Pyrimidinocycle-containing derivative modulators, methods of making and use thereof

Abstract

The present application relates to pyrimidinone derivatives modulators, methods of preparation and use thereof. In particular, the present application relates to compounds of general formula (I), methods of preparation and pharmaceutical compositions containing the same, and their use as SOS1 inhibitors, in the treatment of diseases or conditions such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer, wherein the substituents in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a pyrimidine-containing cyclic derivative inhibitor, its preparation method, and its application. Background Technology

[0002] The RAS (Rat Sarcoma) protein family is encoded by the proto-oncogenes HRAS, NRAS, and KRAS, and consists of four proteins: HRAS, NRAS, KRAS4A, and KRAS4B. RAS proteins play important roles in various cellular processes. RAS exists in two main states in vivo: an inactive state bound to GDP (guanosine diphosphate) and an activated state bound to GTP (guanosine triphosphate). This process is regulated by two types of proteins: guanine nucleotide exchange factor (GEF) promotes the release of GDP from RAS proteins, enabling GTP binding and activation of RAS; and GTPase activating protein (GAP) activates the GTPase activity of RAS proteins, hydrolyzing the GTP bound to RAS proteins into GDP, thus inactivating RAS. Activated RAS protein activates downstream pathways such as CRAF, PI3K / AKT / mTOR, and RalGDS, thereby affecting various cellular functions such as survival, proliferation, metabolism, activity, and angiogenesis. RAS mutations inhibit endogenous and GAP-induced GTPase activity, leading to an increase in activated RAS-GTP, which in turn causes continuous activation of downstream pathways and subsequently triggers cancer.

[0003] RAS mutations are present in many types of cancer, with an average mutation rate of 25% in human cancers. KRAS mutations are most common in pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%).

[0004] SOS1 (Son of Sevenless 1) is an important guanylate exchanger protein. It interacts with growth factor receptor-binding protein 2 (Grb2) to form the SOS1 / Grb2 complex. Upstream receptor tyrosine kinases (RTKs) such as EGFR, HER2, FGFR, ROS, and ALK activate and phosphorylate this complex, recruiting it via its SH2 domain. The RTK / Grb2 / SOS1 complex localizes SOS1 to inactive GDP-RAS located on the plasma membrane, promoting the exchange of GDP and GTP, thereby activating RAS. SOS1 has two binding sites with RAS family proteins: a catalytic site, which binds to GDP-bound RAS family proteins to promote guanylate exchange, converting them to GTP-bound RAS proteins; and an allosteric site, which binds to GTP-bound RAS family proteins, further enhancing SOS1's catalytic function. Inhibition of SOS1 blocks its binding to KRAS, thus locking KRAS proteins in an inactive state.

[0005] While there is significant clinical need to target KRAS-mutated tumors, directly targeting RAS remains a major challenge due to the structural characteristics of the RAS protein itself. To date, no drugs directly targeting KRAS have been marketed. However, significant breakthroughs have recently been achieved with compounds targeting the KRAS G12C mutation. Amgen's AMG510 and Mirati's MRTX-849 have both entered Phase I clinical trials, showing promising early results. SOS1 inhibitors offer a novel treatment option for various KRAS-mutated cancers, attracting increasing attention. Several domestic and international companies are developing research targeting this target. Boehringer Ingelheim has made rapid progress, with its leading compound BI-1701963 already in Phase I clinical trials. Its preclinical compound BI-3406 has also shown promising in vitro and in vivo activity data, although there is still room for improvement in activity.

[0006] In summary, SOS1 inhibitors can target all KRAS-mutated tumors. With high activity and safety, SOS1 inhibitors have great therapeutic potential and broad prospects for clinical application. Summary of the Invention

[0007] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of general formula (I) has the following structure:

[0008]

[0009] in:

[0010] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -O(CH2). n R aa -OC(R) aa R bb ) n1 (CH2) n R cc -NR aa (CH2) n R bb -(CH2) n -、-(CH2) n R aa -(CH2) n OR aa -(CH2) n SR aa -(CH2) n C(O)R aa -(CH2) n C(O)OR aa -(CH2) n S(O) m R aa -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR aa C(O)R bb Or -(CH2) n NR aa S(O) m R bb The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted.

[0011] R aa R bb and R ccEach of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0012] Or, R aa R bb and R cc Any two links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, which may optionally be further substituted.

