the atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R²and R⁹Together with the atoms to which they are attached may form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.

In some embodiments, each J is³、J⁴、J⁵And J⁶Independently is C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical or- (C)_1-4Alkyl radical)_n-V¹(ii) a Wherein

n is 0 or 1;

V¹is halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), halogeno group, NO₂、CN、OH、OR”、SH、SR”、NH₂、NHR”、N(R”)₂、COH、COR”、CO₂H、CO₂R”、CONH₂、CONHR”、CONR”₂、OCOR”、OCONH₂、OCONHR”、OCON(R”)₂、NHCOR”、NR”COR”、NHCO₂R”、NR”CO₂R”、NHCO₂H、NR”CO₂H、NHCONH₂、NHCONHR”、NHCON(R”)₂、SO₂NH₂、SO₂NHR”、SO₂N(R”)₂、NHSO₂R”、NR”SO₂R”；

R' is unsubstituted C_1-4An aliphatic group;

or two identical J's bound to the same atom³、J⁴、J⁵Or J⁶Together may optionally constitute 0.

In some embodiments, the variables are as described for the varieties disclosed herein.

In some embodiments, the compounds of the present invention are as represented in table 1.

TABLE 1

General synthetic method

The compounds of the invention can generally be prepared by those methods depicted in the following general schemes and the preparations that follow. All variables in the following schemes are as defined herein, unless otherwise indicated.

Scheme 1

Scheme 1 above shows a general synthetic route for the preparation of compounds of formula I, wherein Y¹0. Raw materials1(wherein LG₁And LG₂May be but is not limited to a chlorine atom) with a beta-amino ester2Reacting to obtain an adduct3. Reduction of nitro groups followed by cyclocondensation to yield bicyclic compounds4. The amide N-H may be functionalized at this stage to give5。LG₂Can be finally used as a handle for the preparation of the compounds of formula I. In the last step, LG₂May be, for example, replaced by an amine or participate in a palladium-assisted coupling reaction known to those skilled in the art (e.g., Suzuki, Stille).

Alternatively, formula (II)3The compounds may be first functionalized after reduction of the nitro group to form the formula3-bA compound:

it may be subsequently cyclized to yield the compound of formula 5.

Scheme 2

Scheme 2 above shows a general synthetic route for the preparation of compounds of the present invention, wherein Y¹Is NR⁹。5Or lactam function in I5In (C), LG₂Still present, or in I, if it has been derivatized to R¹X¹) Can participate in the conversion of functional groups to form amidine groups (5-aWherein LG is₂Still present, or I-a, if it has been derivatized to R¹X¹)。

Alternatively, scheme 2 above shows a general synthetic route for the preparation of compounds of the invention, wherein Y is¹＝N，R²And R⁹Together forming ring a.5Or lactam function in I5In (C), LG₂Still present, or in I, if it has been derivatized to R¹X¹) Can participate in a multistep cyclization sequence to form ring A: (5-bWherein LG is₂Still present, or I-b if it has been derivatized to R¹X¹)。

Scheme 3

Scheme 3 above shows a general synthetic route for the preparation of compounds of the present invention, wherein Y¹Is NR⁹，R²And R⁹Together form a triazole ring. Activation of4The lactam function in (A) is then replaced by hydrazine to give the compound of formula (II)7An intermediate. Cyclic derivatives7Subsequently with HX₁-R₁And (4) displacement to finally obtain the compound shown as the formula I-b.

Scheme 4

Scheme 4 above shows the preparation of the compounds of the present invention5Another general synthetic route of (1). As shown previously (see scheme 1 for compounds)5) Can be prepared into5aA compound comprising a protecting group on an amine. Amines may be achieved by methods well known in the art5aDeprotection followed by the desired R⁷-halide substitution9Free amine of (a).

Accordingly, the present invention also provides processes for preparing the compounds of the present invention.

One embodiment of the present invention provides a process for preparing a compound of formula I:

wherein

Y¹Is O, X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined herein;

comprising reacting a compound of formula 5:

wherein

R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined herein; LG (Ligno-lead-acid)₂Is a suitable leaving group, e.g., halo, with X1R1 under suitable conditions to produce a compound of formula I. Replacement of LG by X1R1₂There are many ways known to those skilled in the art. For example, if X¹Is NHR⁸O or S, then X¹R¹LG can be replaced in the presence of suitable bases or acids, solvents and conditions₂. Suitable metathesis reactions are known to those skilled in the art and may be found in a variety of sources, including "Merch's Advanced Organic Chemistry". Sulfur linker (wherein X¹Is S) can be oxidized under suitable oxidation conditions to form X therein¹Is SO or SO₂The compound of (1). Compounds of formula I wherein X is¹Is a valence bond, R¹Bonded to X via a carbon atom¹. In these cross-coupling reactions, one of the starting materials is R bonded to the cross-coupling group¹. The raw material can be mixed with5Reacting the compound under cross-coupling conditions to produce a compound of formula I, wherein X¹Is a valence bond, R¹Bonded to X via a carbon atom¹。

The term "cross-coupling reaction" as used herein means a reaction that generates a carbon-carbon bond with the aid of a metal catalyst. Typically, one of the carbon atoms is bonded to a functional group ("cross-coupling group") and the other carbon atom is bonded to a halogen. Examples of cross-coupling reactions include, but are not limited to, Suzuki coupling, Stille coupling, and Negishi coupling.

The term "cross-coupling group" as used herein means a functional group capable of reacting with another functional group (e.g., a halo group) in a cross-coupling reaction to form a carbon-carbon ("C-C") bond. In some embodiments, a C-C bond is formed between two aromatic groups.

The term "cross-coupling conditions" as used herein means the chemical conditions (e.g., temperature, length of reaction time, volume of solvent required) required to enable the cross-coupling reaction to occur.

Examples of cross-coupling groups and their respective cross-coupling conditions include, but are not limited to, Suzuki coupling conditions using boronic acids and boronic esters, use of SnBu₃And Negishi coupling conditions using ZnX.

All three coupling conditions generally involve the use of a catalyst, a suitable solvent, and optionally a base. Suzuki coupling conditions involve the use of a palladium catalyst and a suitable solvent. Examples of suitable palladium catalysts include, but are not limited to, PdCl₂(PPh₃)₂、Pd(Ph₃)₄And PdCl₂(dppf). Suitable bases include, but are not limited to, K₂CO₃And Na₂CO₃. Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and ethanol.

Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent and other optional reagents. Examples of suitable catalysts include, but are not limited to, PdCl₂(PPh₃)₂、Pd(Ph₃)₄And PdCl₂(dppf). Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide.

Negishi coupling conditions involve the use of a catalyst (palladium or nickel) and a suitable solvent. Examples of suitable catalysts include, but are not limited to, Pd₂(dba)₃、Ni(PPh₃)₂Cl₂、PdCl₂(PPh₃)₂And Pd (Ph)₃)₄. Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide.

Suzuki, Stille, and Negishi conditions are known to those skilled in the art and are described in more detail in various references, including "March's Advanced organic chemistry".

As will be appreciated by those skilled in the art, the cross-coupling group is generated from a coupling group precursor. The cross-coupling group precursor is a reagent or reagent group used to generate the cross-coupling group. Examples include, but are not limited to, bis (pinacolato) diboron, used in the generation of boronates; trimethylborate, used for generating boronic acid; bu₃SnCl for stannane generation; and ZnCl₂And is used for the formation of zincate in the Negishi coupling reaction. Examples of suitable coupling group generating conditions include, but are not limited to, the preparation of boronic esters via palladium-mediated catalysis; preparing boronic acid by hydrolyzing boronic ester; stannane was prepared via a two-step process: 1) replacement of halogen metal followed by 2) and Bu₃Metal transfer of SnCl; and preparing the zincate ester via a two-step process: 1) halogen metal substitution followed by 2) ZnCl₂Addition of (1).

Another embodiment provides a process for producing a compound of formula 5, comprising reacting a compound of formula 4:

wherein R is³、R⁴、R⁵、R⁶And R⁷Is as defined herein; LG (Ligno-lead-acid)₂Are suitable leaving groups, such as halo;

and R²-LG₃Reaction of LG wherein₃Is a leaving group capable of being displaced by an NH-amide. Examples of leaving groups include, but are not limited toHalo, tosyl and mesyl.

Another embodiment provides a process for producing a compound of formula 4, comprising reacting a compound of formula 3:

the reaction is carried out in a two-step process. The first step involves reducing the nitro group under suitable reducing conditions, e.g. iron powder, SnCl₂Zinc powder, indium/HCl or H₂Pd, formula for formation3-aA compound:

the second step involves reacting an amine with a compound of formula3-aCyclocondensation of carboxylic acid esters, resulting in compounds of formula4A compound is provided. The ring condensation usually takes place in the presence of an acid or a base. In some embodiments, this two-step process occurs in situ. One example of in situ conditions involves treatment of nitro compounds with iron powder in glacial acetic acid.

Another aspect of the invention provides a method of generating5Alternative means of the compounds. Not of the direct cyclisation formula3-aCompound generation formula4Instead, the amino intermediate may first be functionalized under suitable conditions known to those skilled in the art to yield a compound of formula (la)3-bCompound (I)

For example, amino groups may be substituted with R²-LG₃Reaction of LG wherein₃Is a leaving group capable of being displaced by an amine. Examples of leaving groups include, but are not limited to, halo, tosyl, and mesyl.

Such compounds may then be cyclized under suitable cyclocondensation conditions to form the formula5A compound is provided.

Another embodiment of the present invention provides a generating formula3A process for preparing a compound of formula (I)2A compound:

and formula1Compound reaction:

under suitable replacement conditions, the formula3A compound is provided. Suitable displacement conditions typically comprise a suitable solvent and a suitable base or acid. Examples of suitable displacement conditions include, but are not limited to, K₂CO₃And acetone, Hunig's base/THF.

Another aspect of the invention provides a process for the preparation of a compound of formula I, wherein Y¹Is NR⁹. One embodiment involves reacting a compound of formula I, wherein Y¹Is O, X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined herein; under conditions known in the art to be suitable for converting an amide to an amidine to form a compound of formula I wherein Y¹Is NR⁹(shown as I-a in scheme II). Suitable conditions generally involve amines (R)¹-NHR⁹) Suitable solvents and activated intermediates derived from amides (e.g. thioamides prepared from amides and Lawesson's reagent).

On the other hand, formula5The compounds may be subjected to similar amide conversion conditions to form the formula5-aA compound is provided.5-aOr5-bLG in (1)₂The groups may be used as handles for preparing the compounds of the invention. In the last step, LG₂Can for example be replaced by an amine or take part in a palladium-assisted coupling reaction (e.g. Suzuki, Stille).

In some embodiments, formula I or5A compound of formula (I) wherein Y¹Is O, X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Are as defined herein and can be converted to cyclic amidines, wherein R²And R⁹Together forming ring a. These cyclic amidines (shown as I-b in scheme II) can be prepared via a multi-step cyclization sequence. Ring A varies in size and degree of unsaturation (e.g., 5-8 membered rings). For example, the generation of ring a can be performed using methods similar to those reported in the following literature: soc, 103(14), 4186-4194, 1981; het chem, 19(1), 193- "200, 1982; chem, 43(4), 478-482, 2004; scientific pharm, 57(1), 27-38, 1989; tetrahedron lett, 16(2), 449-469, 2005; chem., 59(17), 5084-.5-aOr5-bLG in (1)₂The groups may be used as handles for preparing the compounds of the invention. In the last step, LG₂Can for example be replaced by an amine or take part in a palladium-assisted coupling reaction (e.g. Suzuki, Stille).

Another aspect of the invention provides protein kinase inhibitor compounds, and thus are useful for treating diseases, disorders and conditions, as well as other uses described herein. In another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds described herein, and optionally a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

The present invention provides compounds and compositions useful as inhibitors of protein kinases. In some embodiments, the protein kinase is Plk. In some embodiments Plk 1.

The compounds and compositions of the invention are particularly useful for treating or lessening the severity of a disease, condition or disorder in which a protein kinase is implicated as an inhibitor of the protein kinase. In one aspect, the invention provides methods of treating or lessening the severity of a disease, disorder or condition in which a protein kinase is implicated. In another aspect, the invention provides a method of treating or lessening the severity of a protein kinase disease, disorder or condition, wherein inhibition of enzyme activity is implicated in the treatment of that disease. In another aspect, the invention provides methods of treating or lessening the severity of a disease, disorder or condition with a compound that inhibits enzymatic activity by binding to a protein kinase. In another aspect, the invention provides methods of treating or lessening the severity of a protein kinase disease, disorder or condition by inhibiting the enzymatic activity of the protein kinase with a protein kinase inhibitor.

In some embodiments, the protein kinase inhibitor is a Plk inhibitor.

One aspect of the present invention pertains to methods for inhibiting protein kinase activity in a patient comprising administering to the patient a compound of formula I or a composition comprising the compound.

In some embodiments, the method is for treating or preventing a disorder selected from the group consisting of: autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma and alzheimer's disease. In some embodiments, the protein kinase is Plk. In other embodiments, the disorder is selected from a proliferative disorder and a neurodegenerative disorder.

Depending on the particular protein kinase-mediated condition to be treated or prevented, additional agents that are normally administered to treat or prevent the condition may be administered with the inhibitors of the invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of the present invention to treat proliferative diseases.

These additional drugs may be administered separately from the compound or composition containing the protein kinase inhibitor as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the protein kinase inhibitor in a single composition.

As inhibitors of protein kinases, the compounds and compositions of the present invention may also be used in biological samples. One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, the method comprising contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein meansIn vitroOr fromIn vivoIncluding, without limitation, cell cultures and extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, and biological sample storage.

Another aspect of the invention relates to protein kinase studies in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and comparative evaluation of novel protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays, such as enzymatic assays and cell-based assays.

The activity of the compounds used as protein kinase inhibitors in the present invention may be determined in vitro, in vivo or in a cell line. In vitro assays include measuring inhibition of kinase activity or ATPase activity of activated kinases. A selective in vitro assay quantifies the ability of an inhibitor to bind to a protein kinase. Binding of the inhibitor can be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by performing a competition experiment in which a new inhibitor is incubated with a kinase bound to a known radioligand. Detailed conditions for determining compounds useful as PLK1, PLK2, PLK3, and PLK4 inhibitors in the present invention are described in the examples below.

One aspect of the invention provides compounds useful in the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include proliferative or hyperproliferative diseases and neurodegenerative diseases.

Examples of proliferative and hyperproliferative diseases include, without limitation, cancer.

The term "cancer" includes, but is not limited to, the following cancers: mammary gland; an ovary; the cervix; the prostate; testis, urogenital tract; an esophagus; larynx, glioblastoma; neuroblastoma; the stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; a bone; a colon; a colorectal region; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; a sarcoma; bladder cancer; liver cancer and biliary tract; kidney cancer; myeloid disorders; lymphoid disorders, hodgkin's disease, hair cells; oral and pharyngeal (oral), lip, tongue, mouth, pharynx; the small intestine; colon-rectum, large intestine, rectum; the brain and central nervous system; chronic Myelogenous Leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, the following cancers: melanoma, lymphoma or a cancer selected from stomach, kidney, or the following: head and neck, oropharynx, non-small cell lung cancer (NSCLC), endometrium, liver cancer, non-Hodgkin's lymphoma, and lung.

For the avoidance of doubt, the term "cancer" also includes, but is not limited to, the following cancers: epidermoid tumors of the mouth: oral cavity, lip, tongue, mouth, pharynx; heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinomas (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcomas, lymphomas, hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon-rectum, colorectal, rectum; genitourinary tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrosoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteoid osteoma, and giant cell tumor; the nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (severe cystadenocarcinoma, myxocystic adenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), mammary glands, blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hair cells, lymphoid disorders, skin, malignant melanoma, Basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and adrenal gland: neuroblastoma. Thus, the term "cancer cell" as provided herein includes cells afflicted by any one of the above conditions.

In some embodiments, the compounds of the present invention are useful for the treatment of cancer, such as colorectal, thyroid, breast and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid tissue deformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, eosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis.

In some embodiments, the compounds of the invention are useful for treating hematopoietic disorders, particularly Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Acute Promyelocytic Leukemia (APL), and Acute Lymphocytic Leukemia (ALL).

Examples of neurodegenerative diseases include, without limitation, Alzheimer's disease.

Another aspect of the invention provides a method of treating or lessening the severity of a disease selected from a proliferative or hyperproliferative disease or a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound.

In certain embodiments, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat the disease. The compounds and compositions according to the methods of the present invention may be administered in any amount and by any route of administration that is effective in treating or lessening the severity of the disease.

In some embodiments, the disease is a protein kinase-mediated disorder. In some embodiments, the disease is a Plk-mediated disease.

The term "protein kinase-mediated condition" as used herein refers to any disease or other deleterious condition in which a protein kinase is known to play a role. Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and alzheimer's disease.

The term "Plk-mediated disorder" as used herein refers to any disease or other deleterious disorder in which Plk plays a role. Such conditions include, without limitation, proliferative or hyperproliferative diseases or neurodegenerative diseases.

In another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally a pharmaceutically acceptable carrier, adjuvant or vehicle.

In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

For example, chemotherapeutic agents or other anti-proliferative agents may be used in combination with the protein kinase inhibitors of the present invention to treat proliferative diseases and cancer.

Examples of known chemotherapeutic agents include, but are not limited to, Gleevec^TMDoxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferon, and platinum derivatives.

Other examples of drugs that may also be used in combination with the inhibitors of the invention include, without limitation: for the treatment of Alzheimer's disease, e.g.And(ii) a For the treatment of Parkinson's disease, such as L-dopa/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; drugs for treating Multiple Sclerosis (MS), e.g. interferon-beta (e.g. interferon-beta)And)、and mitoxantrone; for asthma, e.g. albuterol and(ii) a Drugs for treating schizophrenia, such as zyprexa, risperdal, seroquel and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulating and immunomodulating agents such as cyclosporine, tacrolimus, rapamycin, mycophenolatemofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs; drugs for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; drugs for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; drugs for treating blood disorders, such as corticosteroids, leukemia drugs, and growth factors; and drugs for the treatment of immunodeficiency disorders, such as gamma-globulin.

As described herein, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid excipients, dispersion or suspension aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, SixteenthEdition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) disclose various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces any undesirable biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as serum albumin; buffer substances, such as phosphates; glycine; sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; waxes; polyethylene-polypropylene oxide-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; crushed tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

The protein kinase inhibitor or a pharmaceutical salt thereof may be formulated into a pharmaceutical composition for administration to an animal or human. These pharmaceutical compositions, which comprise a protein kinase inhibitor in an amount effective to treat or prevent a kinase-mediated disorder and a pharmaceutically acceptable carrier, are another embodiment of the present invention. In some embodiments, the protein kinase-mediated disorder is a Plk-mediated disorder.

The exact amount of the compound required for treatment will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular drug, the manner of its administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein denotes physically discrete pharmaceutical units, as appropriate for the patient to be treated. It will be understood, however, that the total daily amount of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and other factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), bucally, as an oral or nasal spray, etc., to humans and other animals, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of from about 0.01mg/kg to about 50mg/kg, preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day, one or more times a day, to achieve the desired therapeutic effect. In a preferred embodiment, the compounds of the invention are administered orally.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the invention, it is often desirable to delay absorption of the compounds following subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of a compound depends on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microencapsulated matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Rectal or vaginal compositions are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, for example starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, for example glycerol, d) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders, for example paraffin, f) absorption accelerators, for example quaternary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerol monostearate, h) absorbents, for example kaolin and bentonite, and i) lubricants, for example talc, calcium stearate, sodium silicate, and the like, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as polymeric polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as polymeric polyethylene glycols and the like.

The active compound may also be in microencapsulated form, containing one or more of the above-mentioned excipients. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. Such dosage forms may also contain, under normal circumstances, other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as appropriate. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of controlling the delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of the present invention may also be employed in compositions for the treatment or prevention of the above-mentioned conditions.

The compounds of the invention may also be present as pharmaceutically acceptable derivatives.

"pharmaceutically acceptable derivative" adducts or derivatives, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

By "pharmaceutically acceptable derivative or prodrug" is meant any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof. Particularly desirable derivatives and prodrugs are those which increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), or which enhance delivery of the parent compound to a biological cavity (e.g., the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of the present invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts, and sulfonate esters.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol, and wool fat.

Administration of the compositions of the invention may be oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously.

The sterile injectable dosage form of the compositions of the present invention may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may 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 acceptable carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any brand of fixed oil may be used, including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as tweens, spans and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, may also be used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention may be administered orally, and any orally acceptable dosage form includes, but is not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule dosage forms, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is mixed with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. They may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes sites or organs readily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these sites or organs.

Topical lower intestinal administration may be carried out using rectal suppositories (see above) or suitable enemas. Topical transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Topical carriers for the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic purposes, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline or, preferably, as solutions in isotonic pH adjusted sterile saline, both with or without preservatives, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

The amount of kinase inhibitor that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. Preferably, the compositions should be formulated so that a dose of between 0.01 and 100mg/kg body weight/day of inhibitor can be administered to a patient receiving these compositions.

It will also be understood that the specific dose and regimen of treatment for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the attending physician, and the severity of the particular disease being treated. The amount of inhibitor will also depend on the particular compound in the composition.

According to another embodiment, the present invention provides a method of treating or preventing a protein kinase-mediated disorder (Plk-mediated disorder in some embodiments), comprising the step of administering to a patient one of the above pharmaceutical compositions. The term "patient" as used herein means an animal, preferably a human.

In some embodiments, the method is for treating or preventing a disorder selected from the group consisting of: proliferative disorders (e.g., cancer), neurodegenerative disorders, autoimmune disorders, inflammatory disorders, and immunologically-mediated disorders. In some embodiments, the method is for treating or preventing a disorder selected from the group consisting of: cancers, such as breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung cancers, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, melanoma, hepatomegaly, cardiac hypertrophy, alzheimer's disease, cystic fibrosis and viral disease or any of the specific diseases or conditions mentioned above.

The compounds of the invention can generally be prepared by methods known to those skilled in the art. These compounds can be analyzed by known methods including, but not limited to, LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). The compounds of the invention can also be tested according to these examples. It should be understood that the specific conditions shown below are merely examples and are not meant to limit the scope of conditions that can be used to prepare, analyze, or test the compounds of the present invention. Rather, the present invention also encompasses conditions known to those skilled in the art for preparing, analyzing and testing the compounds of the present invention.

Examples

The term "rt (min)" as used herein denotes the HPLC retention time in minutes, in relation to the compound. Unless otherwise indicated, the HPLC method used to obtain the reported retention times was as follows:

column: ACE C8 column, 4.6x150mm

Gradient: 0-100% acetonitrile + methanol 50:50(20mM Tris phosphate)

Flow rate: 1.5 mL/min

And (3) detection: 225 nm.

Mass spectral samples were analyzed on a MicroMass Quattro Micro mass spectrometer operating in single MS mode and electron jet ionization mode. The sample was introduced to the mass spectrometer using chromatographic methods.

Recording at 400MHz using a Bruker DPX 400 instrument¹H-NMR spectrum. The following compounds of formula I were prepared and analyzed as follows.

Compounds I-1 to I-273 and I-278 to I-282 were prepared and identified in the following examples as follows.

Example 1：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzoic acid (I-1)

The method A comprises the following steps: methyl 3- (N-cyclopentyl-N- (2-chloro-5-nitropyrimidin-4-yl) amino) propionate

Methyl 3- (cyclopentylamino) propionate (1.78g, 10.4m mole) and potassium carbonate (1.52g, 11).0m mol) in acetone (25ml) at 0 ℃ while stirring, a solution of 2, 4-dichloro-5-nitropyrimidine (2.04g, 10.4m mol) in acetone (15ml) was added during this time. The mixture was stirred at ambient temperature overnight, concentrated, and diluted with ethyl acetate/water. The mixture was extracted with ethyl acetate x3, dried over magnesium sulfate, concentrated to an amber oil, and solidified upon standing. Flash chromatography on silica gel eluting with 30% ethyl acetate/petrol gave methyl 3- (N-cyclopentyl-N- (2-methyl-5-nitropyrimidin-4-yl) amino) propionate as a pale yellow solid (2.24g, 65%). NMR CDCl₃1.50-2.07(8H，m)，2.70-2.82(2H，m)，3.65-3.90(6H，m)，8.72(1H，s)。

The method B comprises the following steps: 2-chloro-9-cyclopentyl-8, 9-dihydro-5H-pyrimido [4.5-b][1，4]Dinitrogen Hetero compound -6(7H) -one

Methyl 3- (N-cyclopentyl-N- (2-chloro-5-nitropyrimidin-4-yl) amino) propionate (2.0g, 6.1mmol) was treated in portions with iron powder (0.7g, 12.4mmol) in glacial acetic acid at 70 ℃ for 6 hours. The mixture was concentrated, triturated with dichloromethane and filtered. The filtrate was adsorbed on silica gel and soxhlet extracted with ethyl acetate for 7 hours. Concentrating the extractive solution to black oil, and triturating with methanol to obtain light brown crystal of 2-chloro-9-cyclopentyl-8, 9-dihydro-5H-pyrimido [4.5-b ]][1，4]Diaza derivatives-6(7H) -one (499mg, 31%). NMR1.46-1.58(4H, m), 1.60-1.72(2H, m), 1.75-1.85(2H, m), 2.64(2H, d), 3.55(2H, d), 4.92-5.03(1H, m), 7.83(1H, s), 9.72(1H, s).