[0013] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -O(CH2). n R dd -OC(R) dd R ee ) n1 (CH2) n R ff -NR dd (CH2) n R ee -(CH2) n -、-(CH2) n R ee -(CH2) n OR dd -(CH2) n SR dd -(CH2) n C(O)R dd -(CH2) n C(O)OR dd -(CH2) n S(O) m R dd -(CH2) n NR dd R ee -(CH2) n C(O)NR dd R ee -(CH2) n NR dd C(O)R ee Or -(CH2) n NR ddS(O) m R ee The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0014] R dd R ee and R ff Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0015] Or, R dd R ee and R ff Any two links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, which may optionally be further substituted.

[0016] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -O(CH2). n R gg -OC(R) gg R hh ) n1 (CH2) n R ii -NR gg (CH2) n R hh -(CH2) n -、-(CH2) n R gg -(CH2) n OR gg -(CH2) n SR gg -(CH2) n C(O)R gg -(CH2) n C(O)OR gg -(CH2) n S(O) m R gg-(CH2) n S(O) m NR gg R hh =NR gg -(CH2) n NR gg R hh -(CH2) n C(O)NR gg R hh -(CH2) n NR gg C(O)R hh Or -(CH2) n NR gg S(O) m R hh The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0017] R gg R hh and R ii Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0018] Or, R aa R bb With R cc Any two links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, which may optionally be further substituted.

[0019] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -O(CH2). n R jj -OC(R) jj R kk ) n (CH2) m R ll -NR jj (CH2) nR kk -(CH2) n -、-(CH2) n R jj -(CH2) n OR jj -(CH2) n SR jj -(CH2) n C(O)R jj -(CH2) n C(O)OR jj -(CH2) n S(O) m R jj -(CH2) n NR jj R kk -(CH2) n C(O)NR jj R kk -(CH2) n NR jj C(O)R kk Or -(CH2) n NR jj S(O) m R hh The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted.

[0020] R jj R kk and R ll Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkathiol, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0021] Or, R jj R kk and R ll Any two links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, which may optionally be further substituted.

[0022] x is an integer from 0 to 8;

[0023] y is an integer from 0 to 5;

[0024] m is 0, 1, or 2;

[0025] n is 0, 1, 2, or 3; and

[0026] n1 can be 0, 1, 2 or 3.

[0027] In a further preferred embodiment of the present invention, a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided, the specific structure of which is as follows:

[0028]

[0029] In a preferred embodiment of the present invention Selected from

[0030] In a preferred embodiment of the present invention Selected from

[0031] In a preferred embodiment of the present invention Selected from

[0032] R a It can be arbitrarily attached to the cyclic carbon or cyclic heteroatom of ring A. When ring A is a heterocyclic group, R a It is attached to a heteroatom or a carbon atom in its neighboring position.

[0033] In a further preferred embodiment of the present invention, a compound of formula (IIa), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided, the specific structure of which is as follows:

[0034]

[0035] in:

[0036] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0037] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0038] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n R gg -OC(R) gg R hh ) n1 (CH2) n R ii -NR gg (CH2) n R hh -(CH2) n -、-(CH2) n R gg -(CH2) n OR hh -(CH2) n SR gg -(CH2) n C(O)R gg -(CH2) n C(O)OR gg -(CH2) n S(O) m R gg -(CH2) n NR gg Rhh -(CH2) n C(O)NR gg R hh -(CH2) n NR gg C(O)R hh Or -(CH2) n NR gg S(O) m R hh The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n3 R a1 -OC(R) a1 R a2 ) n3 (CH2) n4 R a3 -NR a1 (CH2) n3 R a2 -(CH2) n3 -、-(CH2) n3 R a1 -(CH2) n3 OR a1 -(CH2) n3 SRa1 -(CH2) n3 C(O)R a1 -(CH2) n3 C(O)OR a1 -(CH2) n3 S(O) m1 R a1 -(CH2) n3 NR a1 R a2 -(CH2) n3 C(O)NR a1 R a2 -(CH2) n3 NR a1 C(O)R a2 Or -(CH2) n3 NR a1 S(O) m1 R a2 One or more substituents in it are replaced;