The method C comprises the following steps: 2-chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H-pyrimido [4，5-b][1，4]Diaza derivatives -6(7H) -one

2-chloro-9-cyclopentyl-8, 9-dihydro-5H-pyrimido [ 4.5-b)][1，4]Diaza derivatives-6(7H) -one (474.7mg, 1.78mmol) and methyl iodide (0.122ml, 1.96mmol) in DMA (4.5ml) was stirred at-10 ℃ and treated with sodium hydride 60% oil dispersion (75mg, 1.87 mmol). The mixture was warmed to 0 ℃ for 20min and then to 20 ℃ for 40 min. An additional 0.12ml of methyl iodide and 8mg of sodium hydride are added and the mixture is stirred at ambient temperature overnight. Ice was added and the mixture was concentrated under reduced pressure. The residual oil was treated dropwise with water (6ml), filtered and the dark yellow solid dried under high vacuum at 60 ℃ (486mg, 98%). NMR DMSOD⁶1.45-1.72(6H，m)，1.76-1.91(2H，m)，2.61(2H，d)，3.18(3H，s)，3.64(2H，d)，4.65-4.74(1H，m)，8.15(1H，s)。

The method D comprises the following steps: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4，5-b][1，4]Diaza derivatives -2-ylamino) -3-methoxybenzoic acid (I-1)

2-chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (150mg, 0.536mmo l) in ethanol (2.25ml) and water (9ml) with conc. HCl (0.088ml) and 4-amino-3-methylOxybenzoic acid (134mg, 0.804 mmol). The mixture was stirred at 90 ℃ for 24H, concentrated, the residue triturated with methanol/ether, filtered and the solid washed with ethanol and then ether to give 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzoic acid as a dark yellow powder (185.5mg, 84%). NMR DMSOD⁶1.51-1.79(6H，m)，1.82-1.93(2H，m)，2.70-2.75(2Hm)，3.18(3H，s)，3.72-3.78(2H，m)，3.98(3H，s)，4.81-4.93(1H，m)，7.57-7.64(2H，m)，8.15-8.22(2H，m)，9.46(1H，br s)；HPLC rt(min)：6.57。

Example 2：

The method E comprises the following steps: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-2)

Cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzoic acid (150mg, 0.365mmol) was treated with diisopropylethylamine (0.127ml, 0.73mmol) and TBTU (127mg, 0.394mmol) in dichloromethane (5 ml). The mixture was stirred for 25min, then treated with 4-amino-1-methylpiperidine (52mg, 0.453mm0l) and stirred overnight. The mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, 0.02M sodium hydroxide solution x2, brine, dried over magnesium sulfate and concentrated. Trituration with ethyl acetate/diethyl ether gave 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]DinitrogenHetero compound-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide as a colorless solid (132mg, 71%). 1H NMRDMSO D⁶1.50-2.08(14H，m)，2.21(3H，s)，2.55-2.65(2H，m)，2.77-2.87(2H，m)，3.21(3H，s)，3.60-3.70(2H，m)，3.70-3.82(1H，m)，3.98(3H，s)，4.80-4.90(1H，m)，7.42-7.52(2H，m)，7.75(1H，s)，8.10-8.18(2H，m)，8.40(1H，d)；HPLC rt(min)：9.60。

Example 3：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -benzoic acid (I-3)

From 2-chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H-pyrimido [4, 5-b ] using method D][1，4]Diaza derivatives-6(7H) -one and 4-aminobenzoic acid. NMR DMSO D⁶1.59-1.80(6H，m)，1.90-1.98(2H，m)，2.70-2.75(2Hm)，3.18(3H，s)，3.71-3.75(2H，m)，4.91(1H，m)，7.77(2H，d)，7.94(2H，d)，8.17(1H，s)，10.65(1H，brs).HPLCrt(min)：6.39。

Example 4：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1-methylpiperidin-4-yl) benzamide (I-4)

Prepared from compound I-3 and 4-amino-1-methylpiperidine using method E. 1HNMR DMSO D⁶1.62-2.05(14H，m)，2.23(3H，s)，2.60-2.68(2H，m)，2.77-2.86(2H，m)，3.23(3H，s)，3.65-3.70(2H，m)，3.78(1H，m)，4.91(1H，m)，7.76-7.85(4H，m)，8.00(1H，d)，8.11(1H，s)，9.50(1H，s)；HPLCrt(min)：7.50。

Example 5：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- [1- (tert-butoxycarbonyl) piperidin-4-yl]Benzamide (I-5)

Prepared from compound I-1 and 4-amino-1- (tert-butoxycarbonyl) piperidine using method E. NMR DMSO D⁶1.41(9H，s)，1.37-1.98(14H，m)，2.57-2.63(2H，m)，2.80(2H，m)，3.17(3H，s)，3.61-3.69(2H，m)，3.91(3H，s)，3.97(1H，m)，4.83(1H，m)，7.47-7.52(2H，m)，8.07-8.15(3H，m)，8.27(1H，m)；HPLCrt(min)：10.07。

Example 6：

Method F: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (piperidin-4-yl) benzamide (I-6)

To 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b ] at 0 deg.C][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- [1- (tert-butoxycarbonyl) piperidin-4-yl]A solution of benzamide (I-5) (72mg, 0.12mmol) in dichloromethane (3ml) was added trifluoroacetic acid. The reaction mixture was stirred at 0 ℃ for 30 minutes, at room temperature for 60 minutes, and then the solvent was evaporated. The residue was triturated with diethyl ether and the solid filtered to give the TFA salt of the title compound as an off-white solid (70mg, 95%). 1H NMR DMSOD⁶1.55-2.04(14H，m)，2.62-2.70(2H，m)，2.98-3.08(2H，m)，3.19(3H，s)，3.40-3.48(2H，m)，3.65-3.71(2H，m)，3.97(3H，s)，4.09(1H，m)，4.89(1H，m)，7.49-7.56(2H，m)，8.10(1H，s)，8.19(1H，d)，8.30-8.40(2H，d)，8.60-8.69(2H，m)；HPLCrt(min)：7.53。

Example 7：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxyphenyl- (4-tert-butoxycarbonylpiperazin-1-yl) methanone (I-7)

Prepared from compound I-1 and N-tert-butoxycarbonylpiperazine using method E. NMRDMSOD⁶1.41(9H，s)，1.55-1.95(10H，m)，2.57-2.62(2H，m)，3.18(3H，s)，3.27-3.63(8H，m)，3.90(3H，s)，4.80(1H，m)，6.96(1H，d)，7.05(1H，s)，7.72(1H，s)，8.07(1H，s)，8.30(1H，d)；HPLCrt(min)：9.98。

Example 8：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-)methyl-6-oxo-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxyphenyl (piperazin-1-yl) methanone (I-8)

Prepared from compound I-7 using method F. NMR DMSOD⁶1.50-1.91(8H，m)，2.65-2.73(2H，m)，3.15-3.22(7H，m)，7.63-7.70(6H，m)，3.94(3H，s)，4.80(1H，m)，7.12(1H，d)，7.20(1H，s)，8.04(1H，d)，8.10(1H，s)，9.02-9.11(2H，m).HPLCrt(min)：7.81。

Example 9：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-9)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.62-1.73(6H，m)，1.92-1.97(2H，m)，2.58-2.60(2H，m)，2.78-2.80(3H，m)，3.17(3H，s)，3.62-3.64(2H，m)，3.94(3H，s)，4.82(1H，m)，7.46-7.50(2H，m)，7.73(1H，s)，8.08(1H，s)，8.35(1H，m)，8.38(1H，m)；HPLC rt(min)：8.45；MS(ES⁺)425，(ES^-)423。

Example 10：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-Methoxybenzoic acid (I-10)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.08(3H，d)，1.48-1.86(7H，m)，1.98-2.10(1H，m)，2.90-3.00(1H，m)，3.20(3H，s)，3.37(1H，d)，3.56(1H，t)，3.95(3H，s)，4.72-4.85(1H，m)，7.56(1H，s)，7.60(1H，d)，8.13(1H，s)，8.31(1H，d)，8.66(1H，brs)；HPLC rt(min)：7.47；MS(ES⁺)426，(ES^-)424。

Example 11：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2-methoxyethyl) benzamide (I-11)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.62-1.73(6H，m)，1.90-2.0(2H，m)，2.54-2.60(2H，m)，3.17(3H，s)，3.25(3H，s)，3.42-3.46(4H，m)，3.62-3.64(2H，m)，3.95(3H，s)，4.82(1H，m)，7.49-7.52(2H，m)，7.74(1H，s)，8.09(1H，s)，8.41(2H，m)；HPLC rt(min)：8.65；MS(ES⁺)469，(ES^-)467。

Example 12：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-12)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.03(3H，d)，1.50-2.15(14H，m)，2.18(3H，s)，2.76-2.90(3H，m)，3.20(3H，s)，3.28-3.48(2H，m)，3.70-3.80(1H，m)，3.98(3H，s)，7.49-7.52(2H，m)，7.74(1H，s)，8.05-8.12(2H，m)，8.40(1H，d)；HPLCrt(min)：8.95；MS(ES⁺)522，(ES^-)520。

Example 13：

Method G: ethyl 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) piperidine-1-carboxylic acid ester (I-13)

2-chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (100mg, 0.357mmol) and ethyl 4-amino and-1-carboxylate (129. mu.l, 0.714mmol) were heated in isopropanol (2ml) at 90 ℃ for 24H. Diisopropylethylamine (125. mu.l, 0.714mmol) was added and the reaction mixture was heated at 105 ℃ for a further 24 hours. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100%Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, flow rate 25mL/min]To give the title compound (18mg) as an off-white powder. NMR DMSO D⁶1.20(3H，t)，1.28-1.91(14H，m)，2.80-2.96(2H，m)，3.11(3H，s)，3.50-3.58(2H，m)，3.70-3.85(1H，m)，3.90-3.98(2H，m)，4.03(2H，q)，4.60-4.70(1H，m)，6.65(1H，br s)，7.88(1H，s)；HPLC rt(min)：8.09；MS(ES⁺)417，(ES^-)415。

Example 14：

4- (6, 7, 8, 9-tetrahydro-5, 9-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-14)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.65-1.67(2H，m)，1.83-1.85(2H，m)，2.33-2.36(3H，m)，2.50-2.53(2H，m)，2.60-2.63(2H，m)，3.07(3H，s)，3.18(3H，s)，3.29(3H，s)，3.69-3.71(2H，m)，3.94(3H，s)，7.48-7.53(2H，m)，7.75(1H，s)，8.11(2H，m)，8.46(1H，m)；HPLCrt(min)：6.75；MS(ES⁺)454，(ES^-)452。

Example 15：

4- ((3aR, 10aS) -4-cyclopentyl-9-methyl-10-oxo-1, 2, 3, 3a, 4, 9, 10, 10 a-octahydro-4, 5, 7, 9-tetraaza-benzo [ f ] ol-6-ylamino) -3-methoxy-N-methylbenzamide (I-15)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.40-1.60(9H，m)，1.66-1.69(2H，m)，1.79(1H，m)，1.86-1.87(2H，m)，2.04(1H，m)，2.15(1H，m)，2.80(3H，d)，3.20(3H，s)，3.92(3H，s)，4.14(1H，m)，7.55(1H，d)，7.57(1H，s)，7.95(1H，d)，8.22(1H，s)，8.44(1H，d)，8.95(1H，br s)；HPLCrt(min)：9.45；MS(ES⁺)465，(ES^-)463。

Example 16：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-16)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.62-1.65(4H，m)，1.74(2H，m)，1.88(2H，m)，2.79(3H，d)，3.19(3H，s)，3.36-3.40(2H，m)，3.94(3H，s)，5.18(1H，m)，7.45-7.50(2H，m)，7.68(1H，s)，7.99(1H，s)，8.30(1H，m)，8.37(1H，d)；HPLC rt(min)：9.23；MS(ES⁺)453，(ES^-)451。

Example 17：

4- ((S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-17)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.03-1.07(3H，m)，1.55-1.61(4H，m)，1.70-1.78(4H，m)，1.99(1H，m)，2.80(3H，m)，3.18(3H，s)，3.56-3.61(2H，m)，3.94(3H，s)，4.80(1H，m)，7.50-7.52(1H，m)，7.58(1H，m)，8.07-8.10(1H，m)，8.13(1H，brs)，8.47(1H，m)，9.25(1H，brs)；HPLCrt(min)：8.92；MS(ES⁺)439，(ES^-)437。

Example 18：

4- ((R) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-18)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.03-1.07(3H，m)，1.56-1.60(4H，m)，1.72-1.78(4H，m)，1.98(1H，m)，2.80(3H，m)，3.19(3H，m)，3.57-3.63(2H，m)，3.94(3H，s)，4.81(1H，m)，7.50-7.53(1H，m)，7.60(1H，m)，8.06(1H，d)，8.15(1H，m)，8.50(1H，d)，9.49(1H，br s)；HPLC rt(min)：8.92；MS(ES⁺)439，(ES^-)437。

Example 19：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-9- ((R) -pyrrolidin-3-yl) -5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-19)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.118(3H，s)，1.124(3H，s)，2.04(1H m)，2.27(1H，m)，2.80(3H，d)，3.11-3.28(5H, m), 3.40-3.56(4H, m), 3.93(3H, s), 5.42(1H, quintuple), 7.53-7.57(2H, m), 8.10(1H, s), 8.17(1H, d), 8.39(1H, q), 8.55(1H, br s), 9.05(1H, br s), 9.12(1H, br s); HPLC rt (min): 6.14; MS (ES)⁺)454，(ES^-)452。

Example 20：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-9- ((R) -1-methylpyrrolidin-3-yl) -6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-20)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11-1.15(6H，m)，2.00-2.41(2H m)，2.80(3H，d)，2.85-2.95(3H，m)，3.10-3.40(5H，m)，3.51-3.80(4H，m)，3.93(3H，s)，5.36-5.60(1H，m)，7.56-7.59(2H，m)，8.04-8.13(2H，m)，8.46(1H，m)，8.93-9.13(1H，br s)，10.38-10.77(1H，br s)；HPLC rt(min)：7.25；MS(ES⁺)468，(ES^-)466。

Example 21：

4- ((S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-21)

According to the method using appropriate reagentsAnd E, preparing. NMR DMSO D⁶1.06-1.07(3H，d)，1.56-2.03(14H，m)，2.70(3H，d)，3.09(3H，m)，3.19(3H，s)，3.58-3.64(2H，m)，3.95(3H，s)，4.04(1H，m)，4.84(1H，m)，7.56-7.64(2H，m)，8.08(1H，d)，8.22(1H，s)，8.59(1H，d)，9.61(1H，br s)，10.77(1H，br s)；HPLC rt(min)：9.00；MS(ES⁺)522，(ES^-)520。

Example 22：

4- ((R) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-22)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.06-1.07(3H，d)，1.56-1.98(14H，m)，2.71(3H，d)，3.02-3.08(3H，m)，3.19(3H，s)，3.58-3.64(2H，m)，3.95(3H，s)，4.05(1H，m)，4.83(1H，m)，7.57-7.64(2H，m)，8.09(1H，m)，8.23(1H，s)，8.60(1H，d)，9.64(1H，br s)，10.81(1H，br s)；HPLC rt(min)：9.11；MS(ES⁺)522，(ES^-)520。

Example 23：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-23)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.20(6H，s)，1.55-2.08(12H，m)，2.70(3H，s)，3.00-3.14(2H，m)，3.52(3H，s)，3.50-3.85(4H，m)，3.96(3H，s)，3.98-4.08(1H，m)，5.07-5.18(1H，m)，7.56(1H，d)，7.65(1H，s)，8.07(1H，d)，8.10(1H，s)，8.57(1H，d)，9.50(1H，br s)，10.60(1H，br s)；HPLC rt(min)：9.55；MS(ES⁺)536，(ES^-)534。

Example 24：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-4-yl) benzamide (I-24)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.20(6H，s)，1.55-1.90(8H，m)，3.19(3H，s)，3.50-3，60(2H，m)，4.04(3H，s)，5.13-5.22(1H，m)，7.85(1H，d)，7.90(1H，s)，8.11(1H，s)，8.31(1H，d)，8.45(2H，d)，8.77(2H，d)，9.18(1H，brs)，11.78(1H，s)；HPLC rt(min)：9.94；MS(ES⁺)516，(ES^-)514。

Example 25：

Method H: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylazetidin-3-yl) benzamide (I-25)

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (azetidin-3-yl) -3-methoxybenzamide (69mg, 0.14mmol) was dissolved in methanol (1.5 ml). 37% aqueous formaldehyde (66. mu.l, 0.84mmol) and sodium cyanoborohydride (26mg, 0.42mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with 2N HCl and then saturated NaHCO₃The solution is basified. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried (MgSO)₄) And concentrated in vacuo. After crystallization from ethyl acetate, the title compound (33mg) was obtained as a white solid. NMR DMSO D⁶1.10(6H，s)，1.55-1.69(4H，m)，1.69-1.80(2H，m)，1.82-1.95(2H，m)，2.28(3H，s)，3.01(2H，t)，3.38(2H，s)，3.57(2H，t)，3.95(3H，s)，4.39-4.50(1H，m)，5.12-5.25(1H，m)，7.43-7.52(2H，m)，7.71(1H，s)，8.00(1H，s)，8.38(1H，d)，8.63(1H，d)；HPLC rt(min)：9.60；MS(ES⁺)508，(ES^-)506。

Example 26：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((R) -1-methylpyrrolidin-3-yl) benzamide (I-26)

Prepared according to method H using the appropriate reagents. NMR DMSO D⁶1.01(6H，s)，1.52-1.94(9H，m)，2.12-2.20(1H，m)，2.27(3H，s)，2.35-2.42(1H，m)，2.8-2.68(2H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.36-4.475.13-5.26(1H，m)，7.46-7，56(2H，m)，7.69(1H，s)，7.99(1H，s)，8.33-8.41(2H，m)；HPLC rt(min)：9.71；MS(ES⁺)522，(ES^-)520。

Example 27：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2- (1-methyl-1H-imidazol-5-yl) ethyl) benzamide (I-27)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.01(6H，s)，1.55-1.94(8H，m)，2.77-2.85(2H，m)，3.20(3H，s)，3.38(2H，s)，3.45-3.50(2H，m)，3.58(3H，s)，5.15-5.25(1H，m)，6.73(1H，s)，7.45-7.55(2H，m)，7.70(1H，s)，7.99(1H，s)，8.49(1H，d)，8.55-8.59(1H，m)；HPLC rt(min)：9.10；MS(ES⁺)547，(ES^-)545。

Example 28：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (3- (4-methylpiperazin-1-yl) propyl) benzamide (I-28)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.53-1.95(12H，m)，2.15(3H，s)，2.20-2.45(8H，m)，3.19(3H，s)，3.22-3.30(2H，m)，3.38(2H，s)，3.94(3H，s)，5.10-5.21(1H，m)，7.48(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.30-8.40(2H，m)；HPLC rt(min)：9.37；MS(ES⁺)579，(ES^-)577。

Example 29：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-7, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-29)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.59-1.60(4H，m)，1.75-1.82(4H，m)，2.80(3H，d)，3.45(2H，m)，3.93(3H，s)，5.21(1H，m)，7.48(1H，m)，7.56(1H，s)，7.79(1H，s)，8.05(1H，m)，8.44(1H，m)，9.00(1H，v br s)，9.76(1H，s)；HPLCrt(min)：8.97；MS(ES⁺)439，(ES^-)437。

Example 30：

4- (9-cyclopropyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-30)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.83(2H，m)，0.96(2H，q)，1.16(6H，s)，2.79(3H，d)，3.09(1H，m)，3.17(3H，s)，3.71(2H，s)，3.96(3H，s)，7.52-7.56(2H，m)，8.12(1H，s)，8.38(1H，q)，8.53(1H，d)，9.12(1H，br s)；HPLC rt(min)：8.26；MS(ES⁺)425，(ES^-)423。

Example 31：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2- (1-methyl-1H-imidazol-4-yl) ethyl) benzamide (I-31)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.55-1.68(4H，m)，1.70-1.78(2H，m)，1.83-1.93(2H，m)，2.70(2H，t)，3.19(3H，s)，3.39(2H，s)，3.93-3.51(2H，m)，3.60(3H，s)，3.95(3H，s)，5.14-5.25(1H，m)，6.91(1H，s)，7.43-7.52(3H，m)，7.65(1H，s)，7.99(1H，s)，8.37(1H，d)，8.41-8.46(1H，m)；HPLC rt(min)：9.16；MS(ES⁺)547，(ES^-)545。

Examples]32：

9-cyclopentyl-2- [4- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxyphenylamino]-5, 7, 7-trimethyl-5, 7, 8, 9-tetrahydropyrimido [4, 5-b][1，4]Diaza derivatives-6-one (I-32)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.60-2.27(10H，m)，3.25(3H，s)，3.43(2H，s)，3.65-3.90(4H，m)，3.98(3H，s)，5.18-5.29(1H，m)，5.30-5.53(1H，m)，7.15-7.25(2H，m)，7.73(1H，s)，8.03(1H，s)，8.39(1H，d)；HPLC rt(min)：9.67；MS(ES⁺)411，(ES^-)409。

Example 33：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2-morpholinoethyl) benzamide (I-33)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.55-1.92(8H，m)，2.38-2.52(6H，m)，3.19(3H，s)，3.38(2H，s)，3.36-3.44(2H，m)，3.54-3.63(4H，m)，3.94(3H，s)，5.12-5.22(1H，m)，7.45(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.26(1H，br s)，8.37(1H，d)；HPLCrt(min)：9.26；MS(ES⁺)552，(ES^-)550。

Example 34：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2- (pyrrolidin-1-yl) ethyl) benzamide (I-34)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.55-1.93(12H，m)，2.52-2.73(6H，m)，3.19(3H，s)，3.39(2H，s)，2.28-2.46(2H，m)，3.95(3H，s)，5.13-5.22(1H，m)，7.43-7.50(2H，m)，7.69(1H，s)，7.99(1H，s)，8.34-8.42(2H，m)；HPLC rt(min)：9.17；MS(ES⁺)536，(ES^-)534。

Example 35：

4- (6, 7, 8, 9-tetrahydro-9-isopropyl-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-35)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H, s), 1.23(6H, d), 2.80(3H, d), 3.18(3H, s), 3.50(2H, s), 3.95(3H, s), 5.09(1H, heptad), 7.53(1H, dd), 7.57(1H, d), 8.01(1H, s), 8.07(1H, d), 8.41(1H, q), 9.15(1H, br s); hplcrt (min): 8.63; MS (ES)⁺)527，(ES^-)525。

Example 36：

4- (6-cyclopentyl-4, 4-dimethyl-5, 6-dihydro-4H-2, 3, 6, 7, 9, 10 b-hexaazabenzo [ e ] ol-8-ylamino) -3-methoxy-N-methylbenzamide (I-36)

The method I comprises the following steps: 8-chloro-6-cyclopentyl-4, 4-dimethyl-5, 6-dihydro-4H-2, 3, 6, 7, 9, 10b- Hexaazabenzo [ e)]Ao nationality of Olympic

2-chloro-9-cyclopentyl-8, 9-dihydro-7, 7-dimethyl-5H-pyrimidineAnd [4, 5-b ]][1，4]Diaza derivatives-6(7H) -one (0.21g, 0.73mmol) was heated in phosphorus oxychloride (6ml) at 110 ℃ for 4H. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane (4 ml). This latest solution was then added dropwise to a 1M solution of hydrazine in tetrahydrofuran (7.27ml, 7.27 mmol). The reaction mixture was stirred at room temperature overnight. Adding saturated NaHCO₃The solution and the mixture were extracted with ethyl acetate. The organic layer was dried (MgSO₄) Filtered and concentrated in vacuo. The resulting mixture was dissolved in trimethyl orthoformate (4ml) and heated to 110 ℃ for 90 minutes. The reaction mixture was evaporated in vacuo and purified by silica gel chromatography eluting with ethyl acetate to give the title compound as an off-white solid (0.16g, 69% yield). NMR DMSO D⁶1.37(6H, s), 1.52-1.88(8H, m), 3.44(2H, s), 5.23(1H, quintuple), 8.56(1H, s), 9.02(1H, s); MS (ES)⁺)319。

4- (6-cyclopentyl-4, 4-dimethyl-5, 6-dihydro-4H-2, 3, 6, 7, 9, 10 b-hexaazabenzo [ e] Ao-8-ylamino) -3-methoxy-N-methylbenzamide (I-36)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.41(6H, s), 1.55-1.90(8H, m), 2.80(3H, d), 3.50(2H, s), 3.94(3H, s), 5.27(1H, quintuple), 7.51(1H, dd), 7.57(1H, d), 8.08(1H, d), 8.47(1H, q), 8.51(1H, s), 8.97(1H, br s), 9.12(1H, s); HPLC rt (min): 8.54 of; MS (ES)⁺)463，(ES^-)461。

Example 37：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (2- ((S) -3-fluoropyrrolidin-1-yl) ethyl) -3-methoxybenzamide (I-37)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.16(6H，s)，1.62-2.04(9H，m)，2.08-2.50(2H，m)，2.60-3.00(5H，m)，3.25(3H，s)，3.43-3.48(2H，m)，3.44(2H，s)，4.00(3H，s)，5.17-5.38(2H，m)，7.51(1H，d)，7.56(1H，s)，7.74(1H，s)，8.05(1H，s)，8.35-8.48(1H，m)，8.43(1H，d)；HPLC rt(min)：9.57；MS(ES⁺)554，(ES^-)552。

Example 38：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (2-azetidin-1-yl) ethyl) -3-methoxybenzamide (I-38)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.55-2.04(10H.m)，2.35-2.55(2H，m)，3.08-3.25(6H，m)，3.20(3H，s)，3.38(2H，s)，3.75-3.95(1H，m)，3.94(3H，s)，5.15-5.25(1H，m)，7.46(1H，s)，7.50(1H，s)，7.68(1H，s)，7.80(1H，s)，8.24-8.30(1H，m)，8.36(1H，d)；HPLCrt(min)：9.31；MS(ES⁺)522，(ES^-)520。

Example 39：

(R) -3-fluoro-pyrrolidine-1-carboxylic acid 2- [4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamido]-Ethyl ester (I-39)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.55-1.96(8H，m)，2.05-2.15(2H，m)，3.19(3H，s)，3.88(2H，s)，3.45-3.58(6H，m)，3.94(3H，s)，4.09-4.20(2H，m)，7.46(1H，d)，7.50(1H，s)，7.72(1H，s)，7.99(1H，s)，8.37(1H，d)，8.43-8.47(1H，m)；HPLC rt(min)：9.49；MS(ES⁺)598，(ES^-)596。

Example 40：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-9-phenyl-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-40)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.29(6H，s)，2.78(3H，d)，3.29(3H，s)，3.89(3H，s)，3.93(2H，s)，6.86(1H，dd)，7.08(1H，d)，7.38-7.42(3H，m)，7.52-7.57(1H，m)，7.61(2H，t)，8.26-8.30(2H，m)，8.86(1H，br s)；HPLC rt(min)：8.59；MS(ES⁺)461，(ES^-)459。

EXAMPLE 41：

4- (9-cyclopentyl-5-ethyl-6, 7, 8, 9-tetrahydro-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-41)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.00(3H，t)，1.56-1.76(6H，m)，1.88-2.02(2H，m)，2.50-2.56(2H，m)，2.79(3H，d)，3.61-3.64(2H，m)，3.70(2H，q)，3.94(3H，s)，4.74(1H，dt)，7.47(1H，dd)，7.51(1H，d)，7.86(1H，brs)，8.13(1H，s)，8.28-8.33(1H，m)，8.36(1H，d)；HPLC rt(min)：8.76；MS(ES⁺)439，(ES^-)437。

Example 42：

4- (6-cyclopentyl-5, 6-dihydro-4H-2, 3, 6, 7, 9, 10 b-hexaaza-benzo [ e ] ol-8-ylamino) -3-methoxy-N-methylbenzamide (I-42)

Prepared according to method D using appropriate reagents.

NMR DMSO D⁶1.63-1.71(4H，m)，1.73-1.85(2H，m)，1.88-2.00(2H，m)，2.85(3H，d)，3.26-3.31(2H，m)，3.62-3.67(2H，m)，3.99(3H，s)，5.26(1H，dt)，7.53(1H，dd)，7.57(1H，d)，8.02(1H，s)，8.34(1H，d)，8.34-8.39(1H，m)，8.45(1H，s)，9.01(1H，s)；HPLCrt(min)：7.88；MS(ES⁺)435，(ES^-)433。

Example 43：

2- (1H-benzo [ d ]]Imidazol-6-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-43)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.12(6H，s)，1.52-1.65(4H，m)，1.66-1.76(2H，m)，1.82-1.93(2H，m)，3.20(3H，s)，3.40(2H，s)，5.25(1H，dt)，7.69-7.76(2H，m)，7.97(1H，s)，8.26(1H，br s)，9.31(1H，br s)，9.67(1H，br s)；HPLCrt(min)：8.52；MS(ES⁺)406，(ES^-)404。

Example 44：

2- (benzo [ d ]]Thiazol-6-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-44)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.57-1.68(4H，m)，1.69-1.79(2H，m)，1.82-1.94(2H，m)，3.20(3H，s)，3.43(2H，s)，5.22(1H，dt)，7.62(1H，dd)，7.97(1H，s)，7.99(1H，d)，8.65(1H，br s)，9.21(1H，s)，9.70(1H，br s)；HPLCrt(min)：9.99；MS(ES⁺)423，(ES^-)421。

Example 45：

2- (2-oxoindolin-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-45)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.47-1.63(4H，m)，1.64-1.78(2H，m)，1.79-1.90(2H，m)，3.17(3H，s)，3.45(2H，s)，3.47(2H，s)，5.13(1H，dt)，6.79(1H，d)，7.29(1H，d)，7.49(1H，s)，7.83(1H，s)，9.60(1H，br s)，10.33(1H，s)；HPLC rt(min)：8.59；MS(ES⁺)421，(ES^-)419。

Example 46：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-methylbenzamide (I-46)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.50-1.62(4H，m)，1.62-1.75(2H，m)，1.78-1.90(2H，m)，2.77(3H，d)，3.19(3H，s)，3.44(2H，s)，7.39(1H，dd)，7.47(1H，d)，7.59(1H，d)，7.94(1H，s)，8.19(1H，dd)，8.34-8.39(1H，m)，9.85(1H，br s)；HPLC rt(min)：8.80；MS(ES⁺)423，(ES^-)421。

Example 47：

2- (1H-indazol-6-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-47)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.14(6H，s)，1.51-1.77(6H，m)，1.81-1.90(2H，m)，3.19(3H，s)，3.46(2H，s)，5.21(1H，dt)，7.25(1H，dd)，7.69(1H，d)，7.85(1H，s)，7.93(1H，s)，8.01(1H，s)，9.98(1H，br s)，12.97(1H，br s)；HPLCrt(min)：9.25；MS(ES⁺)406，(ES^-)404。

Example 48：

2- (4- (1H-imidazol-1-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-48)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.56-1.69(4H，m)，1.70-1.77(2H，m)，1.83-1.94(2H，m)，3.19(3H，s)，3.42(2H，s)，5.23(1H，dt)，7.69(1H，s)，7.72(1H，s)，7.87-7.93(2H，m)，7.93(1H，s)，8.01(1H，s)，8.23(1H，dd)，9.58(1H，s)，9.79(1H，br s)；HPLCrt(min)：9.75；MS(ES⁺)432，(ES^-)430。

Example 49：

2- (4- (1H-1, 2, 4-triazol-1-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ]][1，4]Diaza derivatives-6(7H) -one (I-49)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.57-1.68(4H，m)，1.69-1.79(2H，m)，1.82-1.95(2H，m)，3.19(3H，s)，3.45(2H，s)，5.19(1H，dt)，7.75-7.83(4H，m)，7.96(1H，s)，8.22(1H，s)，9.23(1H，s)，9.88(1H，brs)；HPLCrt(min)：9.45；MS(ES⁺)433，(ES^-)431。

Example 50：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-isopropoxy-N-methylbenzamide (I-50)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.36(6H，d)，1.57-1.70(4H，m)，1.70-1.81(2H，m)，1.85-1.94(2H，m)，2.78(3H，d)，3.19(3H，s)，3.39(2H，s)，4.68-4.78(1H，m)，5.08-5.18(1H，m)，7.44(1H，d)，7.50(1H，s)，7.62(1H，s)，7.98(1H，s)，8.30-8.35(1H，m)，8.38(1H，d)；HPLCrt(min)：9.84；MS(ES⁺)481，(ES^-)479。

Example 51：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-isopropoxy-N- (1-methylpiperidin-4-yl) benzamide (I-51)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.35(6H，d)，1.55-2.05(14H，m)，2.19(3H，s)，2.78-2.87(2H，m)，3.19(3H，s)，3.39(2H，s)，3.22-3.30(1H，m)，4.73-4.82(1H，m)，5.09-5.20(1H，m)，7.47(1H，d)，7.52(1H，s)，7.34(1H，s)，7.98(1H，s)，8.09(1H，d)，8.38(1H，d)；HPLCrt(min)：10.05；MS(ES⁺)564，(ES^-)562。

Example 52：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1-isopropylazetidin-3-yl) -3-methoxybenzamide (I-52)

Prepared according to method H using the appropriate reagents. NMR DMSO D⁶0.89(6H，d)，1.10(6H，s)，1.55-1.93(8H，m)，2.32-2.42(1H，m)，2.90-3.06(2H，m)，3.19(3H，s)，3.38(2H，s)，3.48-3.61(2H，m)，3.95(3H，s)，4.35-4.47(1H，m)，5.17-5.26(1h，m)，7.49(1H，d)，7.50(1H，s)，7.71(1H，s)，7.99(1H，s)，8.38(1H，d)，8.63(1H，brs)；HPLCrt(min)：9.60；MS(ES⁺)536，(ES^-)534。

Example 53：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1- (cyclopropylmethyl) azetidin-3-yl) -3-methoxybenzamide (I-53)

Prepared according to method H using the appropriate reagents. NMR DMSO D⁶0.00-0.05(2H，m)，0.30-0.35(2H，m)，0.50-0.71(1H，m)，1.00(6H，s)，1.47-1.85(8H，m)，2.17-2.26(2H，m)，2.88-3.00(2Hm)，3.09(3H，s)，3.29(2H，s)，3.48-3.57(2H，m)，3.85(3H，s)，4.32-4.42(1H，m)，5.04-5.14(1H，m)，7.38(1H，d)，4.41(1H，s)，7.61(1H，s)，7.90(1H，s)，8.28(1H，d)，8.53(1H，d)；HPLCrt(min)：9.68；MS(ES⁺)548，(ES^-)546。

Example 54：

Method J: 2- (benzylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-54)

To 2-chloro-9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivativesA solution of-6 (7H) -one (50mg, 0.162mmol) in n-butanol (2ml) was added benzylamine (71. mu.l, 0.648mmol) and diisopropylethylamine (113. mu.l, 0.648 mmol). The reaction mixture was heated to 140 ℃ in a microwave for 90 minutes. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100%Column, gradient 10% -95% B (solvent A: 0.05% TFA solvent B: CH3CN) over 16 min, flow rate 25mL/min]To give the title compound (33mg) as an off-white powder. NMR DMSO D⁶1.10(6H，s)，1.46-1.58(4H，m)，1.60-1.74(4H，m)，3.13(3H，s)，3.42(2H，s)，4.52(2H，d)，4.95-5.04(1H，m)，7.24-7.30(1H，m)，7.31-7.39(4H，m)，7.83(1H，s)，8.64(1H，brs)；HPLC rt(min)：10.36；MS(ES⁺)380，(ES^-)378。

Example 55：

9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-2- (phenethylamino) -5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-55)

Prepared according to method J using appropriate reagents. NMR DMSO D⁶1.07(6H，s)，1.51-1.60(4H，m)，1.62-1.72(2H，m)，1.77-1.89(2H，m)，2.78-2.84(2H，m)，3.13(3H，s)，3.31(2H，d)，3.36-3.45(2H，m)，5.18-5.28(1H，m)，7.17-7.24(3H，m)，7.26-7.32(2H，m)，7.78(1H，s)；HPLC rt(min)：10.64；MS(ES⁺)394，(ES^-)392。

Example 56：

4- (6, 7, 8, 9-tetrahydro-9- (tetrahydro-2H-pyran-4-yl) -5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-56)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.63(2H，brd)，1.91(2H，dq)，2.82(3H，d)，3.18(3H，s)，3.37(2H，t)，3.57(2H，s)，3.94(3H，s)，4.01(2H，dd)，4.92(1H，tt)，7.57(1H，dd)，7.60(1H，d)，8.06(1H，d)，8.09(1H，s)，8.51(1H，q)，9.32(1H，brs)；HPLCrt(min)：7.94；MS(ES⁺)469，(ES^-)467。

Example 57：

2- ((R) -2, 3-dihydro-1H-inden-1-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-6(7H) -one (I-57)

Prepared according to method J using appropriate reagents. NMR DMSO D⁶1.08(6H，s)，1.41-1.57(4H，m)，1.59-1.82(4H，m)，1.91-2.04(1H，m)，2.36-2.45(1H，m)，2.74-2.84(1H，m)，2.90-2.98(1H，m)，3.15(3H，s)，3.29(2H，d)，5.01-5.16(1H，m)，5.32-5.44(1H，m)，6.94(1H，brs)，7.11-7.24(4H，m)，7.81(1H，s)；HPLCrt(min)：10.83；MS(ES⁺)406，(ES^-)404。

Example 58：

4- (9- (cyclopropylmethyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-58)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.27-0.35(2H，m)，0.47-0.53(2H，m)，1.15-1.25(7H，m)，2.80(3H，d)，3.19(3H，s)，3.66(2H，d)，3.72(2H，s)，3.94(3H，s)，7.51(1H，dd)，7.57(1H，d)，8.03(1H，s)，8.07(1H，d)，8.46(1H，q)，9.15(1H，brs)；HPLC rt(min)：8.72；MS(ES⁺)439，(ES^-)437。

Example 59：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1- (cyclopropylmethyl) piperidin-4-yl) -3-methoxybenzamide (I-59)

Prepared according to method H using the appropriate reagents. NMR DMSO D⁶0.00-0.05(2H，m)，0.30-0.35(2H，m)，0.50-0.71(1H，m)，1.00(6H，s)，1.47-1.85(8H，m)，2.17-2.26(2H，m)，2.88-3.00(2Hm)，3.09(3H，s)，3.29(2H，s)，3.48-3.57(2H，m)，3.85(3H，s)，4.32-4.42(1H，m)，5.04-5.14(1H，m)，7.38(1H，d)，4.41(1H，s)，7.61(1H，s)，7.90(1H，s)，8.28(1H，d)，8.53(1H，d)；HPLC rt(min)：9.68；MS(ES⁺)548，(ES^-)546。

Example 60：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclobutane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N-methylbenzamide (I-60)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.67-1.89(9H，m)，2.08-2.10(2H，m)，2.30-2.40(3H，m)，2.85(3H，d)，3.27(3H，s)，3.70(2H，s)，3.99(3H，s)，4.88(1H, quintet), 7.52(1H, d), 7.56(1H, s), 7.79(1H, s), 8.11(1H, s), 8.40(1H, d), 8.44(1H, d); hplcrt (min): 9.30 of; MS (ES)⁺)465，(ES^-)463。

Example 61：

4- ((R) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 8-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-61)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.18(3H, d), 1.31-1.49(1H, m), 1.60-1.81(5H, m), 1.90-1.96(1H, m), 1.97-2.02(1H, m), 2.33-2.40(2H, m), 2.78(3H, d), 3.19(3H, s), 3.96(3H, s), 4.03(1H, t), 4.66(1H, quintuple), 7.46(1H, d), 7.50(1H, s), 7.78(1H, m), 8.10(1H, s), 8.30-8.34(2H, m); HPLC rt (min): 8.70 of; MS (ES)⁺)439，(ES^-)437。

Example 62：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N-methylbenzamide (I-62)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.66-0.69(2H，m)，0.88-0.92(2H，m)，1.48-1.72(6H，m)，1.85-1.91(2H，m)，2.78(3H，d) 3.17(3H, s), 3.48(2H, s), 3.94(3H, s), 4.85(1H, quintuple), 7.46(1H, d), 7.49(1H, s), 7.69(1H, s), 7.90(1H, s), 8.33(1H, m), 8.40(1H, d); HPLC rt (min): 8.80; MS (ES)⁺)451，(ES^-)449。

Example 63：

2- (4-morpholinophenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-63)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.48-1.85(8H，m)，3.10(4H，t)，3.16(3H，s)，3.48(2H，s)，3.75(4H，t)，5.11(1H，dt)，6.98(2H，d)，7.38(2H，d)，7.84(1H，s)，10.01(1H，br s)；HPLC rt(min)：9.47；MS(ES⁺)451，(ES^-)449。

Example 64：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclobutane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-64)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.53-1.71(9H，m)，1.78-1.99(6H，m)，2.08-2.12(2H，m)，2.20-2.33(6H，m)，2.77-2.96(2H，m)，3.19(3H，s)，3.65(2H，s)，3.75-3.84(1H，m), 3.95(3H, s), 4.83(1H, quintet), 7.48(1H, d), 7.50(1H, s), 7.73(1H, s), 8.06(1H, s), 8.13(1H, br d), 8.37(1H, d); hplcrt (min): 9.50 of the total weight of the alloy; MS (ES)⁺)548，(ES^-)546。

Example 65：

4- ((R) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 8-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-65)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.27(3H, d), 1.33-1.42(1H, m), 1.56-1.79(9H), 1.91-2.02(4H, m), 2.20(3H, s), 2.41-2.54(1H, m), 2.66-2.75(1H, m), 2.76-2.86(2H, m), 3.21(3H, s), 3.71-3.79(1H, m), 3.94(3H, s), 4.00-4.05(1H, m), 4.64(1H, quintuple), 7.48(1H, d), 7.49(1H, s), 7.74(1H, s), 8.11(1H, s), 8.13(1H, s), 8.32(1H, d); HPLC rt (min): 8.50 of the total weight of the mixture; MS (ES)⁺)522，(ES^-)520。

Example 66：

4- (9- ((R) -1-cyclopropylmethyl) pyrrolidin-3-yl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-66)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.27-0.35(2H，m)，0.47-0.53(2H，m)，1.15-1.25(7H，m)，2.80(3H，d)，3.19(3H，s)，3.66(2H，d)，3.72(2H，s)，3.94(3H，s)，7.51(1H，dd)，7.57(1H，d)，8.03(1H，s)，8.07(1H，d)，8.46(1H，q)，9.15(1H，brs)；HPLC rt(min)：7.93；MS(ES⁺)508，(ES^-)507。

Example 67：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1- (isopropylpiperidin-4-yl) -3-methoxybenzamide (I-67)

Prepared according to method H using the appropriate reagents. NMR CDCl₃1.05(6H，d)，1.13(6H，s)，1.40-2.41(13H，m)，2.78-2.95(3H，m)，3.20(3H，s)，3.30(2H，s)，3.90(3H，s)，3.90-4.01(1H，m)，5.18-5.30(1H，m)，5.96-6.01(1H，m)，7.17(1H，d)，7.19(1H，s)，7.34(1H，s)，7.55(1H，s)，7.78(1H，s)，8.41(1H，d)；HPLCrt(min)：9.06；MS(ES⁺)564，(ES^-)562。

Example 68：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) -benzamide (I-68)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.07(12H，s)，1.20(6H，s)，1.40-1.95(11H，m)，2.28(3H，s)，3.22(3H，s)，3.30(2H，s)，3.90(3H，s)，4.30-4.40(1H，m)，5.20-5.29(1H，m)，5.33-5.43(1H，m)，7.16(1H，d)，7.19(1H，s)，7.36(1H，s)，7.56(1H，s)，7.78(1H，s)，8.41(1H，d)；HPLCrt(min)：9.07；MS(ES⁺)591，(ES^-)590。

Example 69：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1- (propylpiperidin-4-yl) benzamide (I-69)

Prepared according to method H using the appropriate reagents. NMR CDCl₃0.85(3H，t)，1.13(6H，s)，1.17-1.21(2H，m)，1.47-2.40(19H，m)，2.90-2.99(2H，m)，3.22(3H，s)，3.30(2H，s)，3.90(3H，s)，3.91-4.02(1H，m)，5.18-5.28(1H，m)，5.95-6.00(1H，m)，7.16(1H，d)，7.18(1H，s)，7.34(1H，s)，7.55(1H，s)，7.78(1H，s)，8.41(1H，d)；HPLCrt(min)：9.45；MS(ES⁺)564，(ES^-)562。

Example 70：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1- (isobutylpiperidin-4-yl) -3-methoxybenzamide (I-70)

Prepared according to method H using the appropriate reagents. NMR CDCl₃0.85(6H，d)，1.13(6H，s)，1.41-2.15(16H，m)，2.75-2.85(2H，m)，3.23(3H，s)，3.30(2H，s)，3.90(3H，s)，3.90-3.97(1H，m)，5.20-5.29(1H，m)，5.91-5.97(1H，m)，7.14(1H，s)，7.20(1H，s)，7.34(1H，s)，7.55(1H，s)，7.78(1H，s)，8.41(1H，d)；HPLC rt(min)：9.83；MS(ES⁺)578，(ES^-)576。

Example 71：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1-tert-butylpiperidin-4-yl) -3-methoxybenzamide (I-71)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.10(9H，s)，1.13(6H，s)，1.40-2.09(12H，m)，2.26-2.36(2H，m)，2.97-3.10(2H，m)，3.23(3H，s)，3.30(2H，s)，3.90(3H，s)，3.30-3.10(1H，m)，5.18-5.28(1H，m)，5.95-6.01(1H，m)，7.15(1H，d)，7.20(1H，s)，7.35(1H，s)，7.55(1H，s)，7.78(1H，s)，8.41(1H，d)；HPLCrt(min)：8.83；MS(ES⁺)578，(ES^-)576。

Example 72：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1- (ethylpiperidin-4-yl) -3-methoxybenzamide (I-72)

Prepared according to method H using the appropriate reagents. NMR CDCl₃1.22(3H，t)，1.26(6H，s)，1.50-2.18(11H，m)，2.20-2.34(2H，m)，2.58(2H，q)，3.06-3.13(2H，m)，3.32(3H，s)，3.39(2H，s)，4.00(3H，s)，4.02-4.15(1H，m)，5.27-5.37(1H，m)，6.00-6.07(1H，m)，7.25(1H，d)，7.28(1H，s)，7.43(1H，s)，7.65(1H，s)，7.87(1H，s)，8.50(1H，s)；HPLCrt(min)：9.12；MS(ES⁺)550，(ES^-)548。

Example 73：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- ((S) -1-isopropylpyrrolidin-3-yl) -3-methoxybenzamide (I-73)

Prepared according to method H using the appropriate reagents. NMR DMSOD⁶1.02-1.14(12H，m)，1.53-2.23(10H，m)，2.08-2.15(1H，m)，2.45-3.00(4H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.40(1H，m)，5.19(1H，m)，7.47-7，53(2H，m)，7.70(1H，s)，7.99(1H，s)，8.33-8.40(2H，m)；HPLC rt(min)：9.42；MS(ES⁺)551，(ES^-)549。

Example 74：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-ethoxy-N- (1-methylpiperidin-4-yl) benzamide (I-74)

Prepared according to method D using appropriate reagents. NMR CDCl₃1.18(6H，s)，1.43(3H，t)，1.50(2H，brm)，1.69(6H，brm)，1.97(4H，brm)，2.22(2H，brm)，2.32(3H，s)，2.89(2H，brm)，3.21(3H，s)，3.31(2H，s)，4.05(1H，brm)，4.15(2H，q)，5.22(1H，m)，6.10(NH)，7.17(1H，m)，7.31(1H，s)，7.60(NH)，7.78(1H，s)，8.41(1H，m)；HPLC rt(min)：9.93；MS(ES⁺)550，(ES^-)548。

Example 75：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- ((S) -1- (cyclopropylmethyl) pyrrolidin-3-yl) -3-methoxybenzamide (I-75)

Prepared according to method H using the appropriate reagents. NMR DMSO D⁶-0.01(2H, q), 0.35(2H, m), 0.76(1H, heptad), 1.00(6H, s), 1.45-1.85(9H, m), 2.07(1H, m), 2.18(2H, d), 2.35-2.47(2H, m), 2.60-2.75(2H, m), 3.09(3H, s), 3.28(2H, s), 3.85(3H, s), 4.31(1H, hexamer), 5.09(1H, quintuple), 7.40-7, 47(2H, m), 7.60(1H, s), 7.90(1H, s), 8.24-8.29(2H, m); HPLC rt (min): 9.67; MS (ES)⁺)562，(ES^-)561。

Example 76：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-76)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.73-0.75(2H，m)，0.91-0.98(2H，m)，1.51-1.79(8H，m)，1.84-2.00(5H，m)，2.31-2.42(4H，m)，2.95-3.05(2H，m)，3.23(3H，s)，3.54(2H，s)，3.81-3.94(1H，m)，4.01(3H，s)，4.91(1H，quin)，7.54(1H，d)，7.55(1H，s)，7.58(1H，s)，8.05(1H，s)，8.20(1H，d)，8.45(1H，d)；HPLC rt(min)：8.90；MS(ES⁺)532，(ES^-)534。

Example 77：

4- (-9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1- (2-fluoroethyl) piperidin-4-yl) -3-methoxybenzamide (I-77)

Prepared according to method H using the appropriate reagents. NMR CDCl₃1.13(6H，s)，1.40-1.80(7H，m)，1.85-1.95(2H，m)，1.97-2.05(2H，m)，2.23-2.34(2H，m)，2.66-2.78(2H，m)，2.93-3.02(2H，m)，3.23(3H，s)，3.30(2H，s)，3.91(3H，s)，3.90-4.04(1H，m)，1.45-1.64(2H，m)，5.16-5.28(1H，m)，5.85-5.95(1H，m)，7.15(1H，d)，7.20(1H，s)，7.34(1H，s)，7.56(1H，s)，7.78(1H，s)，8.42(1H，d)；HPLCrt(min)：9.58；MS(ES⁺)568，(ES^-)566。

Example 78：

N- (4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) -2, 2, 2-trifluoroacetamide (I-78)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.52-1.68(4H，m)，1.69-1.78(2H，m)，1.79-1.94(2H，m)，3.17(3H，s)，3.43(2H，s)，5.16(1H，dt)，7.60(2H，d)，7.65(2H，d)，7.92(1H，s)，9.64(1H，brs)，11.19(1H，s)；HPLCrt(min)：9.90；MS(ES⁺)477，(ES^-)475。

Example 79：

2- (1-Acetylindolin-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-6(7H) -one (I-79)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.50-1.68(4H，m)，1.69-1.77(2H，m)，1.78-1.88(2H，m)，2.14(3H，s)，3.12(2H，t)，3.16(3H，s)，3.44(2H，s)，4.10(2H，t)，5.15(1H，dt)，7.26(1H，d)，7.54(1H，s)，7.86(1H，s)，7.97(1H，d)，9.65(1H，br s)；HPLC rt(min)：9.37；MS(ES⁺)449，(ES^-)447。

Example 80：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-methylbenzamide (I-80)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.55-1.69(4H，m)，1.70-1.80(2H，m)，1.82-1.93(2H，m)，2.78(3H，d)，3.18(3H，s)，3.45(2H，s)，5.20(1H，dt)，7.71(2H，d)，7.79(2H，d)，7.97(1H，s)，8.27-8.34(1H，m)，9.86(1H，brs)；HPLCrt(min)：8.73；MS(ES⁺)423，(ES^-)421。

Example 81：

2- (1H-indazol-4-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-81)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.41-1.79(8H，m)，3.20(3H，s)，3.44(2H，s)，5.10(1H，dt)，7.22-7.34(2H，m)，7.51-7.59(1H，m)，7.95(1H，s)，8.27(1H，s)，9.91(1H，br s)，13.10(1H，br s)；HPLC rt(min)：9.32；MS(ES⁺)406，(ES^-)404。

Example 82：

2- (1, 6-dihydro-6-oxopyridin-3-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-82)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.48-1.84(8H，m)，3.16(3H，s)，3.45(2H，s)，5.00-5.09(1H，m)，6.39(1H，d)，7.54(1H，d)，7.61(1H，s)，7.81(1H，s)，9.45(1H，br s)；HPLC rt(min)：7.77；MS(ES⁺)383，(ES^-)381。

Example 83：

2- (1, 6-dihydro-4-methyl-6-oxopyridin-3-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-83)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.39-1.78(8H，m)，2.04(3H，s)，3.16(3H，s)，3.48(2H，s)，6.30(1H，s)，7.49(1H，s)，7.75(1H，br s)，9.39(1H，br s)；HPLCrt(min)：7.86；MS(ES⁺)397，(ES^-)395。

Example 84：

2- (3-methoxy-5-nitrophenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-84)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，1.56-1.77(6H，m)，1.83-1.96(2H，m)，3.19(3H，s)，3.42(2H，s)，3.86(3H，s)，5.29(1H，dt)，7.33(1H，t)，7.60(1H，t)，8.01(1H，s)，8.41(1H，t)，9.88(1H，br s)；HPLC rt(min)：10.48；MS(ES⁺)441，(ES^-)439。

Example 85：

2- (4- (4-methylpiperazin-1-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-85)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.51-1.65(4H，m)，1.66-1.75(2H，m)，1.76-1.86(2H，m)，2.88(3H，s)，2.86-2.94(2H，m)，3.17(3H，s)，3.12-3.24(2H，m)，3.45(2H，s)，3.53(2H，d)，3.79(2H，d)，5.13(1H，dt)，7.00(2H，d)，7.46(2H，d)，7.90(1H，s)，9.75(1H，brs)，9.86(1H，brs)；HPLCrt(min)：9.66；MS(ES⁺)464，(ES^-)462。

Example 86：

2- (4-Morpholinomethyl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-86)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，1.53-1.67(4H，m)，1.69-1.78(2H，m)，1.80-1.94(2H，m)，3.02-3.17(2H，m)，3.19(3H，s)，3.26(2H，d)，3.40(2H，s)，3.62(2H，t)，3.97(2H，d)，4.28(2H，d)，5.21(1H，dt)，7.39(2H，d)，7.79(2H，d)，7.97(1H，s)，9.62(1H，br s)，9.75(1H，br s)；HPLCrt(min)：9.82；MS(ES⁺)465，(ES^-)463。

Example 87：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (2-hydroxyethyl) benzamide (I-87)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，1.56-1.66(4H，m)，1.68-1.81(2H，m)，1.83-1.95(2H，m)，3.20(3H，s)，3.20-3.28(2H，m)，3.41(2H，s)，4.40(2H，t)，5.23(1H，dt)，7.86(2H，d)，7.92-7.99(4H，m)，8.01(1H，s)，9.80(1H，brs)；HPLC rt(min)：8.74；MS(ES⁺)453，(ES^-)451。

Example 88：

N- (4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) -N-methylacetamide (I-88)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，1.52-1.65(4H，m)，1.66-1.73(2H，m)，1.77(3H，s)，1.77-1.86(2H，m)，3.13(3H，s)，3.18(3H，s)，3.44(2H，s)，5.13(1H，dt)，7.29(2H，d)，7.65(2H，d)，7.93(1H，s)，9.80(1H，br s)；HPLCrt(min)：9.38；MS(ES⁺)437，(ES^-)435。

Example 89：

2- (1H-indazol-7-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-89)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.40-1.79(8H，m)，3.20(3H，s)，3.45(2H，s)，5.09(1H，dt)，7.25-7.34(2H，m)，7.53(1H，d)，7.94(1H，s)，8.26(1H，s)，9.95(1H，br s)，13.11(1H，br s)；HPLC rt(min)：9.33；MS(ES⁺)406，(ES^-)404。

Example 90：

9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-2- (phenylamino) -5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-90)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.51-1.89(8H，m)，3.18(3H，s)，3.45(2H，s)，5.16(1H，dt)，7.07(1H，t)，7.34(2H，t)，7.59(2H，d)，7.91(1H，s)，9.77(1H，br s)；HPLC rt(min)：10.38；MS(ES⁺)366，(ES^-)364。

Example 91：

2- (2-methyl-2H-indazol-7-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ] -][1，4]Diaza derivatives-6(7H) -one (I-91)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.53-1.78(6H，m)，1.81-1.93(2H，m)，3.19(3H，s)，3.53(2H，s)，4.22(3H，s)，5.18(1H，dt)，7.05(1H，t)，7.47(1H，d)，7.80(1H，d)，8.02(1H，s)，8.43(1H，s)，9.60(1H，br s)；HPLCrt(min)：10.19；MS(ES⁺)420。

Example 92：

Method K: 2- ([1,2,4]Triazolo [1, 5-a]Pyridin-8-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-92)

To 2-chloro-9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (50mg, 0.16mmol) and Triazolopyridine (22mg, 0.16mmol) in dioxane (1.5mL) was added xanthphos(2.8mg, 0.005mmol), palladium (II) acetate (0.7mg, 0.003mmol) and cesium carbonate (106mg, 0.32 mmol). The reaction mixture was heated to 160 ℃ in a microwave for 40 minutes. The crude mixture was filtered through a pad of celite, washing with methanol. The resulting mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [ Waters SunfireC18, 10uM, 100%Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, flow rate 25mL/min]To give the title compound as a TFA salt (6.2 mg).