[0039] Or, any two R a Link formation C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0040] R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0041] R gg R hh and R ii Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0042] R a1 R a2 and R a3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n5 R b1 -OC(R) b1 R b2 ) n5 (CH2) m5 R b3 -NR b1 (CH2) n5 R b2 -(CH2) n5 -、-(CH2) n5 R b1 -(CH2) n5 OR b1 -(CH2) n5 SR b1 -(CH2) n5 C(O)R b1 -(CH2) n5 C(O)OR b1 -(CH2) n5 S(O) m3 R b1 -(CH2) n5 NR b1 R b2 -(CH2) n5 C(O)NR b1 R b2 -(CH2) n5 NR b1 C(O)R b2 Or -(CH2) n5 NR b1 S(O) m3 R b2 One or more substituents in it are replaced;

[0043] R b1 R b2 and R b3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0044] x is 0, 1, 2, or 3;

[0045] y is 0, 1, 2, 3, 4 or 5;

[0046] n, n1, n2, n3, n4, and n5 are integers from 0 to 5; and

[0047] m, m1, m2 and m3 are 0, 1 or 2.

[0048] In a more preferred embodiment of the present invention, R a and The following are examples of connection methods, but they are not limited to these:

[0049]

[0050] In a further preferred embodiment of the invention, a compound of formula (IV), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided:

[0051]

[0052] in:

[0053] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n6 R mm -(CH2) n6 R mm -(CH2) n6 OR mm -(CH2) n6 SR mm -(CH2) n6 C(O)R mm -(CH2) n6 C(O)OR mm -(CH2) n6 S(O) m4 R mm -(CH2) n6 NR mm R nn -(CH2) n6 C(O)NR mm R nn -(CH2) n6 NR mm C(O)R nn Or -(CH2) n6 NR mm S(O) m4 R nn The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0054] R c Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0055] R mm and R nn Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0056] z is an integer from 0 to 8;

[0057] n6 is 0, 1, 2, or 3; and

[0058] m4 is 0, 1, or 2;

[0059] It represents a single bond or an unsaturated bond, selected from single bonds or double bonds.

[0060] In a further preferred embodiment of the invention, a compound of formula (IV-A), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided:

[0061]

[0062] in:

[0063] M is selected from NR5, -CHR5, O, S, S(O)=NH or S(O)2;

[0064] L is selected from the following: -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-, -CH=CH-, or -C≡C-;

[0065] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n6 R mm -(CH2) n6 R mm-(CH2) n6 OR mm -(CH2) n6 SR mm -(CH2) n6 C(O)R mm -(CH2) n6 C(O)OR mm -(CH2) n6 S(O) m4 R mm -(CH2) n6 NR mm R nn -(CH2) n6 C(O)NR mm R nn -(CH2) n6 NR mm C(O)R nn Or -(CH2) n6 NR mm S(O) m4 R nn The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0066] Rc Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0067] R mm and R nn Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0068] z is an integer from 0 to 4;

[0069] n6 is 0, 1, 2, or 3; and

[0070] m4 can be 0, 1, or 2.

[0071] In a further preferred embodiment of the present invention, R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyloxy, C 1-6Alkyl thiols, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl.

[0072] In a further preferred embodiment of the present invention, R a Selected from hydrogen, halogen, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, C 3-6 Cycloalkoxy or C 3-6 Cycloalkylthio group.

[0073] In a further preferred embodiment of the present invention, R 1 Selected from hydrogen, halogen, amino, or C 1-3 alkyl.

[0074] In a further preferred embodiment of the present invention, R b Selected from hydrogen, halogen, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or halogenated C 1-3 Hydroxyalkyl.

[0075] In a further preferred embodiment of the present invention, a compound of formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided, the specific structure of which is as follows:

[0076]

[0077] in:

[0078] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0079] R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0080] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n R gg -OC(R) gg R hh ) n1 (CH2) n R ii -NR gg (CH2) n R hh -(CH2) n -、-(CH2) n R gg -(CH2) n OR hh -(CH2) n SR gg -(CH2) n C(O)R gg -(CH2) n C(O)OR gg -(CH2) n S(O) m R gg -(CH2) n NR gg R hh -(CH2)n C(O)NR gg R hh -(CH2) n NR gg C(O)R hh Or -(CH2) n NR gg S(O) m R hh The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n3 R a1 -OC(R) a1 R a2 ) n3 (CH2) n4 R a3 -NR a1 (CH2) n3 R a2 -(CH2) n3 -、-(CH2) n3 R a1 -(CH2) n3 OR a1 -(CH2) n3 SR a1 -(CH2)n3 C(O)R a1 -(CH2) n3 C(O)OR a1 -(CH2) n3 S(O) m1 R a1 -(CH2) n3 NR a1 R a2 -(CH2) n3 C(O)NR a1 R a2 -(CH2) n3 NR a1 C(O)R a2 Or -(CH2) n3 NR a1 S(O) m1 R a2 One or more substituents in it are replaced;

[0081] R gg R hh and R ii Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0082] R a1 R a2 and R a3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -O(CH2) n5 R b1-OC(R) b1 R b2 ) n5 (CH2) m5 R b3 -NR b1 (CH2) n5 R b2 -(CH2) n5 -、-(CH2) n5 R b1 -(CH2) n5 OR b1 -(CH2) n5 SR b1 -(CH2) n5 C(O)R b1 -(CH2) n5 C(O)OR b1 -(CH2) n5 S(O) m3 R b1 -(CH2) n5 NR b1 R b2 -(CH2) n5 C(O)NR b1 R b2 -(CH2) n5 NR b1 C(O)R b2 Or -(CH2) n5 NR b1 S(O) m3 R b2 One or more substituents in it are replaced;

[0083] R b1 R b2 and R b3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, methylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0084] n, n1, n2, n3, n4, and n5 are integers from 0 to 5; and

[0085] m, m1, m2 and m3 are 0, 1 or 2.

[0086] In a further preferred embodiment of the invention, the compound of general formula (V), its stereoisomers, or its pharmaceutically acceptable salts are characterized in that...

[0087] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0088] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0089] R7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups or C groups further substituted with hydroxyl groups and halogens 1-3 alkyl;

[0090] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0091] R a Selected from C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 Aryl, 5-10 heteroaryl, -O(CH2) n R gg -OC(R) gg R hh ) n1 (CH2) n R ii -NR gg (CH2) n R hh -(CH2) n -、-(CH2) n R gg -(CH2) n OR hh -(CH2) n SR gg -(CH2) n C(O)R gg -(CH2) n C(O)OR gg -(CH2) n S(O) m R gg -(CH2) n NR gg R hh -(CH2) n C(O)NR gg R hh -(CH2) n NR gg C(O)R hh Or -(CH2) n NR gg S(O) m R hh The C mentioned 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 aryl and 5-10 heteroaryl groups, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 Aryl, 5-10 heteroaryl, -O(CH2) n3 R a1 -OC(R) a1 R a2 ) n3 (CH2) n4 R a3 -NR a1 (CH2) n3 R a2 -(CH2) n3 -、-(CH2) n3 R a1 -(CH2) n3 OR a1 -(CH2) n3 SR a1 -(CH2) n3 C(O)R a1 -(CH2) n3 NR a1 C(O)R a2 -(CH2) n3 C(O)OR a1 -(CH2) n3 S(O) m1 R a1 -(CH2) n3 NR a1 R a2 -(CH2) n3 C(O)NR a1 R a2 -(CH2) n3 NR a1 C(O)R a2 Or -(CH2) n3 NR a1 S(O) m1 R a2 One or more substituents in it are replaced;

[0092] R gg R hh and R ii Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 Aryl or 5-10 heteroaryl groups;

[0093] R a1 R a2 and R a3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 Aryl or 5-10 heteroaryl groups;

[0094] R a The following groups are preferred:

[0095]

[0096] The above preferred groups may be further modified by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, hydroxyl, mercapto, nitro, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, -(CH2) n3 C(O)R a1 Or -(CH2) n3 NHC(O)R a2 One or more substituents in it are replaced;

[0097] R a1 and R a2Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl and C 3-8 Cycloalkyl.

[0098] The present invention also provides a preferred embodiment, providing a compound of general formula (VI), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0099]

[0100] X is selected from hydrogen or an active group, with the active group preferably being halogen, hydroxyl, amino, or carboxyl.

[0101] R1, R2, R a R b The definitions of y are as defined in general formula (IIa).