NMR DMSO D⁶1.13(6H，s)，1.53-1.66(4H，m)，1.68-1.77(2H，m)，1.81-1.90(2H，m)，3.20(3H，s)，3.46(2H，s)，5.15(1H，dt)，7.21(1H，t)，8.05(1H，s)，8.23(1H，d)，8.53(1H，s)，8.64(1H，d)，9.05(1H，brs)；HPLC rt(min)：9.71；MS(ES⁺)407，(ES^-)405。

Example 93：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-cyclopropyl-3-methoxybenzamide (I-93)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.55-0.59(2H，m)，0.68-0.73(2H，m)，1.09(6H，s)，1.54-1.68(4H，m)，1.70-1.78(2H，m)，1.83-1.95(2H，m)，2.79-2.84(1H，m)，3.19(3H，s)，3.38(2H，s)，4.03(3H，s)，5.16-5.22(1H，m)，7.43-7.47(2H，m)，7.70(1H，br s)，7.99(1H，s)，8.32-8.35(2H，m)；HPLC rt(min)：9.60；MS(ES⁺)479，(ES^-)477。

Example 94：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-cyclobutyl-3-methoxybenzamide (I-94)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.58-1.78(8H，m)，1.84-1.91(2H，m)，2.03-2.13(2H，m)，2.18-2.23(2H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.37-4.46(1H，m)，5.15-5.23(1H，m)，7.46-7.49(2H，m)，7.69(1H，s)，7.99(1H，s)，8.36(1H，d)，8.46(1H，d)；HPLC rt(min)：10.10；MS(ES⁺)493，(ES^-)491。

Example 95：

4- [4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylmethyl) -3-methoxybenzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-95)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.45(3H，s)，1.48(9H，s)，1.64-1.97(10H，m)，2.90(2H，brs)，3.25(3H，s)，3.44(2H，s)，4.01(3H，s)，4.02-4.10(2H，brs)，5.21-5.32(1H，m)，7.51-7.54(2H，m)，7.76(1H，s)，8.06(1H，s)，8.18(1H，d)，8.43(1H，s)；HPLC rt(min)：10.50；MS(ES⁺)622，(ES^-)620。

Example 96：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-9- ((R) -1-methylpiperidin-3-yl) -6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-96)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.08(3H，s)，1.10(3H，s)，1.5-1.92(5H，m)，2.00-2.10(2H，m)，2.23(3H，s)，2.79(3H，d)，2.87(1H，br d)，3.18(3H，s)，3.42(2H，s)，3.94(3H，s)，4.86(1H，tt)，7.45(1H，dd)，7.49(1H，d)，7.66(1H，s)，7.99(1H，s)，8.30(1H，q)，8.38(1H，d)；HPLC rt(min)：7.64；MS(ES⁺)482，(ES^-)480。

Example 97：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-9- ((R) -1-methylpiperidin-4-yl) -6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-97)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.66(2H，br d)，1.83(2H，dq)，2.00-2.15(2H，m)，2.24(3H，s)，2.79(3H，d)，2.92(2H，br d)，3.18(3H，s)，3.38(2H，s)，3.94(3H，s)，4.71(1H，tt)，7.47(1H，dd)，7.50(1H，d)，7.68(1H，s)，7.98(1H，s)，8.25-8.34(2H，m)；HPLCrt(min)：7.28；MS(ES⁺)482，(ES^-)480。

Example 98：

2- (4- (5-hydroxy-3-methyl-1H-pyrazol-1-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ] -9-cyclopentyl-8, 9-dihydro-5, 7-trimethyl-5H-pyrimido [4, 5-b ] ] -][1，4]Diaza derivatives-6(7H) -one (I-98)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.51-1.77(6H，m)，1.81-1.92(2H，m)，2.12(3H，s)，3.19(3H，s)，3.46(2H，s)，5.17(1H，dt)，5.36(1H，s)，7.56-7.68(4H，m)，7.90(1H，s)，9.79(1H，br s)；HPLC rt(min)：8.75；MS(ES⁺)462，(ES^-)460。

Example 99：

2- (4- (1H-pyrazol-3-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-99)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.55-1.78(6H，m)，1.82-1.93(2H，m)，3.19(3H，s)，3.48(2H，s)，5.19(1H，dt)，6.67(1H，d)，7.62(2H，d)，7.70(1H，d)，7.78(2H，d)，7.92(1H，s)，9.93(1H，br s)；HPLCrt(min)：8.45；MS(ES⁺)432，(ES^-)430。

Example 100：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylsulfanyl) -N-methylbenzamide (I-100)

The method L comprises the following steps: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylsulfanyl) -benzoic acid

2-chloro-9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-6(7H) -one (100mg, 0.324mmol) was heated at reflux with a solution of 4-mercaptobenzoic acid (50mg, 0.324mmol) in acetonitrile (5mL) for 4H. Additional 4-mercaptobenzoic acid (50mg, 0.324mmol) was added and the reaction mixture was heated at reflux for 16 h. After cooling, the crude reaction mixture was filtered through celite, washing with acetonitrile. The crude product was purified by column chromatography (0% to 10% MeOH: CH2Cl2) triturated with MeOH to give the title compound (37mg, 27% yield) as a white solid. NMR DMSO D⁶1.03(6H，s)，1.20-1.38(6H，m)，1.42-1.53(2H，m)，3.17(3H，s)，3.27(2H，s)，4.47(1H，dt)，7.72(2H，dd)，7.99(2H，dd)，8.02(1H，s)；MS(ES⁺)427，(ES^-)425。

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylThio) -N-methylbenzamide (I-100) has been prepared according to method D using suitable reagents.

NMR DMSO D⁶1.03(6H，s)，1.22-1.44(6H，m)，1.46-1.58(2H，m)，2.80(3H，d)，3.17(3H，s)，3.28(2H，s)，4.51(1H，dt)，7.68(2H，d)，7.91(2H，d)，8.02(1H，s)，8.47-8.53(1H，m)；HPLCrt(min)：8.86；MS(ES⁺)440，(ES^-)438。

Example 101：

2- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (piperidin-4-yl) benzamide (I-101)

Prepared using method F. NMR MeOD1.21(6H, s), 1.61-1.85(8H, m), 2.02-2.15(4H, m), 2.85(2H, br t), 3.23(2H, br d), 3.39(3H, s), 3.48(2H, s), 4.02(3H, s), 4.03-4.10(1H, m), 5.36(1H, quintuple), 7.50-7.54(2H, m), 7.94(1H, s), 8.48(1H, d); HPLC rt (min): 9.00; MS (ES)⁺)522，(ES^-)520。

Example 102：

2- (2-methoxyphenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-102)

Prepared according to method D using appropriate reagents. NMRDMSO D⁶1.14(6H，s)，1.48-1.84(8H，m)，3.18(3H，s)，3.49(2H，s)，3.87(3H，s)，5.07(1H，dt)，6.99(1H，dt)，7.14(1H，dt)，7.19(1H，dt)，7.83(1H，d)，7.94(1H，s)，9.13(1H，br s)；HPLC rt(min)：10.65；MS(ES⁺)396，(ES^-)394。

Example 103：

Methyl 4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxyphenyl carbamate (I-103)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.56(4H，br m)，1.71(2H，br m)，1.82(2H，br m)，3.17(3H，s)，3.35(2H，s)，3.66(3H，s)，3.81(3H，s)，5.11(1H，br m)，6.96(1H，dd)，7.23(1H，s)，7.44(1H，s)，7.90(1H，s)，7.98(1H，d)，9.46(1Hbr s)；HPLC rt(min)：9.60；MS(ES⁺)469，(ES^-)467。

Example 104：

N- (4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxyphenyl) -2-methoxyacetamide (I-104)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.57(4H，br m)，1.71(2H，br m)，1.84(2H，br m)，3.18(3H，s)，3.35(2H，s)，3.39(3H，s)，3.83(3H，s)，3.98(2H，s)，5.13(1H，brm)，7.23(1H，dd)，7.46(2H，s)，7.92(1H，s)，8.06(1H，d)，9.60(1H，br s)；HPLC rt(min)：9.50；MS(ES⁺)483，(ES^-)481。

Example 105：

[4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (2, 2, 2-trifluoroethyl) -3-methoxybenzamide (I-105)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.63(4H，br m)，1.75(2H，br m)，1.89(2H，br m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.10(2H，m)，5.20(1H，m)，7.54(2H，m)，7.73(NH)，8.00(1H，s)，8.43(1H，m)，8.41(1H，s)；HPLCrt(min)：9.94；MS(ES⁺)521，(ES^-)519。

Example 106：

9-cyclopentyl-5, 7, 7-trimethyl-2- [3- (4-methylpiperazine-1-carbonyl) -phenylamino]-5, 7, 8, 9-tetrahydropyrimidino [4, 5-b][1，4]Diaza derivatives-6-one (I-106)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.57(4H，br m)，1.71(2H，br m)，1.85(2H，br m)，2.82-3.34(8H，br m)，3.19(3H，s)，3.36(3H，s)，5.23(1H，m)，6.97(1H，m)，7.31(1H，m)，7.69(1H，m)，7.96(2H，m)，9.33(1H，s)；HPLCrt(min)：9.12；MS(ES⁺)492，(ES^-)490。

Example 107：

Method M: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-yloxy) -3-methoxybenzoic acid (I-107)

To 2-chloro-9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (100mg, 0324mmol) in DMF (5mL) was added vanillic acid (55mg, 0.324mmol) and potassium carbonate (90mg, 0.648 mmol). The reaction mixture was heated at 80 ℃ for 48 hours. After cooling, the solvent was removed in vacuo, the residue was dissolved in methanol and purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100 [ ]Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, flow rate 25mL/min]To give the title compound as a TFA salt (12mg, 7% yield). NMR DMSO D⁶1.06(6H，s)，1.23-1.37(2H，m)，1.38-1.50(2H，m)，1.51-1.62(4H，m)，3.18(3H，s)，3.34(2H，s)，3.76(3H，s)，4.58(1H，dt)，7.26(1H，d)，7.56-7.62(2H，m)，7.99(1H，s)；HPLCrt(min)：7.18；MS(ES⁺)441，(ES^-)439。

Example 108：

2-(2，3-dihydro-2-oxo-1H-benzo [ d]Imidazol-6-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-108)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.44-1.76(6H，m)，1.78-1.92(2H，m)，3.17(3H，s)，3.46(2H，s)，5.13(1H，dt)，6.89(1H，d)，7.05(1H，d)，7.13(1H，s)，7.81(1H，s)，9.75(1H，br s)，10.57(1H，s)，10.67(1H，s)；HPLC rt(min)：8.21；MS(ES⁺)422，(ES^-)420。

Example 109：

2- (2, 3-dihydro-3-oxo-1H-indazol-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ] -][1，4]Diaza derivatives-6(7H) -one (I-109)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.50-1.74(6H，m)，1.79-1.90(2H，m)，3.18(3H，s)，3.46(2H，s)，5.18(1H，dt)，7.27(1H，d)，7.37(1H，dd)，7.85(1H，s)，7.88(1H，s)，9.76(1H，br s)，11.28(1H，br s)；HPLC rt(min)：8.01；MS(ES⁺)422，(ES^-)420。

Example 110：

2- (1-methyl-1H-indazol-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ] -][1，4]Diaza derivatives-6(7H) -one (I-110)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H，s)，1.43-1.77(6H，m)，1.78-1.88(2H，m)，3.18(3H，s)，3.48(2H，s)，4.05(3H，s)，5.14(1H，dt)，7.48(1H，dd)，7.66(1H，d)，7.87(1H，s)，7.96(1H，s)，7.99(1H，s)，10.01(1H，br s)；HPLC rt(min)：9.65；MS(ES⁺)420，(ES^-)418。

Example 111：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) acetamide (I-111)

Prepared according to method D using appropriate reagents. HPLC rt (min): 8.95; MS (ES)⁺)423，(ES^-)421。

Example 112：

N- (4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) acetamide (I-112)

Prepared according to method D using appropriate reagents. Hplcrt (min): 8.74 of; MS (ES)⁺)423，(ES^-)421。

Example 113：

4- ((S) -9-cyclopentyl-7-ethyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (I-113)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.88(3H, t), 1.04(1H, d), 1.25-1.36(1H, m), 1.52-1.85(11H, m), 1.95-2.12(3H, m), 2.20(3H, s), 2.57-2.64(1H, m), 2.78-2.83(2H, m), 3.20(3H, s), 3.41-3.45(2H, m), 3.75-3.80(1H, m), 3.95(3H, s), 4.78(1H, quintuple), 7.48(1H, d), 7.49(1H, s), 7.75(1H, s), 8.07(1H, d), 8.10(1H, s), 8.39(1H, d); HPLC rt (min): 9.70 of; MS (ES)⁺)536，(ES^-)534。

Example 114：

2- (1H-indazol-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-114)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.44-1.93(8H，m)，3.18(3H，s)，3.47(2H，s)，5.14(1H，dt)，7.43(1H，dd)，7.55(1H，d)，7.86(1H，s)，7.98(1H，s)，8.02(1H，s)，9.92(1H，br s)，13.06(1H，br s)；HPLC rt(min)：8.99；MS(ES⁺)406，(ES^-)404。

Example 115：

2- (1H-benzo [ d ]]Imidazol-4-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-115)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.38-1.73(8H，m)，3.20(3H，s)，3.42(2H，s)，4.96(1H，dt)，7.42(1H，t)，7.50(1H，d)，7.70(1H，d)，8.01(1H，s)，9.09(1H，br s)，9.85(1H，br s)；HPLC rt(min)：9.37；MS(ES⁺)406，(ES^-)404。

Example 116：

2- (3-Aminophenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-116)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.53-1.73(6H，m)，1.80-1.92(2H，m)，3.18(3H，s)，3.43(2H，s)，5.19(1H，dt)，6.61(1H，d)，7.14-7.24(3H，m)，7.89(1H，s)，9.67(1H，br s)；HPLC rt(min)：9.16；MS(ES⁺)381，(ES^-)379。

Example 117：

2- (4-Aminophenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-117)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.50-1.92(8H，m)，3.18(3H，s)，3.43(2H，s)，5.16(1H，dt)，7.01-7.10(2H，m)，7.50-7.63(2H，m)，7.89(1H，s)，9.67(1H，brs)；HPLCrt(min)：8.76；MS(ES⁺)381，(ES^-)379。

Example 118：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-ethyl-N-methylbenzamide (I-118)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.18(3H，t)，1.44(2H，br m)，1.57-1.69(6H，br m)，2.51(2H，q)，2.64(3H，m)，2.79(3H，s)，3.45(3H，s)，4.95(1H，m)，7.69(2H，m)，7.78(1H，m)，7.87(1H，s)，8.38(1H，s)；HPLC rt(min)：9.24；MS(ES⁺)451，(ES^-)449。

Example 119：

4- ((S) -9-cyclopentyl-7-ethyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimidinePyrido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -N-cyclobutyl-3-methoxybenzamide (I-119)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.18(3H，t)，1.44(2H，br m)，1.57-1.69(6H，br m)，2.51(2H，q)，2.64(3H，m)，2.79(3H，s)，3.45(3H，s)，4.95(1H，m)，7.69(2H，m)，7.78(1H，m)，7.87(1H，s)，8.38(1H，s)；HPLCrt(min)：10.10；MS(ES⁺)493，(ES^-)491。

Example 120：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzoic acid (I-120)

Prepared according to method D using appropriate reagents. Hplcrt (min): 7.81; MS (ES)⁺)440，(ES^-)438。

Example 121：

3- (2- (pyrrolidin-1-yl) ethoxy) -4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-methylbenzamide (I-121)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，1.61(4H，br m)，1.74(2H，br m)，1.84(2H，br m)，1.91(2H，br m)，2.06(2H，br m)，2.79(3H，m)，3.19(5H，m)，3.43(2H，s)，3.68(4H，br m)，4.42(2H，m)，5.14(1H，m)，7.50-7.55(2H，m)，8.02(1H，s)，8.24(1H，m)，8.38(1H，s)；HPLC rt(min)：8.87；MS(ES⁺)536，(ES^-)534。

Example 122：

4- (9-benzyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-122)

The method N comprises the following steps: 2-chloro-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one

In a pressure test tube, 9-allyl-2-chloro-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b ] is added][1，4]Diaza derivatives-6(7H) -one (1.21g, 4.34mmol, prepared by means of method C) and dichloro (2, 7-dimethyl-octa-2, 6-dien-1, 8-yl) ruthenium (IV) (0.26g, 0.43mmol, prepared according to Tetrahedron Letters, 1965, 47, 4187) were suspended in dioxane (10mL) and water (30 mL). The obtained suspension is mixed inStir at 100 ℃ for two nights. The reaction was cooled to room temperature and filtered through celite. Celite was washed with copious amounts of water and DCM. The filtrates were combined, concentrated under reduced pressure, and partitioned between brine and DCM. The aqueous layer was extracted with dichloromethane (5 × 20mL) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum. This gum was purified by column chromatography (50% EtOAc in hexane, loaded on silica, 100mL silica) to afford a white solid, triturated with diethyl ether. The solid was collected by filtration and washed with diethyl ether (1x2mL) and pentane (3x2mL) to give a milky powder (351mg, 34% yield). NMR DMSO D⁶1.09(6H，s)，3.22(3H，s)，3.25(2H，d)，8.08(1H，s)，8.48(1H，br d)；MS(ES⁺)241。

Method 0: 9-benzyl-2-chloro-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4，5-b][1，4]Diaza derivatives -6(7H) -one

At room temperature, 2-chloro-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b ] is reacted][1，4]Diaza derivatives-6(7H) -one (50mg, 0.21mmol) and benzyl bromide (30. mu.l, 0.25mmol) were treated with sodium hydride 60% oil dispersion (9mg, 0.23mmol) in DMA (0.5 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes, loaded on silica, 50mL silica) to give the title compound as a white solid (63mg, 91%). NMR DMSO D⁶1.00(6H，s)，3.22(3H，s)，3.53(2H，s)，4.91(2H，s)，7.28-7.39(5H，m)，8.12(1H，s)；MS(ES⁺)331。

4- (9-benzyl)-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4，5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-122)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.03(6H，s)，2.75(3H，d)，3.23(3H，s)，3.47(2H，s)，3.90(3H，s)，4.98(2H，brs)，7.2-7.4(6H，m)，7.45(1H，s)，7.72(1H，s)，8.07(1H，s)，8.19(1H，d)，8.27(1H，br d)；HPLCrt(min)：9.00；MS(ES⁺)475，(ES^-)473。

Example 123：

4- (9- (cyclobutylmethyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-123)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.84(4H，br m)，2.05(2H，br m)，2.78(4H，br m)，3.18(3H，s)，3.50(2H，s)，3.78(2H，d)，3.94(3H，s)，7.47(2H，m)，7.67(1H，s)，7.97(1H，s)，8.34(2H，br m)；HPLC rt(min)：9.20；MS(ES⁺)453，(ES^-)451。

Example 124：

2- (1-oxoisoindolin-4-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-124)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.52(4H，br m)，1.69(2H，br m)，1.76(2H，br m)，3.18(3H，s)，3.34(2H，s)，4.40(2H，s)，5.15(1H，m)，7.31(1H，d)，7.40(1H，t)，7.96(1H，s)，8.08(1H，d)，8.52(1H，s)，8.86(1H，s)；HPLCrt(min)：8.90；MS(ES⁺)421，(ES^-)419。

Examples]25：

2- (1-methyl-2-oxoindolin-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-6(7H) -one (I-125)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.54(4H，br m)，1.62(2H，br m)，1.82(2H，br m)，3.12(3H，s)，3.17(3H，s)，3.46(2H，s)，3.55(2H，s)，5.13(1H，m)，6.96(1H，m)，7.39(1H，m)，7.54(1H，s)，7.86(1H，s)，9.89(1H，s)；HPLC rt(min)：9.24；MS(ES⁺)435，(ES^-)433。

Example 126：

6- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-methylpyridine-3-amide (I-126)

Prepared according to method J using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.61(4H，br m)，1.74(2H，br m)，1.90(2H，br m)，2.79(3H，m)，3.20(3H，s)，3.38(2H，s)，5.20(1H，m)，8.02(1H，s)，8.15(1H，m)，8.24(1H，m)，8.42(1H，s)，8.70(1H，s)，9.71(1H，s)；HPLCrt(min)：8.63；MS(ES⁺)424，(ES^-)422。

Example 127：

2- (3-amino-1H-indazol-1-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b [ ] -][1，4]Diaza derivatives-6(7H) -one (I-127)

Prepared using method K. NMR DMSO D⁶1.12(6H，s)，1.61-1.84(6H，m)，1.89-1.96(2H，m)，3.24(3H，s)，3.43(2H，s)，5.39(1H，dt)，6.04(2H、S、NH2)，7.18(1H，t)，7.46(1H，t)，7.85(1H，d)，8.14(1H，s)，8.44(1H，d)；HPLCrt(min)：9.84；MS(ES⁺)406。

Example 128：

2- (3-Nitrophenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-128)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H, s), 1.52-1.65(4H, m), 1.69-1.75(2H, m), 1.84-1.96(2H, m), 3.20(3H, s), 3.39(2H, s), 5.34(1H, quintuple), 7.52(1H, t), 7.73(1H, dd), 7.88(1H, d), 8.02(1H, s), 8.92(1H, d), 9.74(1H, s); hplcrt (min): 10.50; MS (ES)⁺)411，(ES^-)409。

Example 129：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-cyclopentyl-3-methoxybenzamide (I-129)

Prepared according to method D using appropriate reagents. NMR CDCl₃1.13(6H，m)，1.36-1.78(12H，m)，1.88-1.98(2H，m)，2.00-2.10(2H，m)，3.22(3H，s)，3.31(2H，s)，3.91(3H，s)，4.28-4.37(1H，m)，5.18-5.30(1H，m)，5.93(1H，d)，7.14(1H，d)，7.35(1H，s)，7.64(1H，brs)，7.77(1H，s)，8.38(1H，d)；HPLC rt(min)：10.33；MS(ES⁺)507，(ES^-)505。

Example 130：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-tert-butyl-3-methoxybenzamide (I-130)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.22(6H，s)，1.51(9H，s)，1.50-1.87(6H，m)，1.96-2.06(2H，m)，3.32(3H，s)，3.99(2H，s)，5.26-5.38(1H，m)，5.95(1H，s)，7.19(1H，d)，7.43(1H，s)，7.22(1H，brs)，7.86(1H，s)，8.45(1H，d)；HPLCrt(min)：10.36；MS(ES⁺)495，(ES^-)493。

Example 131：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (cyclopropylmethyl) -3-methoxybenzamide (I-131)

Prepared according to method E using appropriate reagents. NMR CDCl₃0.08-0.13(2H，m)，0.35-0.41(2H，m)，0.75-0.84(1H，m)，1.01(6H，s)，1.27-1.65(6H，m)，1.76-1.85(2H，m)，3.08-3.18(2H，m)，3.11(3H，s)，3.19(2H，s)，3.79(3H，s)，5.08-5.18(1H，m)，6.00(1H，t)，7.09(1H，d)，7.25(1H，s)，7.57(1H，brs)，7.64(1H，s)，8.26(1H，d)；HPLCrt(min)：10.00；MS(ES⁺)493，(ES^-)491。

Example 132：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (3, 3, 3-trifluoropropyl) -3-methoxybenzamide (I-132)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.13(6H，s)，1.45-1.80(6H，m)，1.88-1.97(2H，m)，2.35-2，49(2H，m)，3.22(3H，s)，3.31(2H，s)，3.64-3.70(2H，m)，3.91(3H，s)，5.18-5.28(2H，m)，6.28(1H，t)，7.17(1H，d)，7.34(1H，s)，7.68(1H，brs)，7.77(1H，s)，8.41(1H，d)；HPLCrt(min)：10.03；MS(ES⁺)535，(ES^-)533。

Example 133：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-cyclohexyl-3-methoxybenzamide (I-133)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.13(6H，s)，1.10-1.74(14H，m)，1.88-2.05(4H，m)，3.22(3H，s)，3.31(2H，s)，3.95-4.00(1H，m)，3.91(3H，s)，5.18-5.29(1H，m)，5.85(1H，d)，7.14(1H，d)，7.35(1H，s)，7.68(1H，brs)，7.76(1H，s)，8.37(1H，d)；HPLCrt(min)：10.56；MS(ES⁺)521，(ES^-)519。