[0102] This invention also provides a method for preparing the compound described above, the route of which is as follows:

[0103]

[0104] Wherein: X is selected from hydrogen or an active group, and the active group is preferably halogen, hydroxyl, amino or carboxyl;

[0105] Y is selected from hydrogen or an active group, with the active group preferably being halogen, hydroxyl, amino, carboxyl, or...

[0106] R1, R a R b R c L, M, y and z are as described in general formula (IV-A).

[0107] The present invention also provides a preferred embodiment relating to a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0108] The present invention further relates to the use of any of the compounds of general formula (I) shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of SOS1 inhibitors and RAS family protein and / or RAC1 inhibitor medicaments.

[0109] The present invention also provides a preferred embodiment, which also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, in the treatment, prevention and / or treatment of a pre-prepared treatment for a condition mediated by an SOS1 inhibitor, the method comprising administering to a patient a therapeutically effective dose of the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0110] In some embodiments, the compounds and compositions of the present invention may be used in the preparation of medicaments for treating diseases or conditions such as endometrial adenocarcinoma, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0111] The compounds and compositions of the present invention can be used in methods for treating diseases or conditions such as endometrial adenocarcinoma, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0112] In some embodiments, the present invention provides a method for treating cancer, comprising administering a compound or composition of the present invention to a patient suffering from cancer.

[0113] In some embodiments, the compounds or compositions of the present invention are used to treat neurofibromatosis type I (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation arteriovenous malformation syndrome (CMAVM), Costello syndrome (CS), cardiofacial skin syndrome (CFC), Legg's syndrome, and hereditary root fibromatosis.

[0114] Detailed description of the invention

[0115] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0116] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0117] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0118] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0119] wait.

[0120] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; even more preferably, it contains a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0121] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, 1,2,3,6-tetrahydropyridine, and pyranyl, with pyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, 1,2,3,6-tetrahydropyridine, and piperazinyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally linked to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0122] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include: wait.

[0123] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0124] wait.

[0125] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, they are 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0126] wait.

[0127] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0128] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0129] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0130] wait.

[0131] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0132] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably thienyl, pyridazinyl, pyrimidinyl, pyrazolyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0133] wait.

[0134] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0135] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0136] "alkylaminocarbonyl" refers to (alkyl)-NC(O)-, where alkyl is defined as described above.

[0137] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0138] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0139] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0140] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0141] "Alkyne" refers to (CH≡C- or -C≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0142] The term "active group" is selected from groups that can undergo condensation or substitution reactions, such as halogen, hydroxyl, amino, or carboxyl groups.

[0143] "Hydroxy" refers to -OH.

[0144] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0145] "Amino" refers to -NH2.

[0146] “Cyano” refers to -CN.

[0147] "Nitro" refers to -NO2.

[0148] "Carbonyl" refers to -C(O)-.

[0149] "Carboxyl group" refers to -C(O)OH.

[0150] "THF" refers to tetrahydrofuran.

[0151] “MeOH” refers to methanol.

[0152] "DMF" refers to N,N-dimethylformamide.

[0153] "DIPEA" refers to diisopropylethylamine.

[0154] "TFA" refers to trifluoroacetic acid.

[0155] “DMA” stands for N,N-dimethylacetamide.

[0156] “NBS” refers to N-bromosuccinimide.

[0157] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0158] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0159] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0160] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0161] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0162] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0163] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0164] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0165] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0166] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0167] Example

[0168] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0169] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0170] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0171] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0172] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0173] Example 1

[0174] (R)-6-cyclohexyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0175]

[0176] Step 1: 1-Bromo-3-(difluoromethyl)-2-fluorobenzene

[0177]

[0178] 3-Bromo-2-fluorobenzaldehyde (10.0 g, 49.2 mmol) and dry dichloromethane (150 mL) were added sequentially to a 250 mL three-necked flask. Under a nitrogen atmosphere and in an ice bath at 0 °C, diethylaminotrifluoride (13.3 mL, 98.5 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 1 hour, then heated to room temperature and stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL), and washed with saturated brine (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1) to give 1-bromo-3-(difluoromethyl)-2-fluorobenzene (6.5 g, 58.6%).