Example 134：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (tetrahydro-2H-pyran-4-yl) -3-methoxybenzamide (I-134)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.22(6H，s)，1.48-1.85(12H，m)，1.97-2.08(4H，m)，3.32(3H，s)，3.40(2H，s)，3.53-3.61(2H，m)，3.97-4.07(2H，m)，4.00(3H，s)，5.29-5.40(1H，m)，5.97(1H，d)，7.24(1H，d)，7.43(1H，s)，7.77(1H，brs)，7.86(1H，s)，8.48(1H，d)；HPLCrt(min)：9.52；MS(ES⁺)523，(ES^-)521。

Example 135：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-ethoxy-N- (1-isopropylpiperidin-4-yl) benzamide (I-135)

Prepared according to method E using appropriate reagents. NMR CDCl₃1.10(6H，d)，1.22(6H，s)，1.52(3H，t)，1.54-1.86(8H，m)，1.97-2.16(4H，m)，2.35-2.43(2H，m)，2.77-2.89(1H，m)，2.90-3.00(2H，m)，3.32(3H，s)，3.40(2H，s)，3.98-4.07(1H，m)，4.22(2H，q)，5.25-5.36(1H，m)，6.00(1H，d)，7.23(1H，d)，7.41(1H，s)，7.66(1H，s)，7.87(1H，s)，8.49(1H，d)；HPLCrt(min)：9.47；MS(ES⁺)578，(ES^-)576。

Example 136：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (1, 3-dihydroxy-2-methylpropan-2-yl) -3-methoxybenzeneAmide (I-136)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.05(3H，s)，1.14(6H，s)，1.55-1.94(8H，m)，3.13-3.26(2H，m)，3.18(3H，s)，3.28-3.37(2H，m)，3.49(2H，s)，3.96(3H，s)，5.10-5.20(1H，m)，7.54(1H，d)，7.60(1H，s)，8.01(1H，s)，8.15(1H，d)，8.40-8.47(1H，m)，8.85(1H，brs)；HPLCrt(min)：9.47；MS(ES⁺)527，(ES^-)526。

Example 137：

2- (3- (1H-pyrazol-3-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-137)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.13(6H，s)，1.24-1.36(2H，m)，1.50-1.63(4H，m)，1.71-1.86(2H，m)，3.19(3H，s)，3.47(2H，s)，5.21(1H，dt)，6.67(1H，d)，7.38(2H，d)，7.48-7.56(1H，m)，7.75(1H，s)，7.93(1H，d)，8.12(1H，s)，10.01(1H，brs)；HPLC rt(min)：9.58；MS(ES⁺)432，(ES^-)430。

Example 138：

9-cyclopentyl-2- (1-methanesulfonyl-2, 3-dihydro-1H-indol-5-ylamino) -5, 7, 7-trimethyl-5, 7, 8, 9-tetrahydro-pyrimido [4, 5-b][1，4]Diaza derivatives-6-one (I-138)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.13(6H，s)，1.52-1.85(8H，m)，2.97(3H，s)，3.11(2H，t)，3.17(3H，s)，3.45(3H，s)，3.95(2H，t)，5.14(1H，dt)，7.20(1H，d)，7.31(1H，d)，7.62(1H，s)，7.88(1H，s)，9.75(1H，brs)；HPLCrt(min)：9.42；MS(ES⁺)485，(ES^-)484。

Example 139：

5- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) indoline-2, 3-dione (I-139)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.12(6H，s)，1.56-1.76(6H，m)，1.81-1.90(2H，m)，3.18(3H，s)，3.42(2H，s)，5.15(1H，dt)，6.88(1H，d)，7.63(1H，d)，7.92(1H，s)，7.99(1H，s)，9.63(1H，brs)，10.96(1H，s)；HPLCrt(min)：8.75；MS(ES⁺)435，(ES^-)433。

Example 140：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -5- (trifluoromethyl) -N-methylbenzamide (I-140)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.10(6H，s)，1.48-1.70(6H，m)，1.80-1.89(2H，m)，2.78(3H，d)，3.19(3H，s)，3.40(2H，s)，5.25(1H，dt)，7.70(1H，s)，7.99(1H，s)，8.23(1H，s)，8.34(1H，s)，8.58-8.65(1H，m)，9.87(1H，brs)；HPLCrt(min)：9.99；MS(ES⁺)491，(ES^-)490。

Example 141：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (tetrahydro-2H-pyran-4-yl) benzamide (I-141)

Prepared according to method B using the appropriate reagents. NMR DMSOD⁶1.12(6H，s)，1.53-1.80(12H，m)，3.18(3H，s)，3.36-3.43(5H，m)，3.90(2H，m)，3.98(1H，m)，5.18(1H，m)，7.39(1H，m)，7.48(1H，m)，7.63(1H，m)，7.93(1H，s)，8.27(1H，m)，9.75(1H，s)；HPLCrt(min)：9.07；MS(ES⁺)493，(ES^-)492。

Example 142：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N-methyl-3- (trifluoromethoxy) benzamide (I-142)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.09(6H，s)，1.55(4H，brm)，1.69-1.81(4H，brm)，2.79(3H，m)，3.18(3H，s)，3.36(2H，s)，5.11(1H，m)，7.83(2H，m)，7.98(1H，s)，8.28(1H，m)，8.50(1H，s)，8.64(1H，s)；HPLCrt(min)：9.78；MS(ES⁺)507，(ES^-)505。

Example 143：

3- [3- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -benzoylamino]-azetidine-1-carboxylic acid tert-butyl ester (I-143)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.39(9H，s)，1.53(4H，m)，1.66(2H，m)，1.83(2H，m)，3.19(3H，s)，3.31(2H，s)，3.85(2H，m)，4.10(2H，m)，4.61(1H，m)，5.25(1H，m)，7.30-7.37(2H，m)，7.68(1H，m)，7.96(1H，s)，8.27(1H，s)，8.89(1H，m)，9.29(1H，s)；HPLCrt(min)：9.98；MS(ES⁺)565，(ES^-)563。

Example 144：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2-methoxyethyl) benzamide (I-144)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.11(6H, s), 1.54(4H, m), 1.67(2H, m), 1.82(2H, m), 3.19(3H, s), 3.27(2H, m), 3.85 masked signals, 4.10(2H, m), 5.22(1H, m), 7.35(1H, m), 7.46(1H, m), 7.65(1H, m), 7.93(1H, s), 8.20(1H, s), 8.46(1H, m), 9.68(1H, s); HPLC rt (min): 9.04; MS (ES)⁺)467，(ES^-)466。

Example 145：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl-3, 3, 3-trifluoropropionamide (I-145)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.50-1.67(6H，brm)，1.81(2H，brm)，3.18(3H，s)，3.44(2H，s)，3.50(2H，m)，5.21(1H，m)，7.14(1H，m)，7.28(2H，m)，7.92(2H，m)，9.87(NH)，10.34(1H，s)；HPLCrt(min)：9.63；MS(ES⁺)491，(ES^-)489。

Example 146：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) -N-methylacetamide (I-146)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.52-1.63(4H, m), 1.67-1.73(2H, m), 1.78(3H, s), 1.81-1.88(2H, m), 3.14(3H, s), 3.18(3H, s), 3.36(2H, s), 5.23(1H, quintuple), 6.84(1H, d), 7.29(1H, t), 7.49(1H, d), 7.93(1H, s), 7.98(1H, s), 9.38(1H, s); HPLC rt (min): 9.40; MS (ES)⁺)437，(ES^-)435。

Example 147：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) -2-methoxyacetamide (I-147)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.51-1.57(4H, m), 1.65-1.71(2H, m), 1.81-1.87(2H, m), 3.18(3H, s), 3.32(2H, s), 3.37(3H, s), 3.97(2H, s), 5.26(1H, quintuple), 7.10-7.17(2H, m), 7.34(1H, d), 7.94(1H, s), 8.00(1H, s), 9.14(1H, s), 9.59(1H, s); HPLC rt (min): 9.30 of; MS (ES)⁺)453，(ES^-)451。

Example 148：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N, N-dimethylbenzamide (I-148)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.56(4H，m)，1.70(2H，m)，1.81(2H，m)，2.91(3H，s)，2.98(3H，s)，3.18(3H，s)，3.42(2H，s)，5.19(1H，m)，7.00(1H，m)，7.34(1H，m)，7.53(1H，m)，7.86(1H，s)，7.95(1H，s)，9.70(1H，s)；HPLC rt(min)：9.21；MS(ES⁺)437，(ES^-)435。

Example 149：

2- (3- (2-oxopyrrolidin-1-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-149)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.15(6H, s), 1.60(4H, m), 1.77(2H, m), 1.91(2H, m), 2.12(2H, m), 2.51 masked signals, 3.24(3H, s), 3.37(2H, s), 3.87(2H, m), 5.32(1H, m), 7.19(1H, m), 7.27(1H, m), 7.52(1H, m), 8.01(1H, s), 8.04(1H, m), 9.22(1H, s); HPLC rt (min): 9.52; MS (BS)⁺)449，(ES^-)447。

Example 150：

N- [3- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -phenyl]-methanesulfonamide (I-150)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.55-1.65(4H，s)，1.68-1.73(2H，m)，1.80-1.89(2H, m), 2.94(3H, s), 3.18(3H, s), 3.32(2H, s), 5.25(1H, quintet), 6.71(1H, d), 7.15(1H, t), 7.47(1H, d), 7.59(1H, s), 7.93(1H, s), 9.16(1H, s), 9.56(1H, br s); HPLC rt (min): 9.10; MS (ES)⁺)459，(ES^-)457。

Example 151：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) cyclobutaneamide (I-151)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.48-1.59(4H, m), 1.63-1.73(2H, m), 1.76-1.89(3H, m), 1.90-1.98(1H, m), 2.04-2.14(2H, m), 2.16-2.27(2H, m), 3.19(3H, s), 3.18-3.26(1H, m), 3.34(2H, s), 5.27(1H, quintuple), 7.03-7.12(2H, m), 7.27(1H, d), 7.93(1H, s), 7.99(1H, s), 9.08(1H, s), 9.59(1H, s); HPLC rt (min): 9.80; MS (ES)⁺)463，(ES^-)461。

Example 152：

9-cyclopentyl-2- [3- (3-cyclopropyl-3-fluoro-azetidine-1-carbonyl) -phenylamino]-5, 7, 7-trimethyl-5, 7, 8, 9-tetrahydro-pyrimido [4, 5-b][1，4]Diaza derivatives-6-one (I-152)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.20(2H, m), 0.36(2H, m), 0.86(6H, s), 1.16(1H, m), 1.34(4H, m), 1.46(2H, m), 1.63(2H, m), 2.95(3H, s), 3.08 masked signal, 3.79(2H, m), 3.96-4.08(2H, m), 5.01(1H, m), 6.89(1H, m), 7.07(1H, m), 7.73(1H, s), 7.83(1H, s), 9.09(1H, s); hplcrt (min): 10.03; MS (ES)⁺)507，(ES^-)505。

Example 153：

2- (3- (pyridin-3-yl) phenylamino) -9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-153)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.06(6H，s)，1.19-1.28(2H，m)，1.47-1.58(4H，m)，1.70-1.83(2H，m)，3.19(3H，s)，3.33(2H，s)，5.16-5.24(1H，m)，7.20(1H，d)，7.37(1H，t)，7.49(1H，dd)，7.62(1H，d)，7.98(1H，s)，8.00-8.02(1H，m)，8.14-8.15(1H，m)，8.58(1H，dd)，8.82(1H，d)，9.30(1H，s)；HPLCrt(min)：10.10；MS(ES⁺)443，(ES^-)441。

Example 154：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) benzamide (I-154)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.08(6H, s), 1.34-1.42(2H, m), 1.49-1.56(4H, m), 1.78-1.86(2H, m), 3.19(3H, s), 3.33(2H, s), 5.28(1H, quintuple), 7.15-7.22(2H, m), 7.30-7.32(1H, m), 7.51-7.61(3H, m), 7.94-8.00(3H, m), 8.26(1H, s), 9.20(1H, s), 10.17(1H, s); hplcrt (min): 9.70 of; MS (ES)⁺)485，(ES^-)483。

Example 155：

Methyl 3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) phenyl) carbamate (I-155)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.08(6H, s), 1.48-1.57(4H, m), 1.64-1.73(2H, m), 1.79-1.88(2H, m), 3.18(3H, s), 3.29(2H, s), 3.64(3H, s), 5.26(1H, quintuple), 6.88(1H, d), 7.11(1H, t), 7.26(1H, d), 7.90(1H, s), 7.93(1H, s), 9.11(1H, s), 9.50(1H, s); HPLC rt (min): 9.40; MS (ES)⁺)439，(ES^-)437。

Example 156：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (azetidin-3-yl) benzamide (I-156)

Prepared using method F. NMR DMSO D⁶1.11(6H，s)，1.53(4H，m)，1.67(2H，m)，1.81(2H，m)，3.18(3H，s)4.07(4H，m)，4.81(1H，m)，5.24(1H，m)7.41(2H，m)，7.70(1H，m)，7.97(1H，s)，8.24(1H，m)，8.72(2H，brs)，9.05(1H，m)，9.72(1H，m)；HPLCrt(min)：8.38；MS(ES⁺)464，(ES^-)463。

Example 157：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) -1-methylpiperidine-4-amide (I-157)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.35(2H，brm)，1.50-1.81(8H，brm)，1.96(2H，brm)，2.51(1H，brm)，2.72(3H，s)，2.91(2H，m)，3.12(3H，s)，3.43(2H，m)，3.44(2H，s)，5.07(1H，m)，7.10(2H，m)，7.31(1H，m)，7.73(1H，s)，7.96(1H，s)，10.20(1H，s)；HPLCrt(min)：8.96；MS(ES⁺)506，(ES^-)504。

Example 158：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -4-methoxyphenyl) acetamide (I-158)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.12(6H，s)，1.45-1.70(6H，m)，1.76-1.88(2H，m)，2.00(3H，s)，3.17(3H，s)，3.46(2H，s)，3.83(3H，s)，5.21(1H，dt)，7.01-7.11(2H，m)，7.93-7.96(1H，m)，8.26-8.34(1H，m)，9.84(1H，s)；HPLCrt(min)：8.85；MS(ES⁺)453，(ES^-)452。

Example 159：

3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-cyclopropylbenzamide (I-159)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.56(2H，m)，0.68(2H，m)，1.12(6H，s)，1.55(4H，m)，1.67(2H，m)，1.91(2H，m)，2.83(1H，m)，3.18(3H，s)，3.43(2H，s)，5.20(1H，m)，7.36-7.44(2H，m)，7.60(1H，m)，7.93(1H，s)，8.16(1H，s)，8.38(1H，m)，9.70(1H，s)；HPLC rt(min)：9.19；MS(ES⁺)449，(ES^-)448。

Example 160：

4- (9- (2, 2, 3, 3, 3-pentafluoropropyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-160)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，s)，2.79(3H，d)，3.22(3H，s)，3.66(2H，s)，3.92(3H，s)，4.83(2H，t)，7.42(1H，dd)，7.50(1H，d)，7.89(1H，s)，8.14(1H，d)，8.15(1H，s)，8.35(1H，q)；HPLCrt(min)：9.00；MS(ES⁺)517，(ES^-)515。

Example 161：

4- (9- (3-chlorophenyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-161)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.23(6H，s)，2.77(3H，d)，3.29(3H，s)，3.82(2H，s)，3.87(3H，s)，6.96(1H，dd)，7.32(1H，d)，7.34-7.38(2H，m)，7.49-7.54(2H，m)，7.57(1H，d)，7.60(1H，s)，8.17(1H，s)，8.23(1H，q)；HPLCrt(min)：8.99；MS(ES⁺)495，(ES^-)493。

Example 162：

N- (5- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -2-methylphenyl) acetamide (I-162)

Prepared according to method D using appropriate reagents. NMR DMSOD⁶1.08(6H，s)，1.57(4H，brm)，1.70(2H，brm)，1.84(2H，brm)，2.02(3H，s)，2.11(3H，s)，3.17(3H，s)，3.34(2H，s)，5.24(1H，m)，7.02(1H，m)，7.28(1H，m)，7.83(1H，s)，7.92(1H，s)，9.09(1H，s)，9.27(1H，s)；HPLC rt(min)：8.91；MS(ES⁺)437，(ES^-)435。

Example 163：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -4-methylphenyl) acetamide (I-163)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.07(6H，s)，1.41(4H，brm)，1.45-1.70(4H，brm)，1.99(3H，s)，2.17(3H，s)，3.17(3H，s)，3.30(2H，s)，5.07(1H，m)，7.04-7.13(2H，m)，7.89(2H，m)，8.21(1H，s)，9.77(1H，s)；HPLCrt(min)：9.01；MS(ES⁺)437，(ES^-)435。

Example 164：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) phenyl) piperidine-1-amide (I-164)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.46-1.61(10H, m), 1.64-1.69(2H, m), 1.81-1.89(2H, m), 3.18(3H, s), 3.32(2H, s), 3.38-3.41(4H, m), 5.26(1H, quintuple), 6.89(1H, d), 7.06(1H, t), 7.16(1H, d), 7.88-7.90(1H, m), 7.92(1H, s), 8.31(1H, s), 9.03(1H, s); hplcrt (min): 9.70 of; MS (ES)⁺)492，(ES^-)490。

Example 165：

N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -2, 6-difluorophenyl) acetamide (I-165)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.17(6H，s)，1.53(4H，brm)，1.60-1.76(4H，brm)，2.13(3H，s)，3.23(3H，s)，3.48(2H，s)，5.03(1H，m)，7.23(1H，m)，7.64(1H，m)，7.95(1H，s)，9.57(1H，s)，9.83(1H，s)；HPLCrt(min)：8.90；MS(ES⁺)459，(ES^-)457。

Example 166：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- (3, 3-difluorocyclobutyl) -3-methoxybenzamide (I-166)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.53-1.68(4H，m)，1.69-1.80(2H，m)，1.82-1.94(2H，m)，2.69-2.86(2H，m)，2.90-3.04(2H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.28(1H，dt)，5.19(1H，dt)，7.48(1H，d)，7.49(1H，s)，7.72(1H，s)，8.00(1H，s)，8.40(1H，d)，8.66(1H，d)；HPLCrt(min)：10.04；MS(ES⁺)529，(ES^-)528。

Example 167：

4- (9-cyclobutyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-167)

Prepared according to method D using appropriate reagents. NMR CDCl₃1.22(6H, s), 1.76-1.85(2H, m), 2.14(2H, double quintet), 2.30-2.33(2H, m), 3.05(3H, d), 3.32(3H, s), 3.51(2H, s), 4.00(3H, s), 5.09(1H, quintet), 6.14(1H, q), 7.30(1H, dd), 7.47(1H, d), 7.64(1H, s), 7.90(1H, s), 8.58(1H, d); hplcrt (min): 8.98 of; MS (ES)⁺)439，(ES^-)437。

Example 168：

4- (6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-9-neopentyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-168)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.96(9H，s)，1.10(6H，s)，2.78(3H，s)，3.21(3H，s)，3.60(2H，s)，3.79(2H，s)，3.93(3H，s)，7.49(2H，m)，7.71(1H，s)，8.00(1H，s)，8.35(2H，m)；HPLC rt(min)：9.30；MS(ES⁺)455，(ES^-)453。

Example 169：

4- (9- ((2, 2-Difluorocyclopropyl) methyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-169)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.11(6H，d)，1.44(1H，br m)，1.67(1H，brm)，2.17(1H，brm)，2.78(3H，d)，3.20(3H，s)，3.46(2H，brm)，3.63(1H，d)，3.93(3H，s)，4.14(1H，brm)，7.46(2H，brm)，7.76(1H，s)，8.04(1H，s)，8.32(2H，brd)；HPLCrt(min)：8.70；MS(ES⁺)475，(ES^-)473。

Example 170：

4- (9- (3, 3-difluorocyclobutyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-170)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，2.76-2.95(4H，m)，2.78(3H，d)，3.21(3H，s)，3.48(2H，s)，3.93(3H，s)，4.58-4.64(1H，m)，7.43-7.54(2H，m)，7.87(1H，s)，8.09(1H，s)，8.30-8.38(2H，m)；HPLC rt(min)：8.35；MS(ES⁺)475，(ES^-)473。

Example 171：

4- (9- (3, 3-difluorocyclobutyl) -6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (tetrahydro-2H-pyran-4-yl) -3-methoxybenzamide (I-171)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.54-1.65(2H，m)，1.75-1.79(2H，m)，2.78-2.98(4H，m)，3.21(3H，s)，3.34-3.43(2H，m)，3.48(2H，s)，3.85-3.89(1H，m)，3.90-3.93(1H，m)，3.95(3H，s)，3.98-4.05(1H，m)，4.56-4.63(1H，m)，7.48-7.51(2H，m)，7.88(1H，s)，8.10(1H，s)，8.19(1H，d)，8.33(1H，d)；HPLC rt(min)：8.86；MS(ES⁺)545，(ES^-)544。

Example 172：

4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b ]][1，4]Diaza derivatives-2-ylamino) -N- ((S) -tetrahydrofuran-3-yl) -3-methoxybenzamide (I-172)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，m)，1.55-1.68(4H，m)，1.69-1.77(2H，m)，1.84-1.95(4H，m)，2.12-2.21(1H，m)，3.19(3H，s)，3.38(2H，s)，3.59(1H，dd)，3.68-3.76(1H，m)，3.83-3.91(2H，m)，3.95(3H，s)，4.45-4.49(1H，m)，5.19(1H，dt)，7.47-7.52(2H，m)，7.70(1H，s)，7.99(1H，s)，8.35-8.41(2H，m)；HPLC rt(min)：9.37；MS(ES⁺)509，(ES^-)507。

Example 173：

4- ((S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-cyclopentyl-3-methoxybenzamide (I-173)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.02(3H，d)，1.50-1.83(14H，m)，1.89-1.94(2H，m)，2.08-2.11(1H，m)，2.83-2.88(1H，m)，3.19(3H，s)，3.37-3.45(1H，m)，3.95(3H，s)，4.20-4.26(1H，m)，4.71-4.76(1H，m)，7.47(1H，d)，7.49(1H，s)，7.75(1H，s)，8.10(1H，s)，8.14(1H，d)，8.38(1H，d)；HPLCrt(min)：10.10；MS(ES⁺)493，(ES^-)491。

Example 174：

4- ((S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (tetrahydro-2H-pyran-4-yl) -3-methoxybenzamide (I-174)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.02(3H, s), 1.52-1.78(11H, m), 2.04-2.12(1H, m), 2.84-2.90(1H, m), 3.19(3H, s), 3.39-3.46(4H, m), 3.89(2H, brdd), 3.95(3H, s), 3.96-4.06(1H, m), 4.74(1H, quintuple), 7.49(1H, d), 7.50(1H, s), 7.76(1H, s),8.10(1H，s)，8.17(1H，d)，8.40(1H，d)；HPLCrt(min)：9.20；MS(ES⁺)509，(ES^-)507。

example 175：

4- ((S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-cyclopropyl-3-methoxybenzamide (I-175)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.55-0.59(2H，m)，0.68-0.73(2H，m)，1.02(3H，d)，1.47-1.85(7H，m)，2.04-2.12(1H，m)，2.79-2.88(2H，m)，3.19(3H，s)，3.36-3.46(2H，m)，3.94(3H，s)，4.69-4.75(1H，m)，7.45(1H，d)，7.47(1H，s)，7.75(1H，s)，8.10(1H，s)，8.34(1H，d)，8.38(1H，d)；HPLCrt(min)：9.10；MS(ES⁺)465，(ES^-)463。

Example 176：

N-cyclopentyl-4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxybenzamide (I-176)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.66-0.69(2H, m), 0.89-0.91(2H, m), 1.46-1.71(12H, m), 1.85-1.95(4H, m), 3.17(3H, s), 3.48(2H, s), 3.95(3H, s), 4.23(1H, quintuple peak)) 4.85(1H, quintet), 7.47(1H, d), 7.49(1H, s), 7.66(1H, s), 7.99(1H, s), 8.13(1H, d), 8.38(1H, d); HPLC rt (min): 10.00; MS (ES)⁺)505，(ES^-)503。

Example 177：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (tetrahydro-2H-pyran-4-yl) benzamide (I-177)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.67(2H, brt), 0.90(2H, brt), 1.51-1.78(11H, m), 1.75-1.85(2H, m), 3.17(3H, s), 3.36-3.42(2H, m), 3.48(2H, s), 3.89(2H, brd), 3.99(3H, s), 3.99-4.03(1H, m), 4.85(1H, quintuple), 7.93(1H, d), 7.94(1H, s), 7.70(1H, s), 7.99(1H, s), 8.16(1H, d), 8.40(1H, d); HPLC rt (min): 9.10; MS (ES)⁺)521，(ES^-)519。

Example 178：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N-cyclopropyl-3-methoxybenzamide (I-178)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.56-0.59(2H, m), 0.66-0.73(4H, m), 0.84-0.91(2H, m), 1.50-1.76(6H, m), 1.85-1.95(2H, m), 2.79-2.83(1H, m), 3.10(3H, s), 3.49(2H, s), 3.94(3H, s), 4.85(1H, quintuple), 7.45(1H, d), 7.47(1H, s), 7.69(1H, s), 7.99(1H, s), 8.33(1H, d), 8.38(1H, d); hplcrt (min): 9.00; MS (ES)⁺)477，(ES^-)475。

Example 179：

(S) -4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (tetrahydrofuran-3-yl) benzamide (I-179)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.67(2H，brm)，0.90(2H，brm)，1.50-1.69(6H，brm)，1.88-1.91(3H，m)，2.16(1H，m)，3.17(3H，s)，3.48(2H，s)，3.60(1H，m)，3.61(1H，m)，3.84(2H，m)，3.95(3H，s)，4.46(1H，m)，4.85(1H，m)，7.50(2H，m)，7.70(1H，s)，7.99(1H，s)，8.38(1H，m)，8.41(1H，s)；HPLC rt(min)：7.39；MS(ES⁺)507，(ES^-)505。

Example 180：

4- (6, 7, 8, 9-tetrahydro-9- ((S) -tetrahydrofuran-3-yl) -5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-180)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，d)，1.92(1H，m)，2.31(1H，m)，2.78(3H，d)，3.19(3H，s)，3.47(2H，m)，3.63(1H，q)，3.80(2H，m)，3.93(3H，s)，3.98(1H，m)，5.44(1H，m)，7.48(2H，m)，7.77(1H，s)，8.03(1H，s)，8.35(2H，m)；HPLC rt(min)：7.80；MS(ES⁺)455，(ES^-)453。