[0179] Step 2: 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one

[0180]

[0181] In a 250 mL round-bottom flask, 1-bromo-3-(difluoromethyl)-2-fluorobenzene (6.5 g, 28.8 mmol), tributyl(1-ethoxyethylene)tin (12.4 g, 34.5 mmol), dioxane (150 mL), and triethylamine (7.2 g, 72 mmol) were added sequentially. Under nitrogen protection, bis(triphenylphosphine)palladium chloride (220 mg, 0.3 mmol) was added with stirring. The reaction mixture was stirred at 100 °C for 12 hours, then treated with 1 N hydrochloric acid and stirred for 16 hours. The mixture was extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1) to give 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one (3.5 g, yield: 64.3%).

[0182] Step 3: (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0183]

[0184] In a 100 mL round-bottom flask, 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one (3.5 g, 18.6 mmol) and tetrahydrofuran (30 mL) were added sequentially. Then, (R)-(+)-tert-butylsulfinamide (3.4 g, 27.9 mmol) and Ti(OEt)4 (13.2 g, 46.5 mmol) were added with stirring. The reaction mixture was stirred at 80 °C for 5 hours, then cooled to room temperature and quenched with ice water. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1) to give (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (4.2 g, yield: 77.5%).

[0185] MS m / z(ESI): 292.3 [M+H] + .

[0186] Step 4: (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0187]

[0188] (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (4.2 g, 14.2 mmol), tetrahydrofuran (30 mL), and sodium borohydride (818 mg, 21.6 mmol) were added sequentially to a 100 mL reaction flask. The reaction mixture was stirred at -78 °C for 3 hours and then quenched with ice water. The mixture was extracted with ethyl acetate and the organic phase was concentrated. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1) to give (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, yield: 45.1%).

[0189] MS m / z(ESI): 294.1 [M+H] + .

[0190] Step 5: (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine

[0191]

[0192] (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, 6.5 mmol), dioxane (20 mL), and 4M HCl dioxane solution (5 mL) were added to a 50 mL reaction flask sequentially. The reaction mixture was stirred at room temperature for 3 hours, then concentrated, ethyl acetate was added, the mixture was filtered, and dried to obtain the product, which was used directly in the next reaction step.

[0193] MS m / z(ESI): 190.0 [M+H] + .

[0194] Step 6: 6-Chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0195]

[0196] 5-Amino-2-chloroisonicotinic acid methyl ester (18.6 g, 100 mmol) and acetonitrile (300 mL) were added to a 500 mL reaction flask, followed by the addition of 50 mL of 4 M HCl dioxane solution at room temperature. The reaction mixture was stirred at 100 °C for 12 hours, then cooled to room temperature. The pH was adjusted to 6 with 2 M NaOH solution, resulting in the precipitation of a large amount of white solid. The solid was filtered and dried to obtain the product 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (15.0 g, 76.9%).

[0197] MS m / z(ESI): 196.0 [M+H] + .

[0198] Step 7: 6-Cyclohexyl-2-methylpyridano[3,4-d]pyrimidin-4(3H)-one

[0199]

[0200] In a 50 mL reaction flask, 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1.5 g, 7.9 mmol), cyclohexylboronic acid (0.98 g, 7.9 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (210 mg, 0.3 mmol), and sodium carbonate (1.65 g, 15.5 mmol) were dissolved in dioxane / water (20 mL / 3 mL). Under nitrogen protection, the mixture was reacted at 90 °C for 8 hours with stirring. The reaction was stopped, water (3 mL) was added to quench the reaction, the mixture was concentrated, and extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (dichloromethane / methanol: 10 / 1) to give 6-cyclohexyl-2-methylpyridano[3,4-d]pyrimidin-4(3H)-one (1.2 g, 64.3%).

[0201] MS m / z(ESI): 244.1 [M+H] + .

[0202] Step 8: 4-Chloro-6-cyclohexyl-2-methylpyridano[3,4-d]pyrimidine

[0203]

[0204] 6-Cyclohexyl-2-methylpyridano[3,4-d]pyrimidin-4(3H)-one (1.2 g, 4.9 mmol) and phosphorus oxychloride (12 mL) were added to a 50 mL reaction flask. The reaction mixture was stirred at 100 °C for 4 hours, cooled to room temperature, concentrated, and poured into ice water. The pH was adjusted with NaHCO3, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (dichloromethane / methanol: 10 / 1) to obtain 4-chloro-6-cyclohexyl-2-methylpyridano[3,4-d]pyrimidin (860 mg, 65.6%).