Example 181：

4- (6, 7, 8, 9-tetrahydro-9- ((R) -tetrahydrofuran-3-yl) -5, 7, 7-trimethyl-6-oxo-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-181)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，d)，1.92(1H，m)，2.31(1H，m)，2.78(3H，d)，3.19(3H，s)，3.47(2H，m)，3.63(1H，q)，3.80(2H，m)，3.93(3H，s)，3.98(1H，m)，5.44(1H，m)，7.48(2H，m)，7.77(1H，s)，8.03(1H，s)，8.35(2H，m)；HPLC rt(min)：7.80；MS(ES⁺)455，(ES^-)453。

Example 182：

(R) -4- (9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (tetrahydro-2H-pyran-4-yl) benzamide (I-182)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(3H，d)，1.58-1.91(11H，m)，2.10-2.20(1H，m)，2.88-2.96(1H，m)，3.25(3H，s)，3.36-3.54(4H，m)，3.90-3.97(2H，m)，4.02(3H，s)，4.03-4.12(1H，m)，4.75-4.85(1H，m)，7.54-7.57(2H，m)，7.83(1H，s)，8.17(1H，s)，8.24(1H，d)，8.46(1H，d)；HPLC rt(min)：9.24。

Example 183：

4- ((R) -9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((S) -tetrahydrofuran-3-yl) benzamide (I-183)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(3H，d)，1.48-1.63(3H，m)，1.65-1.85(4H，m)，1.85-2.022.10-2.23(1H，m)，2.30(3H，s)，2.95-3.05(1H，m)，3.19(3H，s)，3.35-3.42(1H，m)，3.54-3.65(2H，m)，3.66-3.75(1H，m)，3.80-3.90(2H，m)，3.97(3H，s)，4.42-4.52(1H，m)，4.76-4.87(1H，m)，7.52-7.62(2H，m)，8.04-8.15(2H，m)，8.52(1H，d)，9.27(1H，brs)；HPLCrt(min)：9.11。

Example 184：

(R) -4- (9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-cyclopropyl-3-methoxybenzamide (I-184)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.55-0.59(2H, m), 0.67-0.73(2H, m), 1.02(3H, d), 1.52-1.83(7H, m), 2.05-2.10(1H, m), 2.79-2.88(2H, m), 3.19(3H, s), 3.59-3.45(2H, m), 3.94(3H, s), 4.73(1H, quintuple), 7.45(1H, d), 7.47(1H, s), 7.78(1H, s), 8.09(1H, s), 8.33(1H, d), 8.83(1H, d); hplcrt (min): 9.40; MS (ES)⁺)465，(ES^-)463。

Example 185：

(R) -N-cyclopentyl-4- (9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-185)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.02(3H, d), 1.50-1.61(6H, m), 1.63-1.83(8H, m), 1.86-1.96(2H, m), 2.04-2.11(1H, m), 2.83-2.88(1H, m), 3.19(3H, s), 3.36-3.46(1H, m), 3.95(3H, s), 4.18-4.28(1H, m), 4.74(1H, quintuple), 7.47(1H, d), 7.48(1H, s), 7.75(1H, s), 8.10(1H, s), 8.15(1H, s), 8.38(1H, d); HPLC rt (min): 10.10; MS (ES)⁺)493，(ES^-)491。

Example 186：

(R) -N-cyclobutyl-4- (9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-186)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.02(3H, d), 1.50-1.83(9H, m), 2.03-2.12(3H, m), 2.19-2.23(2H, m), 2.81-2.90(1H, m), 3.19(3H, s), 3.30-3.33(1H, m), 3.43(1H, t), 3.65(3H, s), 4.43(1H, q), 4.73(1H, quintuple), 7.48(1H, dd), 7.49(1H, s), 7.76(1H, s), 8.10(1H, s), 8.39(1H, d), 8.47(1H, d); hplcrt (min): 9.90 of; MS (ES)⁺)479。

Example 187：

(R) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (tetrahydrofuran-3-yl) benzamide (I-187)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.62(4H，brm)，1.74(2H，brm)，1.89(3H，brm)，2.16(1H，brm)，3.19(3H，s)，3.38(2H，s)，3.60(1H，m)，3.71(1H，m)，3.86(2H，m)，3.95(3H，s)，4.45(1H，m)，5.20(1H，m)，7.51(2H，m)，7.70(1H，s)，7.99(1H，s)，8.39(2H，m)；HPLCrt(min)：9.40；MS(ES⁺)509。

Example 188：

9-cyclopentyl-2- (2-methoxyphenylamino) -5-methyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-188)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.52-1.75(6H, m), 1.85-1.95(2H, m), 2.52-2.58(2H, m), 3.16(3H, s), 3.58-3.62(2H, m), 3.86(3H, s), 4.75(1H, quintuple), 6.93(2H, dt)7.02(1H, dd), 7.61(1H, s), 8.04(1H, s), 8.21(1H, dd); hplcrt (min): 10.07; MS (ES)⁺)368。

Example 189：

2- (2-methoxyphenylamino) -5, 9-dimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-189)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶2.58-2.61(2H，m)，3.03(3H，s)，3.17(3H，s)，3.65-3.69(2H，m)，3.87(3H，s)，6.90-6.97(2H，m)7.01-7.03(1H，m)，7.62(1H，s)，8.07(1H，s)，8.30-8.33(1H，m)；HPLCrt(min)：8.61；MS(ES⁺)314。

Example 190：

4- (9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-190)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.87(3H，t)，1.09(1H，t)，1.28(1H，m)，1.69(8H，brm)，2.07(1H，brm)，2.60(1H，m)，2.78(3H，d)，3.19(3H，s)，3.40(2H，m)，3.94(3H，s)，4.77(1H，brm)，7.48(2H，m)，7.76(1H，s)，8.11(1H，s)，8.33(1H，brd)，8.38(1H，d)；HPLCrt(min)：9.40；MS(ES⁺)453。

Example 191：

4- (9- (bicyclo [2.2.1 ]]Hept-2-yl) -5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-methylbenzamide (I-191)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶0.95-1.08(2H，m)，1.06(3H，s)，1.08(3H，s)，1.16-1.58(6H，m)，1.95-2.06(1H，m)，2.18-2.23(1H，m)，2.58-2.65(1H，m)，2.79(3H，d)，3.22(3H，s)，3.30(1H，d)，3.52(1H，d)，3.94(3H，s)，4.24-4.31(1H，m)，7.44-7.51(2H，m)，7.77(1H，s)，8.12(1H，s)，8.30-8.36(1H，m)，8.39(1H，d)；HPLCrt(min)：9.78；MS(ES⁺)479。

Example 192：

3-methoxy-N-methyl-4- (5, 7, 7-trimethyl-9- (morpholin-2-ylmethyl) -6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) benzamide (I-192)

Prepared according to method 0 using appropriate reagents.NMR DMSO D⁶1.10(6H，s)，2.40-2.48(1H，m)，2.60-2.69(2H，m)，2.78(3H，d)，2.78-2.85(1H，m)，3.19(3H，s)，3.34(2H，s)，3.34-3.44(1H，m)，3.52-3.60(2H，m)，3.68-3.78(2H，m)，3.85-3.95(1H，m)，3.93(3H，s)，7.45(1H，d)，7.48(1H，d)，7.69(1H，s)，7.99(1H，s)，8.30-8.35(1H，m)，8.31(1H，d)；HPLC rt(min)：6.88；MS(ES⁺)484。

Examples]93：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (furan-2-ylmethyl) -3-methoxybenzamide (I-193)

Prepared according to method E using appropriate reagents. Hplcrt (min): 9.90 of; MS (ES)⁺)519。

Example 194：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((tetrahydrofuran-2-yl) methyl) benzamide (I-194)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.70 of; MS (ES)⁺)523。

Example 195：

4- (9-cyclopentyl-5, 7, 7-trimethyl)6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b ] yl][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((tetrahydrofuran-2H-pyran-4-yl) methyl) benzamide (I-195)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.60 parts of; MS (ES)⁺)537。

Example 196：

N- (cyclohexylmethyl) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-196)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.90-0.96(2H, m), 1.10(6H, s), 1.15-1.14(3H, m), 1.54-1.73(12H, m), 1.84-1.91(2H, m), 3.11(2H, t), 3.19(3H, s), 3.38(2H, s), 3.94(3H, s), 5.18(1H, quintuple), 7.47(1H, d), 7.50(1H, s), 7.69(1H, s), 7.99(1H, s), 8.32-8.37(2H, m); hplcrt (min): 10.90 of; MS (ES)⁺)535。

Example 197：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2-methoxyethyl) benzamide (I-197)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.40; MS (ES)⁺)497。

Example 198：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (3-methoxypropyl) benzamide (I-198)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.60 parts of; MS (ES)⁺)511。

Example 199：

9-cyclopentyl-2- (2-methoxy-4- (morpholine-4-carbonyl) phenylamino) -5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-199)

Prepared according to method E using appropriate reagents. Hplcrt (min): 9.50 of the total weight of the alloy; MS (ES)⁺)509。

Example 200：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-phenylbenzamide (I-200)

Prepared according to method E using appropriate reagents. Hplcrt (min): 10.30 of; MS (ES)⁺)515。

Example 201：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((tetrahydrofuran-2-yl) methyl) benzamide (I-201)

Prepared according to method E using appropriate reagents. Hplcrt (min): 10.20; MS (ES)⁺)529。

Example 202：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-3-ylmethyl) benzamide (I-202)

Prepared according to method E using appropriate reagents. Hplcrt (min): 9.50 of the total weight of the alloy; MS (ES)⁺)530。

Example 203：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-phenethylbenzamide (I-203)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.10(6H, s), 1.58-1.66(4H, m), 1.70-1.78(2H, m), 1.84-1.92(2H, m), 2.85(2H, t), 3.19(3H, s), 3.38(2H, s), 3.48(2H, q), 3.94(3H, s), 5.18(1H, quintuple), 7.19-7.33(5H, m), 7.45(1H, d), 7.49(1H, s), 7.70(1H, s), 7.99(1H, s), 8.37(1H, d), 8.47(1H, brt); hplcrt (min): 10.40; MS (ES)⁺)543。

Example 204：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 4R) -4-hydroxycyclohexyl) -3-methoxybenzamide (I-204)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.19-1.43(4H，m)，1.55-1.93(12H，m)，3.19(3H，s)，3.34-3.45(1H，m)，3.38(2H，s)，3.68-3.79(1H，m)，3.94(3H，s)，4.57(1H，d)，5.19(1H，dt)，7.46(1H，d)，7.47(1H，s)，7.68(1H，s)，7.99(1H，s)，8.02(1H，s)，8.36(1H，d)；HPLCrt(min)：9.21；MS(ES⁺)537。

Example 205：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1-hydroxycyclohexyl) methyl) -3-methoxy-benzamide (I-205)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.10(6H，s)，1.16-1.26(1H，m)，1.29-1.80(15H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.28(2H，d)，3.38(2H，s)，3.95(3H，s)，4.43(1H，s)，5.19(1H，dt)，7.51(1H，d)，7.53(1H，s)，7.70(1H，s)，7.99(1H，s)，8.16(1H，t)，8.38(1H，d)；HPLCrt(min)：10.06；MS(ES⁺)551。

Example 206：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyrrolidin-1-yl) benzamide (I-206)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.10(6H，s)，1.57-1.92(12H，m)，2.90-2.99(4H，m)，3.19(3H，s)，3.38(2H，s)，3.94(3H，s)，5.18(1H，dt)，7.41(1H，d)，7.43(1H，s)，7.69(1H，s)，7.99(1H，s)，8.37(1H，d)，9.27(1H，s)；HPLCrt(min)：9.57；MS(ES⁺)508。

Example 207：

4- (9-cyclopentyl)Yl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-3-yl) benzamide (I-207)

Prepared according to method E using appropriate reagents. Hplcrt (min): 9.85; MS (ES)⁺)516。

Example 208：

9-cyclopentyl-2- (4- (3-cyclopropyl-3-fluoroazetidine-1-carbonyl) -2-methoxyphenylamino) -5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7) -one (I-208)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.44(2H，brs)，0.61(2H，d)，1.09(6H，s)，1.35-1.45(1H，m)，1.53-1.80(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.38(2H，s)，3.94(3H，s)，3.96-4.13(2H，m)，4.20-4.51(2H，m)，5.19(1H，dt)，7.24(1H，s)，7.25(1H，d)，7.73(1H，s)，7.99(1H，s)，8.37(1H，d)；HPLCrt(min)：10.37；MS(ES⁺)537。

Example 209：

(R) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2, 3-dihydro-1H-inden-1-yl) -3-methoxy-benzamide (I-209)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.10(6H，m)，1.55-1.79(6H，m)，1.82-1.95(2H，m)，1.96-2.06(1H，m)，2.43-2.51(1H，m)，2.82-2.93(1H，m)，2.96-3.07(1H，m)，3.19(3H，s)，3.38(2H，s)，3.94(3H，s)，5.19(1H，dt)，5.61(1H，q)，7.18-7.31(4H，m)，7.55-7.60(2H，m)，7.71(1H，s)，8.00(1H，s)，8.39(1H，d)，8.67(1H，d)；HPLCrt(min)：10.60；MS(ES⁺)555。

Example 210：

N- (bicyclo [2.2.1 ]]Hept-2-yl) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-210)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.12-1.23(3H, m), 1.48-1.75(11H, m), 1.84-1.92(2H, m), 2.18-2.28(2H, m), 3.18(3H, s), 3.37(2H, s), 3.67-3.75(1H, m), 3.94(3H, s), 5.18(1H, quintuple), 7.46(1H, d), 7.47(1H, s), 7.68(1H, s), 7.91(1H, d), 7.98(1H, s), 8.34(1H, d); hplcrt (min): 10.70 of; MS (ES)⁺)533。

Example 211：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (3-hydroxy-2, 2-dimethylpropyl) -3-methoxybenzamide (I-211)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.84(6H, s), 1.09(6H, s), 1.55-1.65(4H, m), 1.70-1.77(2H, m), 1.84-1.92(2H, m), 3.10(2H, d), 3.15(2H, d), 3.19(3H, s), 3.38(2H, s), 3.95(3H, s), 4.69(1H, t), 5.18(1H, quintuple), 7.48(1H, d), 7.50(1H, s), 7.71(1H, s), 7.99(1H, s), 8.33-8.39(2H, m); hplcrt (min): 9.80; MS (ES)⁺)525。

Example 212：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-4-ylmethyl) benzamide (I-212)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H, s), 1.56-1.67(4H, m), 1.69-1.75(2H, m), 1.84-1.93(2H, m), 3.19(3H, s), 3.38(2H, s), 3.95(3H, s), 4.51(2H, d), 5.19(1H, quintuple), 7.31(2H, d), 7.55(1H, d), 7.56(1H, s), 7.73(1H, s), 8.00(1H, s), 8.41(1H, d), 8.51(2H, d), 9.02(1H, t); hplcrt (min): 9.40; MS (ES)⁺)530。

Example 213：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (4-methoxybenzyl) benzamide (I-213)

Prepared according to method E using appropriate reagents. HPLC rt (min): 10.20; MS (ES)⁺)559。

Example 214：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (4- (methylsulfonyl) benzyl) benzamide (I-214)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.40; MS (ES)⁺)607。

Example 215：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N, N-dimethylbenzamide (I-215)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.70 of; MS (ES)⁺)467。

Example 216：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (((1S, 2S) -2-hydroxycyclohexyl) methyl) -3-methoxybenzamide (I-216)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.14-1.25(1H, m), 1.28-1.40(4H, m), 1.51-1.67(10H, m), 1.84-1.92(2H, m), 3.09-3.19(1H, m), 3.19(3H, s), 3.24-3.31(1H, m), 3.38(2H, s), 3.73(1H, brs), 3.94(3H, s), 4.42(1H, d), 5.18(1H, quintuple), 7.47(1H, d), 7.50(1H, s), 7.70(1H, s), 7.99(1H, s), 8.36-8.38(2H, m); hplcrt (min): 10.20; MS (ES)⁺)551。

Example 217：

(S) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-methoxypropan-2-yl) benzamide (I-217)

Prepared according to method E using appropriate reagents. HPLC rt (min): 9.80; MS (ES)⁺)511。

Example 218：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N-propylbenzamide (I-218)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.89(3H，t)，1.09(6H，s)，1.53(2H，dt)，1.53-1.77(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.18-3.25(2H，m)，3.38(2H，s)，3.94(3H，s)，5.18(1H，dt)，7.47(1H，d)，7.50(1H，s)，7.69(1H，s)，7.99(1H，s)，8.32-8.39(2H，m)；HPLC rt(min)：9.97；MS(ES⁺)481。

Example 219：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-ethyl-3-methoxybenzamide (I-219)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.09(6H，s)，1.13(3H，t)，1.57-1.78(6H，m)，1.82-1.92(2H，m)，3.18(3H，s)，3.24-3.34(2H，m)，3.38(2H，s)，3.94(3H，s)，5.18(1H，dt)，7.47(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.35-8.39(2H，m)；HPLCrt(min)：9.65；MS(ES⁺)467。

Example 220：

9-cyclopentyl-2- (2-methoxy-4- (3-methoxyazetidine-1-carbonyl) phenylamino) -5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-220)

Prepared according to method B using the appropriate reagents. NMR DMSOD⁶1.09(6H，s)，1.53-1.77(6H，m)，1.82-1.92(2H，m)，3.18(3H，s)，3.22(3H，s)，3.37(2H，s)，3.79-3.89(1H，m)，3.92(3H，s)，4.13-4.27(3H，m)，4.43-4.53(1H，m)，5.17(1H，dt)，7.21(1H，d)，7.23(1H，s)，7.71(1H，s)，7.98(1H，s)，8.35(1H，d)；HPLCrt(min)：9.69；MS(ES⁺)509。

Example 221：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-2-yl) benzamide (I-221)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.10(6H, s), 1.56-1.77(6H, m), 1.86-1.94(2H, m), 3.20(3H, s), 3.42(2H, s), 4.00(3H, s), 5.21(1H, quintuple), 7.16(1H, dd), 7.72-7.77(3H, m), 7.82-7.86(1H, m), 8.01(1H, s), 8.21(1H, d), 8.38(1H, dd), 8.46(1H, d), 10.69(1H, s); hplcrt (min): 10.30 of; MS (ES)⁺)516。

Example 222：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyrimidin-4-yl)) Benzamide (I-222)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.03(6H, s), 1.51-1.70(6H, m), 1.79-1.86(2H, m), 3.13(3H, s), 3.32(2H, s), 3.93(3H, s), 5.13(1H, quintuple), 7.66-7.69(2H, m), 7.74(1H, s), 7.95(1H, s), 8.16(1H, d), 8.40-8.43(1H, m), 8.64(1H, d), 8.88(1H, s), 11.07(1H, s); hplcrt (min): 10.10; MS (ES)⁺)517。

Example 223：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (thiazol-2-yl) benzamide (I-223)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.03(6H, s), 1.52-1.73(6H, m), 1.78-1.84(2H, m), 3.13(3H, s), 3.32(2H, s), 3.93(3H, s), 5.13(1H, quintet), 7.19(1H, d), 7.49(1H, d), 7.71-7.74(3H, m), 7.95(1H, s), 8.44(1H, d), 12.42(1H brs); HPLC rt (min): 10.30 of; MS (ES)⁺)522。

Example 224：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyrazin-2-yl) benzamide (I-224)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.58-1.80(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.50(2H，s)，4.01(3H，s)，5.17(1H，dt)，7.79(1H，d)，7.83(1H，s)，8.05(1H，s)，8.29(1H，t)，8.43(1H，d)，8.50(1H，s)，9.46(1H，s)，11.12(1H，s)；HPLC rt(min)：9.99；MS(ES⁺)517。

Example 225：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((1R, 2S) -2-phenylcyclopropyl) benzamide (I-225)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.21-1.27(1H，m)，1.32-1.39(1H，m)，1.56-1.79(6H，m)，1.82-1.92(2H，m)，2.03-2.11(1H，m)，2.86-3.04(1H，m)，3.19(3H，s)，3.38(2H，s)，3.94(3H，s)，5.19(1H，dt)，7.15-7.20(3H，m)，7.24-7.32(2H，m)，7.45-7.51(2H，m)，7.70(1H，s)，7.99(1H，s)，8.38(1H，d)，8.57(1H，d)；HPLC rt(min)：10.50；MS(ES⁺)555。

Example 226：

(R) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (1-phenylethyl) benzylAmide (I-226)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.50(3H，d)，1.53-1.78(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，5.16-5.23(2H，m)，7.23(1H，t)，7.33(2H，t)，7.39(2H，d)，7.53(2H，d)，7.71(1H，s)，7.99(1H，s)，8.38(1H，d)，8.66(1H，d)；HPLC rt(min)：10.39；MS(ES⁺)543。

Example 227：

N- (2-Chloropyridin-4-yl) 4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-227)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.58-1.80(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.51(2H，s)，4.01(3H，s)，5.17(1H，dt)，7.66(1H，s)，7.67(1H，d)，7.77(1H，dd)，7.95(1H，s)，8.05(1H，d)，8.27(1H，t)，8.33(1H，d)，10.69(1H，s)；HPLCrt(min)：10.46；MS(ES⁺)550。

Example 228：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (2-methoxypyridin-3-yl) benzamide (I-228)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.14(6H，s)，1.58-1.80(6H，m)，1.82-1.92(2H，m)，3.19(3H，s)，3.50(2H，s)，3.93(3H，s)，3.99(3H，s)，5.15(1H，dt)，7.06(1H，dd)，7.66(1H，d)，7.69(1H，s)，7.98-8.05(3H，m)，8.23(1H，t)，8.88(1H，bs)，9.64(1H，s)；HPLCrt(min)：10.51；MS(ES⁺)546。

Example 229：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (((1S, 2R) -2-hydroxycyclohexyl) methyl) -3-methoxybenzamide (I-229)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.93-0.99(1H，m)，1.09(6H，s)，1.10-1.20(2H，m)，1.36-1.46(1H，m)，1.52-1.91(12H，m)，3.07-3.13(1H，m)，3.19(3H，s)，3.35-3.45(2H，m)，3.38(2H，s)，3.94(3H，s)，4.82(1H，d)，5.18(1H，dt)，7.48(1H，d)，7.50(1H，s)，7.70(1H，s)，7.99(1H，s)，8.32(1H，t)，8.36(1H，d)；HPLCrt(min)：10.17；MS(ES⁺)551。

Example 230：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (cyclopentylmethyl3-Methoxybenzamide (I-230)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.21-1.30(2H，m)，1.43-1.79(12H，m)，1.83-1.96(2H，m)，2.11-2.19(1H，m)，3.15-3.22(2H，m)，3.19(3H，s)，3.38(2H，s)，3.94(3H，s)，5.18(1H，dt)，7.47(1H，d)，7.50(1H，s)，7.69(1H，s)，7.99(1H，s)，8.36(1H，d)；HPLCrt(min)：10.65；MS(ES⁺)521。

Example 231：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (5-methyl-1H-pyrazol-3-yl) benzamide (I-231)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.59-1.90(8H，m)，2.23(3H，s)，3.18(3H，s)，3.50(2H，s)，3.99(3H，s)，5.15(1H，dt)，6.41(1H，brs)，7.70(1H，d)，7.76(1H，s)，8.03(1H，s)，8.19(1H，d)，10.69(1H，s)；HPLCrt(min)：9.57；MS(ES⁺)519。

Example 232：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (3-methylisothiazol-5-yl) benzamide (I-232)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.14(6H，s)，1.59-1.82(6H，m)，1.84-1.98(2H，m)，2.36(3H，s)，3.19(3H，s)，3.51(2H，s)，4.01(3H，s)，5.16(1H，dt)，6.93(1H，s)，7.74(1H，d)，7.75(1H，s)，8.05(1H，s)，8.27(1H，d)，9.01(1H，brs)，12.19(1H，s)；HPLCrt(min)：10.15；MS(ES⁺)536。

Example 233：

N- (cyanomethyl) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-233)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.56-1.80(6H，m)，1.82-1.88(2H，m)，3.19(3H，s)，3.38(2H，s)，3.95(3H，s)，4.31(2H，d)，5.18(1H，dt)，7.50(1H，d)，7.52(1H，s)，7.75(1H，s)，8.00(1H，s)，8.43(1H，d)，9.07(1H，t)；HPLC rt(min)：9.34；MS(ES⁺)478。

Example 234：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (3-trifluoromethyl) pyridin-4-yl)) benzamide (I-234)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.15(6H, s), 1.58-1.78(6H, m), 1.82-1.92(2H, m), 3.19(3H, s), 3.52(2H, s), 3.99(3H, s), 5.14(1H, quintuple), 7.64-7.69(2H, m), 7.75-7.79(1H, m), 8.05(1H, d), 8.20-8.24(1H, m), 8.89(1H, d), 9.00(1H, s), 9.15(1H, brs), 10.23(1H, brs); hplcrt (min): 10.70 of; MS (ES)⁺)584。

Example 235：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- ((5-methylisoxazol-3-yl) methyl) benzamide (I-235)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H, s), 1.54-1.67(4H, m), 1.69-1.76(2H, m), 1.82-1.93(2H, m), 2.37(3H, s), 3.19(3H, s), 3.38(2H, s), 3.94(3H, s), 4.46(2H, d), 5.18(1H, quintuple), 6.15(1H, s), 7.52(1H, d), 7.53(1H, s), 7.72(1H, s), 7.99(1H, s), 8.40(1H, d), 8.96(1H, t); hplcrt (min): 9.70 of; MS (ES)⁺)534。

Example 236：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (5-methylthiazol-2-yl) benzamide (I-236)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.12(6H, s), 1.58-1.82(6H, s), 1.83-1.91(2H, m), 2.38(3H, s), 3.19(3H, s), 3.50(2H, s), 4.00(3H, s), 5.16(1H, quintuple), 7.24(1H, s), 7.79(1H, d), 7.85(1H, s), 8.05(1H, s), 8.27(1H, d), 8.78(1H, brs), 12.44(1H, brs); hplcrt (min): 10.50; MS (ES)⁺)536。

Example 237：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2- (2-hydroxyethoxy) ethyl) -3-methoxybenzamide (I-237)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.54-1.69(4H, s), 1.70-1.81(2H, m), 1.84-1.93(2H, m), 3.19(3H, s), 3.38(2H, s), 3.40-3.47(4H, m), 3.49-3.55(4H, m), 3.94(3H, s), 4.62(1H, t), 5.18(1H, quintuple), 7.48(1H, d), 7.51(1H, s), 7.70(1H, s), 7.99(1H, s), 8.38(1H, d), 8.42(1H, t); hplcrt (min): 9.00; MS (ES)⁺)527。