[0205] MS m / z(ESI): 262.1 [M+H] + .

[0206] Step 9: (R)-6-cyclohexyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine

[0207]

[0208] 4-Chloro-6-cyclohexyl-2-methylpyrido[3,4-d]pyrimidine (260 mg, 1 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (189 mg, 1 mmol), DIEA (260 mg, 2 mmol), and ethanol (5 mL) were added to a 25 mL reaction flask. The reaction mixture was stirred at 100 °C for 12 hours, cooled to room temperature, concentrated, and poured into ice water. It was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was recrystallized from ethyl acetate and petroleum ether to give the product (R)-6-cyclohexyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (160 mg, 38.6%).

[0209] MS m / z (ESI): 415.2 [M+H] + .

[0210] Example 2

[0211] (R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4-amine

[0212]

[0213] Step 1: (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine

[0214]

[0215] Using 1-bromo-2-fluoro-3-(trifluoromethyl)benzene as a raw material, the product (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine was obtained by referring to steps two to five of Example 1.

[0216] MS m / z(ESI): 208.0 [M+H] + .

[0217] Step 2: 2-Methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0218]

[0219] In a 50 mL reaction flask, 1.5 g (7.9 mmol) of 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one, 1.3 g (15.5 mmol) of piperidine, and 2.1 g (15.5 mmol) of potassium carbonate were dissolved in 10 mL of DMF. The mixture was stirred at 90 °C for 8 hours under nitrogen protection. The reaction was stopped, quenched with 20 mL of water, concentrated, and extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (dichloromethane / methanol: 10 / 1) to give 1.2 g (64.0%) of 2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0220] MS m / z (ESI): 245.1 [M+H] + .

[0221] Step 3: 4-Chloro-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidine

[0222]

[0223] Using 2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one as a raw material, the product 4-chloro-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin was obtained by referring to step 8 of Example 1.

[0224] MS m / z(ESI): 263.1 [M+H] + .

[0225] Step 4: (R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4-amine

[0226]

[0227] Using 4-chloro-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidine as a raw material, the product (R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidine-4-amine was obtained by referring to step nine of Example 1.

[0228] MS m / z (ESI): 434.1 [M+H] + .

[0229] Example 3

[0230] 6-((1S,4S)-2-azabicyclo[2.2.2]octane-2-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0231]

[0232] Step 1: 6-((1s,4s)-2-azabicyclo[2.2.2]octane-2-yl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0233]

[0234] Using 2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one as a raw material, the product 6-((1s,4s)-2-azabicyclo[2.2.2]octan-2-yl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one was obtained by referring to the second step of Example 2.

[0235] MS m / z(ESI): 271.1 [M+H] + .

[0236] Step 2: (1s,4s)-2-(4-chloro-2-methylpyridano[3,4-d]pyrimidin-6-yl)-2-azabicyclo[2.2.2]octane

[0237]

[0238] Using 6-((1s,4s)-2-azabicyclo[2.2.2]octan-2-yl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one as the raw material, the product (1s,4s)-2-(4-chloro-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-azabicyclo[2.2.2]octane was obtained by referring to step 8 of Example 1.

[0239] MS m / z(ESI): 289.1 [M+H] + .

[0240] Step 3: 6-((1S,4S)-2-azabicyclo[2.2.2]octane-2-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0241]

[0242] Using (1s,4s)-2-(4-chloro-2-methylpyridano[3,4-d]pyrimidin-6-yl)-2-azabicyclo[2.2.2]octane as a raw material, the product 6-((1S,4S)-2-azabicyclo[2.2.2]octan-2-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpyridano[3,4-d]pyrimidin-4-amine was obtained by referring to step nine of Example 1.

[0243] MS m / z (ESI): 460.2 [M+H] + .

[0244] Example 4

[0245] 2-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-yl)pyrido[3,4-d]pyrimidin-4-amine

[0246]

[0247] Step 1: (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine

[0248]

[0249] Using 1-bromo-2-methyl-3-(trifluoromethyl)benzene as a raw material, the product (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was obtained by referring to steps two to five of Example 1.

[0250] MS m / z(ESI): 204.0 [M+H] + .

[0251] Step 2: 2-Methyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0252]

[0253] Using 2-methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one as a raw material, the product 2-methyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was obtained by referring to the second step of Example 2.