Example 238：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N-isopropyl-3-methoxybenzamide (I-238)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.17(6H, s), 1.54-1.69(4H, m), 1.72-1.79(2H, m), 1.82-1.93(2H, m), 3.19(3H, s), 3.38(2H, s), 3.94(3H, s), 4.11(1H, dt), 5.19(1H, quintuple), 7.48(1H, d), 7.49(1H, s), 7.68(1H, s), 7.99(1H, s), 8.08(1H, d), 8.36(1H, d); hplcrt (min): 10.10; MS (ES)⁺)481。

Example 239：

(S) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1-hydroxy-3-methylbut-2-yl) -3-methoxybenzamide (I-239)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.89(3H，d)，0.91(3H，d)，1.09(6H，s)，1.58-1.77(6H，m)，1.83-1.97(3H，m)，3.19(3H，s)，3.38(2H，s)，3.53(2H，t)，3.76-3.85(1H，m)，3.95(3H，s)，4.60(1H，t)，5.19(1H，dt)，7.51(1H，d)，7.52(1H，s)，7.69(1H，s)，7.86(1H，d)，7.99(1H，s)，8.36(1H，d)；HPLCrt(min)：9.75；MS(ES⁺)525。

Example 240：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1-hydroxy-2-Methylprop-2-yl) -3-methoxybenzamide (I-240)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.32(6H，s)，1.57-1.90(8H，m)，3.18(3H，s)，3.38(2H，s)，3.52(2H，d)，3.94(3H，s)，4.96(1H，t)，5.19(1H，dt)，7.40-7.44(3H，m)，7.68(1H，s)，7.99(1H，s)，8.36(1H，d)；HPLCrt(min)：9.61；MS(ES⁺)511。

Example 241：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (3-hydroxypropyl) -3-methoxy-N- (thiazol-2-yl) benzamide (I-241)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.54-1.79(8H，m)，1.82-1.93(2H，m)，3.18(3H，s)，3.28-3.36(2H，m)，3.38(2H，s)，3.46(2H，dd)，3.94(3H，s)，4.50(1H，t)，5.18(1H，dt)，7.47(1H，d)，7.50(1H，s)，7.69(1H，s)，7.99(1H，s)，8.34-8.39(2H，m)；HPLC rt(min)：9.02；MS(ES⁺)497。

Example 242：

(S) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2, 3-dihydroxypropyl) -3-methoxybenzamide (I-24)2)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.53-1.77(6H，m)，1.82-1.94(2H，m)，3.19(3H，s)，3.18-3.24(1H，m)，3.38(2H，s)，3.30-3.43(3H，m)，3.60-3.66(1H，m)，3.94(3H，s)，4.61(1H，t)，4.85(1H，d)，5.19(1H，dt)，7.50(1H，d)，7.53(1H，s)，7.70(1H，s)，7.99(1H，s)，8.34-8.41(2H，m)；HPLCrt(min)：8.62；MS(ES⁺)513。

Example 243：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (3-hydroxybutyl) -3-methoxybenzamide (I-243)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.07-1.10(3H，m)，1.09(6H，s)，1.51-1.89(10H，m)，3.18(3H，s)，3.28-3.38(2H，m)，3.39(2H，s)，3.63-3.70(1H，m)，3.93(3H，s)，4.54(1H，d)，5.18(1H，dt)，7.46(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.32-8.39(2H，m)；HPLC rt(min)：9.31；MS(ES⁺)511。

Example 244：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 2R) -2-hydroxycyclopentyl) -3-methylOxybenzamide (I-244)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.44-1.52(2H，m)，1.53-1.78(8H，m)，1.81-1.96(3H，m)，1.97-2.04(1H，m)，3.18(3H，s)，3.38(2H，s)，3.94(3H，s)，3.94-4.03(2H，m)，4.80(1H，d)，5.19(1H，dt)，7.48(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.11(1H，d)，8.36(1H，d)；HPLCrt(min)：9.55；MS(ES⁺)523。

Example 245：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((2, 2-difluorocyclopropyl) methyl) -3-methoxybenzamide (I-245)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.26-1.36(1H，m)，1.55-1.70(5H，m)，1.70-1.79(2H，m)，1.82-1.94(2H，m)，1.95-2.09(1H，m)，3.19(3H，s)，3.31-3.39(2H，m)，3.39(2H，s)，3.95(3H，s)，5.18(1H，dt)，7.50(1H，d)，7.52(1H，s)，7.76(1H，bs)，7.99(1H，s)，8.38(1H，d)，8.65(1H，t)；HPLC rt(min)：10.00；MS(ES⁺)529。

Example 246：

N- (cyclobutylmethyl) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamide (I-246)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.58-2.04(14H，m)，2.50-2.56(1H，m)，3.18(3H，s)，3.30(2H，t)，3.38(2H，s)，3.94(3H，s)，5.18(1H，dt)，7.47(1H，d)，7.49(1H，s)，7.69(1H，s)，7.99(1H，s)，8.32-8.38(2H，m)；HPLCrt(min)：10.42；MS(ES⁺)507。

Example 247：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (pyridin-4-ylmethyl) benzamide (I-247)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.66-0.69(2H，m)，0.89-0.91(2H，m)，1.51-1.55(2H，m)，1.60-1.64(2H，m)，1.69(2H，m)，1.89(2H，m)，3.17(3H，s)，3.44(2H，m)，3.95(3H，s)，4.50-4.52(2H，m)，4.85(1H，m)，7.30-7.31(2H，m)，7.55-7.57(2H，m)，7.73(1H，s)，8.00(1H，s)，8.44(1H，s)，8.50-8.51(2H，m)，9.03(1H，m)；HPLC rt(min)：9.08；MS(ES⁺)528。

Example 248：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- (furan-2-ylmethyl) -3-methoxybenzamide (I-248)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.72(2H，m)，0.90(2H，m)，1.50-1.54(2H，m)，1.60-1.64(2H，m)，1.69(2H，m)，1.89(2H，m)，3.17(3H，s)，3.48(2H，brs)，3.94(3H，s)，4.47-4.48(2H，m)，4.85(1H，m)，6.27(1H，m)，6.41(1H，m)，7.53(2H，m)，7.59(1H，brs)，7.70(1H，brs)，7.99(1H，brs)，8.41(1H，d)；HPLCrt(min)：9.58；MS(ES⁺)517。

Example 249：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (pyridin-3-ylmethyl) benzamide (I-249)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.67-0.68(2H，m)，0.90-0.91(2H，m)，1.50-1.54(2H，m)，1.59-1.64(2H，m)，1.69(2H，m)，1.89(2H，m)，3.17(3H，s)，3.45-3.48(2H，m)，3.94(3H，s)，4.50-4.51(2H，m)，4.58(1H，m)，7.37(1H，m)，7.52-7.55(2H，m)，7.71-7.73(2H，m)，7.99(1H，s)，8.42-8.47(2H，m)，8.56(1H，s)，9.00(1H，m)；HPLCrt(min)：9.12；MS(ES⁺)528。

Example 250：

2- (4- (1H-imidazol-2-yl) -2-methoxyphenylamino) -9-cyclopentyl-5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-250)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.56-1.81(6H，m)，1.82-1.97(2H，m)，3.19(3H，s)，3.30-3.40(2H，m)，3.94(3H，s)，5.14-5.25(1H，m)，7.1(2H，brs)，7.49-7.54(1H，m)，7.59-7.65(2H，m)，7.97(1H，s)，8.30-8.36(1H，m)，12.40(1H，s)；HPLCrt(min)：9.50；MS(ES⁺)462。

Example 251：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- ((1R, 4R) -4-hydroxycyclohexyl) -3-methoxybenzamide (I-251)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.67(2H，m)，0.90(2H，m)，1.20-1.28(2H，m)，1.34-1.43(2H，m)，1.50-1.54(2H，m)，1.59-1.87(10H，m)，3.16(3H，s)，3.47(2H，m)，3.73(1H，m)，3.94(3H，s)，4.58(1H，m)，4.86(1H，m)，7.45-7.47(2H，m)，7.68(1H，m)，7.98-8.04(2H，m)，8.38(1H，m)；HPLCrt(min)：8.84；MS(ES⁺)535。

Example 252：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- (((1S, 2S) -2-hydroxycyclohexyl) methyl) -3-methoxybenzamide (I-252)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.66-0.67(2H，m)，0.90-0.91(2H，m)，1.15-1.18(2H，m)，1.23-1.35(4H，m)，1.501-1.69(10H，m)，1.88(2H，m)，3.17(3H，s)，3.48(2H，m)，3.73(1H，m)，3.94(3H，s)，4.42(1H，m)，4.84(1H，m)，7.46-7.50(2H，m)，7.70(1H，brs)，7.99(1H，brs)，8.36-8.41(2H，m)；HPLCrt(min)：9.85；MS(ES⁺)549。

Example 253：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -3-methoxy-N- (pyrrolidin-1-yl) benzamide (I-253)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.66-0.68(2H，m)，0.90-0.91(2H，m)，1.49(2H，m)，1.50-1.54(2H，m)，1.60-1.61(2H，m)，1.64-1.78(4H，m)，1.88(2H，m)，2.95(4H，m)，3.17(3H，s)，3.48(2H，m)，3.94(3H，s)，4.84(1H，m)，7.41(2H，m)，7.69(1H，s)，7.99(1H，s)，8.40(1H，m)，9.28(1H，s)；HPLCrt(min)：9.20；MS(ES⁺)506。

Example 254：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1- (hydroxymethyl) cyclopentyl) -3-methoxybenzamide (I-254)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.52-1.78(12H, m), 1.83-1.92(2H, m), 1.95-2.05(2H, m), 3.19(3H, s), 3.38(2H, s), 3.58(2H, d), 3.94(3H, s), 4.89(1H, t), 5.19(1H, quintuple), 7.44-7.46(2H, m), 7.63(1H, s), 7.68(1H, s), 7.99(1H, s), 8.36(1H, d); hplcrt (min): 10.10; MS (ES)⁺)537。

Example 255：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (pyridin-2-ylmethyl) benzamide (I-255)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.08(6H, s), 1.54-1.67(4H, m), 1.68-1.78(2H, m), 1.85-1.93(2H, m), 3.16(3H, s), 3.38(2H, s), 3.95(3H, s), 4.57(2H, d), 5.19(1H, quintuple), 7.25-7.28(1H, m), 7.32(1H, d), 7.57(1H, d), 7.58(1H, s), 7.74(1H, s), 7.76(1H, t), 8.00(1H, s), 8.41(1H, d), 8.51(1H, d), 9.04(1H, 1H)，t)；HPLC rt(min)：9.60；MS(ES⁺)530。

Example 256：

9-cyclopentyl-2- (4- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyphenylamino) -5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-256)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.55-1.95(8H, m), 3.19(3H, s), 3.38(2H, s), 3.65(4H, s), 3.92(3H, s), 5.20(1H, quintuple), 7.42(1H, d)7.50(1H, s), 7.71(1H, s), 7.99(1H, s), 8.38(1H, d); hplcrt (min): 9.06; MS (ES)⁺)464。

Example 257：

9-cyclopentyl-2- (4- (5, 5-dimethyl-4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyphenylamino) -5, 7, 7-trimethyl-8, 9-dihydro-5H-pyrimido [4, 5-b][1，4]Diaza derivatives-6(7H) -one (I-257)

Prepared according to method D using appropriate reagents. NMR DMSO D⁶1.09(6H, s), 1.24(6H, s), 1.55-1.95(8H, m), 3.18(3H, s), 3.32(2H, s), 3.38(2H, s), 3.92(3H, s), 5.18(1H, quintuple), 7.38(1H, dd)7.46(1H, s), 7.67(1H, s), 7.99(1H, s), 8.36(1H, d); hplcrt (min): 9.43; MS (ES)⁺)492。

Example 258：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 3R) -3- (hydroxycyclopentyl) -3-methoxybenzamide (I-258)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.87(6H, s), 1.21-1.31(2H, m), 1.37-1.53(7H, m), 1.60-1.74(4H, m), 1.80-1.87(1H, m), 2.96(3H, s), 3.16(2H, s), 3.72(3H, s), 4.00(1H, brs), 4.23(1H, dd), 4.31(1H, d), 4.96(1H, quintuple), 7.23(1H, d), 7.25(1H, s), 7.46(1H, s), 7.77(1H, s), 7.91(1H, d), 8.13(1H, d); hplcrt (min): 9.20; MS (BS)⁺)523。

Example 259：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 3R) -3- (hydroxycyclopentyl) methyl) -3-methoxybenzamide (I-259)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.09(6H, s), 1.18-1.27(1H, m), 1.34-1.47(2H, m), 1.57-1.69(5H, m), 1.72-.93(6H, m), 2.33-2.41(1H, m), 3.19(3H, s), 3.34(2H, s), 3.39(2H, s), 3.94(3H, s), 4.14(1H, brd), 4.38(1H, d), 5.18(1H, quintuple), 7.47(1H, d), 7.50(1H, s), 7.69(1H, s), 7.99(1H, s), 8.35-8.37(2H, m); HPLCrt(min)：9.30；MS(ES⁺)537。

Example 260：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 3R) -3- (hydroxymethyl) cyclopentyl) -3-methoxybenzamide (I-260)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.08(6H, s), 1.23-1.29(1H, m), 1.50-1.68(6H, m), 1.70-1.76(2H, m), 1.78-1.98(5H, m), 2.16-2.24(1H, m), 3.19(3H, s), 3.30(2H, t), 3.38(2H, s), 3.94(3H, s), 4.22-4.28(1H, m), 4.55(1H, t), 5.18(1H, quintuple), 7.46(1H, d), 7.47(1H, s), 7.68(1H, s), 7.99(1H, s), 8.13(1H, d), 8.35(1H, d); hplcrt (min): 9.40; MS (ES)⁺)537。

Example 261：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (4-methoxyphenyl) benzamide (I-261)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H, s), 1.56-1.69(4H, m), 1.70-1.79(2H, m), 1.83-1.93(2H, m), 3.19(3H, s), 3.39(2H, s), 3.75(3H, s), 3.98(3H, s), 5.21(1H, quintuple), 6.93(2H, d), 7.59-7.66 (3H, s) ((2H, s))4H，m)，7.76(1H，s)，8.01(1H，s)，8.44(1H，d)，9.98(1H，s)；HPLCrt(min)：10.19；MS(ES⁺)545。

Example 262：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- (3-hydroxypropyl) -3-methoxybenzamide (I-262)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.67(2H，m)，0.90(2H，m)，1.50-1.71(6H，m)，1.89-1.91(2H，m)，3.17(3H，s)，3.29-3.34(4H，m)，3.44-3.47(4H，m)，3.94(3H，s)，4.50(1H，m)，4.84(1H，m)，7.46-7.50(2H，m)，7.69(1H，s)，7.99(1H，s)，8.35-8.41(2H，m)；HPLC rt(min)：8.58；MS(ES⁺)495。

Example 263：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N-isopropyl-3-methoxybenzamide (I-263)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.67(2H，m)，0.90(2H，m)，1.17(3H，s)，1.18(3H，s)，1.50-1.70(6H，m)，1.80(2H，m)，3.17(3H，s)，3.48(2H，s)，3.95(3H，s)，，4.10(1H，m)，4.85(1H，m)，7.49(2H，m)，7.69(1H，s)，7.99(1H，s)，8.10(1H，d)，8.40(1H，d)；HPLCrt(min)：9.58；MS(ES⁺)479。

Example 264：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2-hydroxyethyl) -3-methoxybenzamide (I-264)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.19(6H, s), 1.52-1.67(4H, m), 1.69-1.81(2H, m), 1.82-1.94(2H, m), 3.19(3H, s), 3.30-3.34(2H, brm), 3.38(2H, s), 3.48-3.53(2H, m), 3.94(3H, s), 4.75(1H, t), 5.18(1H, quintuple), 7.49(1H, d), 7.51(1H, s), 7.69(1H, s), 7.99(1H, s), 8.35(1H, s), 8.37(1H, d); hplcrt (min): 8.87; MS (ES)⁺)483。

Example 265：

(S) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1- (hydroxypropan-2-yl) -3-methoxybenzamide (I-265)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.10(6H，s)，1.14(3H，d)，1.52-1.67(4H，m)，1.69-1.81(2H，m)，1.82-1.94(2H，m)，3.19(3H，s)，3.31-3.34(1H，m)，3.38(2H，s)，344-3.50(1H, m), 3.95(3H, s), 3.99-4.06(1H, m), 4.74(1H, t), 5.19(1H, quintuple), 7.49(1H, d), 7.50(1H, s), 7.69(1H, s), 7.96(1H, s), 7.99(1H, s), 8.37(1H, d); hplcrt (min): 9.15 of; MS (ES)⁺)497。

Example 266：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (1- (hydroxymethyl) cyclopentyl) -3-methoxybenzamide (I-266)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.65-0.72(2H，m)，0.75-0.80(2H，m)，1.09(6H，s)，1.57-1.94(8H，m)，3.18(3H，s)，3.38(2H，s)，3.53(2H，d)，3.93(3H，s)，4.80(1H，t)，5.18(1H，dt)，7.50(1H，d)，7.52(1H，s)，7.68(1H，s)，7.99(1H，s)，8.37(1H，d)，8.61(1H，s)；HPLCrt(min)：9.26；MS(ES⁺)510，(ES^-)508。

Example 267：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1S, 4S) -4-fluorocyclohexyl) -3-methoxybenzamide (I-267)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.55-1.79(12H，m)，1.85-2.02(4H，m)，3.19(3H，s)，3.38(2H，s)，3.85-3.94(1H，m)，3.94(3H，s)，4.85(1H，d)，5.19(1H，dt)，7.49(1H，d)，7.50(1H，s)，7.69(1H，s)，7.99(1H，s)，8.13(1H，d)，8.37(1H，d)；HPLCrt(min)：10.17；MS(ES⁺)540，(ES^-)538。

Example 268：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- ((1R, 2R) -2-hydroxycyclohexyl) -3-methoxybenzamide (I-268)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.09(6H，s)，1.19-1.30(4H，m)，1.55-1.79(8H，m)，1.81-1.96(4H，m)，3.19(3H，s)，3.38(2H，m)，3.38-3.48(1H，m)，3.56-3.67(1H，m)，3.95(3H，s)，4.62(1H，d)，5.19(1H，dt)，7.49(1H，d)，7.51(1H，s)，7.69(1H，s)，7.98(1H，d)，7.99(1H，s)，8.37(1H，d)；HPLCrt(min)：9.74；MS(ES⁺)538，(ES^-)536。

Example 269：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- (3, 3-difluorocyclobutyl) -3-methoxybenzamide (I-269)

Using appropriate reagent rootsPrepared according to procedure E. NMR DMSOD⁶0.63-0.71(2H，m)，0.87-0.93(2H，m)，1.44-1.76(6H，m)，1.84-1.94(2H，m)，2.70-2.82(2H，m)，2.90-3.02(2H，m)，3.17(3H，s)，3.48(2H，s)，3.95(3H，s)，4.23-4.31(1H，m)，4.85(1H，dt)，7.48(1H，d)，7.49(1H，s)，7.72(1H，s)，7.99(1H，s)，8.43(1H，d)，8.66(1H，d)；HPLC rt(min)：9.75；MS(ES⁺)528，(ES^-)526。

Example 270：

(S) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2-hydroxypropyl) -3-methoxybenzamide (I-270)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.06(3H，d)，1.14(6H，s)，1.54-1.78(6H，m)，1.82-1.94(2H，m)，3.13-3.24(2H，m)，3.16(3H，s)，3.38(2H，s)，3.73-3.82(1H，m)，3.95(3H，s)，4.77(1H，d)，5.18(1H，dt)，7.50(1H，d)，7.52(1H，s)，7.69(1H，s)，7.99(1H，s)，8.30-8.40(2H，m)；HPLCrt(min)：9.10；MS(ES⁺)498，(ES^-)496。

Example 271：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- (1-hydroxy-2-methylpropan-2-yl) -3-methoxybenzamide (I-271)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.66-0.69(2H，m)，0.89-0.92(2H，m)，1.32(6H，s)，1.48-1.69(6H，m)，1.89(2H，m)，3.17(3H，s)，3.44-3.48(2H，m)，3.51-3.52(2H，m)，3.95(3H，s)，4.85(1H，m)，4.96(1H，m)，7.42-7.43(3H，m)，7.68(1H，s)，7.99(1H，s)，8.38(1H，d)；HPLCrt(min)：9.23；MS(ES⁺)510，(ES^-)508。

Example 272：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- ((1R, 2R) -2-hydroxycyclopentyl) -3-methoxybenzamide (I-272)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶0.67(2H，m)，0.90(2H，m)，1.49-1.50(2H，m)，1.55-1.68(8H，m)，1.86-1.89(3H，m)，2.00-2.01(1H，m)，3.17(3H，s)，3.48(2H，m)，3.95(3H，s)，3.97-4.00(2H，m)，4.80(1H，m)，4.85(1H，m)，7.47-7.49(2H，m)，7.69(1H，s)，7.99(1H，s)，8.11(1H，m)，8.39(1H，d)；HPLCrt(min)：9.16；MS(ES⁺)522，(ES^-)520。

Example 273：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxy-N- (3, 3, 3-trifluoro-2-hydroxypropyl) benzamide (I-278)

Prepared according to method E using appropriate reagents. NMR DMSO D⁶1.09(6H，s)，1.57-1.94(8H，m)，3.19(3H，s)，3.21-3.28(1H，m)，3.38(2H，s)，3.59-3.68(1H，m)，3.94(3H，s)，4.12-4.24(1H，m)，5.18(1H，dt)，6.54(1H，d)，7.52(1H，d)，7.53(1H，s)，7.72(1H，s)，7.99(1H，s)，8.39(1H，d)，8.65(1H，t)；HPLCrt(min)：9.67；MS(ES⁺)552，(ES^-)550。

Example 274：

4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -N- (2-fluoroethyl) -3-methoxybenzamide (I-279)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.09(6H，s)，1.55-1.80(6H，m)，1.82-1.93(2H，m)，3.19(3H，s)，3.38(2H，s)，3.53(1H，q)，3.60(1H，q)，3.94(3H，s)，4.48(1H，t)，4.60(1H，t)，5.18(1H，dt)，7.52(1H，d)，7.53(1H，s)，7.71(1H，s)，7.99(1H，s)，8.39(1H，d)，8.61(1H，t)；HPLCrt(min)：9.54；MS(ES⁺)486，(ES^-)484。

Example 275：

3- (4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzamido) propanBase acetate (I-273)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.15(6H，s)，1.58-1.70(8H，m)，1.83-1.87(2H，m)，2.01(3H，s)，3.18(3H，s)，3.33-3.37(2H，m)，3.47-3.52(2H，m)，3.94(3H，s)，4.04-4.08(2H，m)，5.11(1H，m)，7.52(1H，d)，7.59(1H，s)，8.03(2H，m)，8.54(1H，m)，9.28(1H，brs)；HPLCrt(min)：9.64；MS(ES⁺)540，(ES^-)538。

Example 276：

(1r, 4r) -4- (4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b)][1，4]Diaza derivatives-2-ylamino) -3-methoxybenzoylamino) cyclohexyl acetate (I-280)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶1.14(6H，s)，1.44-1.96(15H，m)，2.00(3H，s)，3.17(3H，s)，3.50(3H，s)，3.82(1H，m)，3.95(3H，s)，4.59(1H，m)，5.13(1H，m)，7.50-7.55(2H，m)，8.01(1H，s)，8.08(1H，d)，8.20(1H，d)，9.00(1H，brs)；HPLC rt(min)：10.04；MS(ES⁺)580，(ES^-)578。

Example 277：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylAmino) -N- ((1s, 4s) -4-fluorocyclohexyl) -3-methoxybenzamide (I-281)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.63-0.71(2H，m)，0.86-0.94(2H，m)，1.47-1.99(16H，m)，3.17(3H，s)，3.47(2H，s)，3.83-3.91(1H，m)，3.95(3H，s)，4.78-4.89(2H，m)，7.49(1H，d)，7.50(1H，s)，7.69(1H，s)，7.99(1H，s)，8.13(1H，d)，8.39(1H，d)；HPLC rt(min)：9.88；MS(ES⁺)538，(ES^-)536。

Example 278：

4- (9 '-cyclopentyl-5' -methyl-6 '-oxo-5', 6 ', 8', 9 '-tetrahydrospiro [ cyclopropane-1, 7' -pyrimido [4, 5-b ]][1，4]Diaza derivatives]-2' -ylamino) -N- ((1R, 3R) -3-hydroxycyclopentyl) -3-methoxybenzamide (I-282)

Prepared according to method E using appropriate reagents. NMR DMSOD⁶0.63-0.69(2H，m)，0.86-0.93(2H，m)，1.43-1.75(9H，m)，1.83-2.09(5H，m)，3.17(3H，s)，3.48(2H，s)，3.94(3H，s)，4.19-4.26(1H，m)，4.46(1H，dt)，4.53(1H，d)，4.85(1H，dt)，7.46(1H，d)，7.48(1H，s)，7.69(1H，s)，7.99(1H，s)，8.14(1H，d)，8.39(1H，d)；HPLCrt(min)：8.83；MS(ES⁺)522，(ES^-)520。

Example 279: plk1 assay

The compounds of the invention can be evaluated as human Plk kinase inhibitors using the following assay.

Plk1 inhibition assay：

Compounds can be screened for their ability to inhibit Plk1 using a radioactive phosphate binding assay. At 25mM HEPES (pH7.5), 10mM MgC l₂The assay was performed in a mixture with 1mM DTT. The final substrate concentration was 50. mu.M [ gamma. -33P ]]ATP (136mCi33P ATP/mmolATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 10. mu.M peptide (SAM68 protein. DELTA. 332-443). The assay was performed in the presence of 15nM P lk1(A20-K338) at 25 ℃. Assay stock buffer solutions were prepared containing all reagents as listed above, with the exception of ATP and the test compound of interest. 30 μ L of stock solution was placed in 96-well plates followed by the addition of 2 μ L of DMSO stock solution, containing serial dilutions of test compound (usually starting at a final concentration of 10 μ M, in 2-fold serial dilutions), in duplicate (final DMSO concentration 5%). The plates were preincubated at 25 ℃ for 10 min, and 8. mu.L of [ gamma. -33P ] was added]ATP (final concentration 50. mu.M) initiates the reaction.

After 60 minutes, 100. mu. L0.14M phosphoric acid was added to terminate the reaction. The multi-sieve phosphocellulose filter 96-well plates (Millipore, Cat No. maphnob50) were pre-treated with 100 μ L0.2M phosphoric acid, followed by the addition of 125 μ L of the terminated assay mixture. Plates were washed with 4x200 μ L0.2M phosphoric acid. After drying, 100 μ L of 0pt iphase 'Supermix' liquid Scintillation cocktail reagent (Perkin Elmer) was added to the wells, followed by Scintillation counting (1450Mi crebotataliquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis of the initial rate data using the Prism Software package (GraphPad Prism version3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

Plk1 inhibition assay：

Compounds were screened for their ability to inhibit Plk1 using a radioactive phosphate binding assay. In 25mM HEPES (pH7.5), 10mM MgCl₂0.1% BSA in a mixture with 2mM DTT. Finally, the product is processedThe substrate concentration of (2) was 150. mu.M (for<1nM of 350. mu.M [ gamma. -33P ]]ATP (115mCi33P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300. mu.M (for<1nM determination 450. mu.M) peptide (KKKISDELMDATFADQEAK). At 25 ℃ at 4nM (for<1nM determination 1nM) in the presence of Plk 1. Assay stock buffer solutions were prepared containing all reagents as listed above, with the exception of ATP and the test compound of interest. 30 μ L of stock solution was placed in 96-well plates followed by the addition of 2 μ L of DMSO stock solution, containing serial dilutions of test compound (usually starting at a final concentration of 10 μ M, in 2-fold serial dilutions), in duplicate (final DMSO concentration 5%). The plates were preincubated at 25 ℃ for 10 min, and 8. mu.L of [ gamma. -33P ] was added]ATP (final concentration 150. mu.M for<A determination of 350. mu.M at 1nM) elicited a response.

The reaction was stopped after 90 min (240 min for <1nM determinations) by adding 100. mu. L0.14M phosphoric acid. The multi-sieve phosphocellulose filter 96-well plates (Millipore, cat No. maphnob50) were pre-treated with 100 μ L0.2M phosphoric acid, followed by the addition of 125 μ L of the terminated assay mixture. Plates were washed with 4x200 μ L0.2M phosphoric acid. After drying, 100 μ L Optiphase 'Supermix' Liquid Scintillation cocktail reagent (PerkinElmer) was added to the wells, followed by Scintillation counting (1450Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis of the initial rate data using the Prism Software package (GraphPad Prism version3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In general, the compounds of the invention are effective in terms of inhibition of Plk 1. The following compounds showed Ki below 10nM in the radioactive binding assay: i-2, I-5, I-4, I-6, I-9, I-11, I-12, I-16, I-17, I-18, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-31, I-32, I-33, I-34, I-36, I-37, I-38, I-39, I-47, I-48, I-51, I-52, I-53, I-58, I-59, I-60, I-62, I-64, I-67, I-68, I-69, I-70, I-71, I-72, I-73, i-74, I-75, I-76, I-77, I-80, I-85, I-87, I-93, I-94, I-95, I-96, I-99, I-101, I-103, I-104, I-105, I-108, I-113, I-118, I-119, I-123, I-129, I-130, I-131, I-132, I-133, I-134, I-135, I-136, I-157, I-158, I-163, I-166, I-167, I-169, I-170, I-171, I-172, I-173, I-174, I-175, I-176, I-177, i-178, I-179, I-180, I-181, I-182, I-183, I-184, I-185, I-186, I-187, I-190, I-191, I-192, I-193, I-194, I-195, I-196, I-197, I-198, I-199, I-200, I-201, I-202, I-203, I-204, I-205, I-206, I-207, I-208, I-209, I-210, I-211, I-212, I-213, I-214, I-216, I-217, I-218, I-219, I-220, I-221, I-222, I-223, i-224, I-225, I-226, I-227, I-228, I-229, I-230, I-231, I-232, I-233, I-234, I-235, I-236, I-237, I-238, I-239, I-240, I-241, I-242, I-243, I-244, I-245, I-246, I-247, I-248, I-249, I-250, I-251, I-252, I-253, I-254, I-255, I-256, I-257, I-258, I-259, I-260, I-261, I-262, I-263, I-264, I-265, I-266, i-267, I-268, I-269, I-270, I-271, I-272, I-273, I-278, I-279, I-280, I-282. The following compounds showed Ki between 10nM and 100nM in the radioactive binding assay: i-1, I-3, I-7, I-8, I-10, I-14, I-15, I-19, I-20, I-30, I-35, I-40, I-42, I-43, I-44, I-45, I-46, I-49, I-50, I-56, I-63, I-65, I-66, I-78, I-79, I-81, I-86, I-89, I-90, I-91, I-92, I-97, I-98, I-102, I-109, I-110, I-111, I-112, I-114, I-116, I-117, I-120, I-122, i-124, I-125, I-137, I-138, I-139, I-141, I-143, I-144, I-145, I-147, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-156, I-159, I-160, I-161, I-162, I-164, I-165, I-168, I-188, I-192, I-215. The following compounds showed Ki's between 100nM and 4 μ M in the radioactive binding assay: i-29, I-41, I-54, I-55, I-57, I-61, I-82, I-83, I-84, I-88, I-100, I-106, I-115, I-121, I-127, I-128, I-140, I-146, I-148, I-189. The following compounds were insoluble under the assay conditions: i-126 and I-142. The following compounds were not active within the assay limits: i-13 and I-107.

Plk2 inhibition assay：

Compounds can be screened for their ability to inhibit Plk2 using a radioactive phosphate binding assay. In 25mM HEPES (pH7.5), 10mM MgCl₂0.1% BSA in a mixture with 2mM DTT. The final substrate concentration was 200. mu.M [ gamma. -33P ]]ATP (57mCi33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300. mu.M peptide (KKKISDELMDATFADQEAK). The assay was performed in the presence of 25 nMLPlk 2 at 25 ℃. Assay stock buffer solutions were prepared containing all reagents as listed above, with the exception of ATP and the test compound of interest. 30 μ L of stock solution was placed in 96-well plates followed by the addition of 2 μ L of DMSO stock solution, containing serial dilutions of test compound (usually starting at a final concentration of 10 μ M, in 2-fold serial dilutions), in duplicate (final DMSO concentration 5%). The plates were preincubated at 25 ℃ for 10 min, and 8. mu.L of [ gamma. -33P ] was added]ATP (final concentration 200. mu.M) initiated the reaction.

After 90 minutes, 100. mu. L0.14M phosphoric acid was added to terminate the reaction. The multi-sieve phosphocellulose filter 96-well plates (Millipore, cat No. maphnob50) were pre-treated with 100 μ L0.2M phosphoric acid, followed by the addition of 125 μ L of the terminated assay mixture. Plates were washed with 4x200 μ L0.2M phosphoric acid. After drying, 100 μ L of Opt iphase 'Supermix' liquid Scintillation cocktail reagent (Perkin Elmer) was added to the wells, followed by Scintillation counting (1450Microbetaliquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis of the initial rate data using the Prism Software package (GraphPad Prism version3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

Plk3 inhibition assay：

Compounds can be screened for their ability to inhibit Plk3 using a radioactive phosphate binding assay. At 25mM HEPES (pH7.5), 10mM MgC l₂With 1mM DTT mixtures were measured. The final substrate concentration was 75. mu.M [ gamma. -33P ]]ATP (60mCi33P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 10. mu.M peptide (SAM68 protein. DELTA. 332-443). The assay was performed in the presence of 5nM Plk3(S38-A340) at 25 ℃. Assay stock buffer solutions were prepared containing all reagents as listed above, with the exception of ATP and the test compound of interest. 30 μ L of stock solution was placed in 96-well plates followed by addition of 2 μ L of LDMSO stock, containing serial dilutions of test compound (usually starting at a final concentration of 10 μ M, diluted in 2-fold serial dilutions), in duplicate (final DMSO concentration 5%). The plates were preincubated at 25 ℃ for 10 min, and 8. mu.L of [ gamma. -33P ] was added]ATP (final concentration 75. mu.M) initiated the reaction.

After 60 minutes, 100. mu. L0.14M phosphoric acid was added to terminate the reaction. The multi-sieve phosphocellulose filter 96-well plates (Millipore, Cat No. maphnob50) were pre-treated with 100 μ L0.2M phosphoric acid, followed by the addition of 125 μ L of the terminated assay mixture. Plates were washed with 4x200 μ L0.2M phosphoric acid. After drying, 100 μ L of Opt iphase 'Supermix' liquid Scintillation cocktail reagent (Perkin Elmer) was added to the wells, followed by Scintillation counting (1450Microbetaliquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from a non-linear regression analysis of the initial rate data using the Prism Software package (GraphPad Prism version3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

Plk4 inhibition assay：

Compounds can be screened for their ability to inhibit Plk4 using a radioactive phosphate binding assay. At 8mM OPS (pH7.5), 10mM MgC l₂0.1% BSA in a mixture with 2mM DTT. The final substrate concentration was 15. mu.M [ gamma. -33P ]]ATP (227mCi33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300. mu.M peptide (KKKMDATFADQ). The assay was performed in the presence of 25nM Plk4 at 25 ℃. Preparation of an assay stock buffer solution containing all the reagents, ATP, as listed aboveAnd with the exception of the test compound. 30 μ L of stock solution was placed in 96-well plates followed by addition of 2 μ L of LDMSO stock, containing serial dilutions of test compound (usually starting at a final concentration of 10 μ M, diluted in 2-fold serial dilutions), in duplicate (final DMSO concentration 5%). The plates were preincubated at 25 ℃ for 10 min, and 8. mu.L of [ gamma. -33P ] was added]ATP (final concentration 15. mu.M) initiated the reaction.

After 180 minutes, 100. mu. L0.14M phosphoric acid was added to terminate the reaction. The multi-sieve phosphocellulose filter 96-well plates (Millipore, Cat No. maphnob50) were pre-treated with 100 μ L0.2M phosphoric acid, followed by the addition of 125 μ L of the terminated assay mixture. Plates were washed with 4x200 μ L0.2M phosphoric acid. After drying, 100 μ L Optiphase 'Supermix' Liquid Scintillation cocktail reagent (Perkin Elmer) was added to the wells followed by Scintillation counting (1450Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis of the initial rate data using the Prism Software package (GraphPad Prism version3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

While we have described a number of embodiments of this invention, it is apparent that our basic examples can be altered to provide other embodiments that employ or encompass the compounds, methods, and processes of this invention. It is, therefore, to be understood that the scope of the invention is to be limited by the claims rather than by the specific embodiments represented by the examples.

Claims (43)

1. A compound of formula I:

wherein

X¹Is a valence bond, O, NR⁸Or S, SO or SO₂；

Y¹Is O or NR⁹；

R¹Is H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; wherein said R¹Optionally by 0-5J¹Substitution; with the proviso that when X¹When it is a valence bond, R¹Is not H;

R²is H, C_1-10Aliphatic radical, - (C)_1-10Aliphatic radical) - (C_3-10Cycloaliphatic radical), C_3-8Cycloaliphatic radicals, halogen C_1-4An aliphatic group; wherein said R²Optionally by 0-4J²Substitution;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl or 5-10 membered heteroaryl; wherein each R³、R⁴、R⁵And R⁶Optionally and independently by 0-5J, respectively³、J⁴、J⁵And J⁶Substitution;

R⁷is H, C (O) R, C (O) OR OR C (O) NRR', C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, - (C)_1-6Aliphatic radical) - (C_3-10Cycloaliphatic group), - (C)_1-6Aliphatic radical) - (C_6-10Aryl) or- (C)_1-6Aliphatic group) - (5-10 membered heteroaryl) or- (C_1-6Aliphatic group) - (3-6 membered heterocyclyl; wherein said R⁷Optionally by 0-5J⁷Substitution;

or

R³And R⁴Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the carbon atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁴The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁴Substitution;

R⁵and R⁶Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the carbon atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R⁵And R⁶The rings constituting the monocyclic ring are optionally substituted with 0-4J 56;

R³and R⁵Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the carbon atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁵The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁵Substitution;

R³and R⁷Optionally forming a 4-8 membered saturated or partially unsaturated monocyclic ring together with the atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R³And R⁷The rings constituting the monocyclic ring are optionally substituted by 0-4J³⁷Substitution;

R⁵and R⁷Optionally forming a 3-8 membered saturated or partially unsaturated monocyclic ring together with the atoms to which they are attached, containing 0-4 heteroatoms independently selected from O, N and S; said is prepared from R⁵And R⁷The rings constituting the monocyclic ring are optionally substituted by 0-4J⁵⁷Substitution;

R⁸is H, C_1-6Aliphatic radical, C_3-8Cycloaliphatic, C (O) R, C (O) OR OR C (O) NRR';

R⁹is H or unsubstituted C_1-6An aliphatic group; or

R²And R⁹Optionally forming a 5-8 membered aromatic or non-aromatic monocyclic ring together with the atoms to which they are attached, containing 2-4 heteroatoms independently selected from O, N and S; said is prepared from R²And R⁹The rings constituting the monocyclic ring are optionally substituted by 0-4J²⁹Substitution;

each J¹Independently is C_1-6Haloalkyl, halo, NO₂CN, Q or-Z-Q; or, two J¹Together may optionally form ═ O;

z is C_1-6Aliphatic radicals, optionally substituted by 0 to 3 occurrences of-NR-, -O-, -S-, -C (O) -, -C (═ NR) -, -C (═ NOR) -, -SO-or-SO₂-substitution; each Z is optionally substituted by 0-2J^ZSubstitution;

q is H; c_1-6An aliphatic group; a 3-8 membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N and S; or a 7-12 membered aromatic or non-aromatic bicyclic ring system having 0-5A heteroatom independently selected from O, N and S; each Q is optionally substituted by 0-5J^QSubstitution;

each J²Is halo or halo C_1-4An aliphatic group;

each J³、J⁴、J⁵And J⁶Independently is C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical or- (C)_1-4Alkyl radical)_n-V¹(ii) a Wherein

n is 0 or 1;

V¹is halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), halogeno group, NO₂、CN、OH、OR”、SH、SR”、NH₂、NHR”、N(R”)₂、COH、COR”、CO₂H、CO₂R”、CONH₂、CONHR”、CONR”₂、OCOR”、OCONH₂、OCONHR”、OCON(R”)₂、NHCOR”、NR”COR”、NHCO₂R”、NR”CO₂R”、NHCO₂H、NR”CO₂H、NHCONH₂、NHCONHR”、NHCON(R”)₂、SO₂NH₂、SO₂NHR”、SO₂N(R”)₂、NHSO₂R”、NR”SO₂R”；

Or V¹Is a cyclic group selected from C_3-6A cycloaliphatic, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl; wherein the cyclic group is optionally substituted with 0-3J^VSubstitution;

r' is unsubstituted C_1-4An aliphatic group;

or two identical J's bound to the same atom³、J⁴、J⁵Or J⁶Together may optionally form ═ O;

each J^ZAnd J^VIndependently is halo, C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical, NO₂、CN、-NH₂、-NH(C_1-4Aliphatic group), -N (C)_1-4Aliphatic radical)₂、-OH、-O(C_1-4Aliphatic group), -CO₂H、-CO₂(C_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group) or halo (C)_1-4Aliphatic groups);

each J^Q、J⁷、J²⁹、J³⁴、J⁵⁶、J³⁵、J³⁷And J⁵⁷Independently is M or-Y-M;

each Y is independently unsubstituted C_1-6Aliphatic radicals, optionally substituted by 0 to 3 occurrences of-NR-, -O-, -S-, -C (O) -, -SO-or-SO₂-substitution;

each M is independently H, C_1-6Aliphatic radical, C_3-6Cycloaliphatic, halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), 3-6 membered heterocyclic group, C_6-10Aryl, halo, NO₂、CN、OH、OR’、SH、SR’、NH₂、NHR’、N(R’)₂、COH、COR’、CO₂H、CO₂R’、CONH₂、CONHR’、CONR’₂、OCOR’、OCONH₂、OCONHR’、OCON(R’)₂、NHCOR’、NR’COR’、NHCO₂R’、NR’CO₂R’、NHCO₂H、NR’CO₂H、NHCONH₂、NHCONHR’、NHCON(R’)₂、SO₂NH₂、SO₂NHR’、SO₂N(R’)₂、NHSO₂R 'or NR' SO₂R', or two M together may optionally form ═ O;

r is H or unsubstituted C_1-6An aliphatic group;

r' is unsubstituted C_1-6An aliphatic group; or two R' groups together with the atoms to which they are bonded form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N and S.

2. The compound of claim 1, wherein:

R¹is H, C_1-10Aliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; wherein said R¹Optionally by 0-5J¹Substitution; with the proviso that when X¹When it is a valence bond, R¹Is not H;

R⁷is H, C (O) R, C (O) OR OR C (O) NRR', C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, - (C)_1-6Aliphatic radical) - (C_3-10Cycloaliphatic group), - (C)_1-6Aliphatic radical) - (C_6-10Aryl) or- (C)_1-6Aliphatic group) - (5-10 membered heteroaryl); wherein said R⁷Optionally by 0-5J⁷Substitution;

q is H; c_1-6An aliphatic group; a 3-8 membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N and S; or an 8-12 membered aromatic or non-aromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N and S; each Q is optionally substituted by 0-5J^QSubstitution; and

each M is independently H, C_1-6Aliphatic radical, C_3-6Cycloaliphatic, halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), 3-6 membered heterocyclic group, halogeno group, NO₂、CN、OH、OR’、SH、SR’、NH₂、NHR’、N(R’)₂、COH、COR’、CO₂H、CO₂R’、CONH₂、CONHR’、CONR’₂、OCOR’、OCONH₂、OCONHR’、OCON(R’)₂、NHCOR’、NR’COR’、NHCO₂R’、NR’CO₂R’、NHCO₂H、NR’CO₂H、NHCONH₂、NHCONHR’、NHCON(R’)₂、SO₂NH₂、SO₂NHR’、SO₂N(R’)₂、NHSO₂R 'or NR' SO₂R’。

3. The compound of claim 2, wherein X¹Is NR⁸。

4. The compound of claim 2, wherein Y is¹Is O.

5. The compound of claim 4, wherein R¹Is C_6-10Aryl or 5-10 membered heteroaryl, wherein R¹Is provided with 0-5J¹And (4) substitution.

6. The compound of claim 5, wherein R²Is C_1-10Aliphatic radicals or C_3-10Cycloaliphatic radical, in which R is²Is covered with 0-4J²And (4) substitution.

7. The compound of claim 6, wherein R²is-CH₃。

8. The compound of claim 6, wherein R³And R⁴Form a 3-6 membered monocyclic ring together with the carbon atom to which they are attached, is substituted with 0-5R³Or R⁴And (4) substitution.

9. The compound of claim 6, wherein R³And R⁵Form a 3-6 membered monocyclic ring together with the carbon atom to which they are attached, is substituted with 0-5R³Or R⁵And (4) substitution.

10. The compound of claim 6, wherein each R³、R⁴、R⁵And R⁶Independently is selected from H, C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl or 5-10 membered heteroaryl, wherein each R³、R⁴、R⁵And R⁶Independently by 0-5J respectively³、J⁴、J⁵And J⁶And (4) substitution.

11. The compound of claim 6, wherein each R³And R⁴Independently is H, C_1-6Aliphatic radicals or C_3-8Cycloaliphatic radical, in which each R is³And R⁴Independently by 0-5J respectively³And J⁴And (4) substitution.

12. The compound of claim 6, wherein R³And R⁴One of them is H, and the other is H,the other is C_1-6Aliphatic radicals or C_3-8Cycloaliphatic radical, in which R is not H³And R⁴Independently by 0-5J respectively³And J⁴And (4) substitution.

13. The compound of claim 1, wherein each J³And J⁴Independently a halo group.

14. The compound of claim 1, wherein R⁵And R⁷Together with the atoms to which they are attached form a 3-6 membered saturated or partially unsaturated monocyclic ring, substituted with 0-5J⁵Or J⁷And (4) substitution.

15. The compound of claim 6, wherein R⁷Is selected from C_1-10Aliphatic radical, C_3-10Cycloaliphatic radical, C_6-10Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein R⁷Is covered with 0-5J⁷And (4) substitution.

16. The compound of claim 6, wherein R⁷Is selected from C_1-10Aliphatic radical, C_3-8A cycloaliphatic group, phenyl, 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 5-pyridazinyl, 3, 5-pyrimidinyl and 3-8 membered heterocyclyl, wherein R is⁷Is covered with 0-5J⁷And (4) substitution.

17. The compound of claim 1, wherein R⁷Is not 3-amino-2, 4-pyrimidine.

18. The compound of claim 6, wherein R⁷Is selected from C_3-6Alkyl radical, C_3-6Cycloalkyl, phenyl or a 5-6 membered heterocyclyl group, wherein said heterocyclyl group contains 1 oxygen heteroatom, wherein R⁷Is covered with 0-5J⁷And (4) substitution.

19The compound of claim 6, wherein R⁷Is C_4-5Cycloalkyl, wherein R⁷Is covered with 0-5J⁷And (4) substitution.

20. The compound of claim 6, wherein R⁷Is C_4-5Cycloalkyl, substituted by 1 or 2-F.

21. The compound of claim 6, wherein R⁷Is unsubstituted C_4-5A cycloalkyl group.

22. The compound of claim 6, wherein R⁷Is cyclopentyl, having 0 to 5J⁷And (4) substitution.

23. The compound of claim 6, wherein R⁷Is cyclopentyl, substituted by 1 or 2-F.

24. The compound of claim 6, wherein R⁷Is an unsubstituted cyclopentyl group.

25. The compound of claim 1, wherein R⁸Is H.

26. The compound of claim 1, represented by formula II:

wherein

R¹Is optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R²is H or an optionally substituted group selected from C_1-10Aliphatic radical and C_3-10A cycloaliphatic group;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radicals or C_3-10A cycloaliphatic group; wherein each R³、R⁴、R⁵And R⁶Optionally respectively 0-5J³、J⁴、J⁵And J⁶Substitution; or

R³And R⁴May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R³and R⁵May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R⁵and R⁷May form, together with the atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R²and R⁹Together with the atoms to which they are attached may form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.

27. The compound of claim 1, represented by formula III:

wherein

R¹Is optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R²is H or an optionally substituted group selected from C_1-10Aliphatic radical and C_3-10A cycloaliphatic group;

each R³、R⁴、R⁵And R⁶Independently is H, C_1-10Aliphatic radicals or C_3-10A cycloaliphatic group; wherein each R³、R⁴、R⁵And R⁶Optionally respectively 0-5J³、J⁴、J⁵And J⁶Substitution; or

R³And R⁴May be combined with the carbon atom to which they are attachedA monocyclic ring which is optionally substituted 3-6 membered saturated or partially unsaturated;

R³and R⁵May form, together with the carbon atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R⁵and R⁷May form, together with the atoms to which they are attached, an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;

R²and R⁹Together with the atoms to which they are attached may form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.

28. The compound of claim 1, wherein

Each J³、J⁴、J⁵And J⁶Independently is C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical or- (C)_1-4Alkyl radical)_n-V¹(ii) a Wherein

n is 0 or 1;

V¹is halo (C)_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group), halogeno group, NO₂、CN、OH、OR”、SH、SR”、NH₂、NHR”、N(R”)₂、COH、COR”、CO₂H、CO₂R”、CONH₂、CONHR”、CONR”₂、OCOR”、OCONH₂、OCONHR”、OCON(R”)₂、NHCOR”、NR”COR”、NHCO₂R”、NR”CO₂R”、NHCO₂H、NR”CO₂H、NHCONH₂、NHCONHR”、NHCON(R”)₂、SO₂NH₂、SO₂NHR”、SO₂N(R”)₂、NHSO₂R”、NR”SO₂R”；

R' is unsubstituted C_1-4An aliphatic group;

or two identical J's bound to the same atom³、J⁴、J⁵Or J⁶Together may optionally constitute ═ O.

29. A compound selected from the group consisting of:

30. a compound selected from the group consisting of:

31. a composition comprising a compound of any one of claims 1-30 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

32. Use of a composition according to claim 31 or a compound according to any one of claims 1 to 30 in the manufacture of a medicament for treating cancer in a patient.

33. The use of claim 32, wherein the use is for treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma or a cancer selected from colon, breast, stomach, ovary, cervix, lung, central nervous system, kidney, prostate, bladder or pancreas in a patient.

34. The use of claim 32, wherein the use is for the treatment of cancer and comprises the step of disrupting mitosis of cancer cells by administering to the subject

a) The composition of claim 31; or

b) The compound of any one of claims 1-30

Suppression of P1k 1.

35. A process for preparing a compound of formula I:

wherein

Y¹Is O, and X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

comprising reacting a compound of formula 5:

wherein

R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28; LG (Ligno-lead-acid)₂Is a halo group;

and X¹R¹The reaction is carried out in the presence of a catalyst,

wherein the content of the first and second substances,

a) if X is¹Is NHR⁸O or S, then X¹R¹By replacement of LG in the presence of a suitable base or acid, and a solvent₂To produce a compound of formula I; or

b) If X is¹Is a valence bond and R¹Bonded to X via a carbon atom¹Then the compound of formula I is generated by a cross-coupling reaction selected from Suzuki coupling, Stille coupling or Negishi coupling.

36. The method of claim 35, further comprising reacting a compound of formula 4:

wherein R is³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28; and LG₂Is a halo group;

and R²-LG₃Step of reaction wherein LG₃Is a halo group; to produce the compound of formula 5.

37. The process of claim 36, further comprising cyclizing the amine compound of formula 3-a with the carboxylic acid ester in the presence of a base or acid:

wherein LG₂Is halo, R³、R⁴、R⁵、R⁶And R⁷Is in accordance withAs defined in any one of claims 1 to 28.

38. The method of claim 37, further comprising reacting a compound of formula 3:

wherein LG₂Is halo, and R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 24;

with iron powder, SnCl₂Zinc powder, indium/HCl or H₂At least one step of reacting in Pd to produce a compound of formula 3-a.

39. The method of claim 37, further comprising

a) Amino groups and R in Compounds of formula 3-a²-LG₃Reacting to produce a compound of formula 3-b:

wherein LG₂And LG₃Is halo, and R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

b) cyclizing the amine of formula 3-b with the carboxylic acid ester in the presence of a base or acid to produce a compound of formula 4.

40. The method of claim 38, further comprising reacting a compound of formula 2:

wherein R is³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

with a compound of formula 1:

wherein LG₁And LG₂Each is halo;

in the presence of a solvent and an acid or base to produce the compound of formula 3.

41. A process for preparing a compound of formula I:

wherein Y is¹Is NR⁹And X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

comprising reacting a compound of formula I, wherein Y¹Is O, and X¹、R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

whereby the lactam group of formula I is reacted with NHR⁹Reaction to produce a compound of formula I, wherein Y¹Is NR⁹。

42. A process for preparing a compound of formula 5-a:

wherein LG₂Is halo, and R²、R³、R⁴、R⁵、R⁶、R⁷And R⁹Is as defined in any one of claims 1 to 28;

comprising reacting a compound of formula 5:

wherein LG₂Is halo, and R²、R³、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28;

whereby the lactam group of formula I is reacted with NHR⁹Reacting to generate the compound shown in the formula 5-a.

43. The method of claim 42, further comprising treating with X¹R¹Replacement of LG₂To produce a compound of formula I, wherein Y¹Is NR⁹And X¹、R¹、R²、R²、R⁴、R⁵、R⁶And R⁷Is as defined in any one of claims 1 to 28.