[0254] MS m / z(ESI): 286.1 [M+H] + .

[0255] Step 3: (1R,4R)-2-(4-chloro-2-methylpyridano[3,4-d]pyrimidin-6-yl)-5-methyl-2,5-diazabicyclo[2.2.2]octane

[0256]

[0257] Using 2-methyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one as the starting material, the product (1R,4R)-2-(4-chloro-2-methylpyrido[3,4-d]pyrimidin-6-yl)-5-methyl-2,5-diazabicyclo[2.2.2]octane was obtained by referring to step 8 of Example 1.

[0258] MS m / z (ESI): 304.1 [M+H] + .

[0259] Step 4: 2-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-yl)pyrido[3,4-d]pyrimidine-4-amine

[0260]

[0261] Using (1R,4R)-2-(4-chloro-2-methylpyridano[3,4-d]pyrimidin-6-yl)-5-methyl-2,5-diazabicyclo[2.2.2]octane as a raw material, the product 2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridano[3,4-d]pyrimidin-4-amine was obtained by referring to step nine of Example 1.

[0262] MS m / z (ESI): 471.2 [M+H] + .

[0263] Example 5

[0264] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0265]

[0266] Step 1: 4,6-Dichloro-2-methylpyrimidine-5-carboxylic acid

[0267]

[0268] 4,6-Dichloro-2-methylpyrimidin-5-carboxaldehyde (4 g, 22.7 mmol) was dissolved in tert-butanol (60 mL), and NaH₂PO₄ (9.55 g, 79.6 mmol) and water (10 mL) were added. The reaction mixture was cooled to 0 °C in an ice bath, and then sodium hypochlorite (7.66 g, 84.7 mmol) was slowly added. After the addition was complete, the reaction was stirred for 1 hour. The reaction mixture was concentrated to remove most of the tert-butanol, then poured into water, and the pH was adjusted to 5 with dilute hydrochloric acid. Ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness to give 4,6-dichloro-2-methylpyrimidin-5-carboxylic acid (3.1 g, 71% yield).

[0269] MS m / z(ESI): 207.0 [M+H] +

[0270] Step 2: 4,6-Dichloro-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide

[0271]

[0272] 4,6-Dichloro-2-methylpyrimidin-5-carboxylic acid (1 g, 4.8 mmol) was dissolved in DMF (25 mL), and 1-(fluoromethyl)cyclopropane-1-amine (517 mg, 5.8 mmol), HATU (2.75 g, 7.2 mmol), and DIEA (1.38 g, 9.7 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by column chromatography to give 4,6-dichloro-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide.

[0273] MS m / z(ESI): 278.2 [M+H] +

[0274] Step 3: (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide

[0275]

[0276] 4,6-Dichloro-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide (500 mg, 1.8 mmol) was dissolved in DMSO (15 mL), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (408 mg, 2.2 mmol) and DIEA (515 mg, 3.6 mmol) were added separately. The reaction mixture was stirred overnight at 80 °C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide.

[0277] MS m / z (ESI): 431.2 [M+H] +

[0278] Step 4: (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidine-5-carboxamide

[0279]

[0280] (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidin-5-carboxamide (200 mg, 0.464 mmol) was dissolved in DMF (12 mL), and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboropentan (184 mg, 0.928 mmol) and saturated sodium carbonate aqueous solution (3 mL) were added. Pd(dppf)Cl2·CH2Cl2 (36 mg, 0.0464 mmol) was added to the reaction solution under nitrogen protection. The reaction was stirred at 100 °C for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to obtain (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidine-5-carboxamide.

[0281] MS m / z (ESI): 467.2 [M+H] +

[0282] Step 5: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0283]

[0284] (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(1-(fluoromethyl)cyclopropyl)-2-methylpyrimidine-5-carboxamide (100 mg, 0.214 mmol) was dissolved in trifluoroacetic acid (10 mL). The reaction was stirred at 100 °C for 2 hours. The reaction mixture was evaporated to dryness. The crude product was purified by prep-HPLC to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridano[4,3-d]pyrimidine-5(6H)-one.

[0285] MS m / z(ESI): 421.2 [M+H] +

[0286] Example 6

[0287] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0288]

[0289] Step 1: 4,6-Dichloro-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidin-5-carboxamide

[0290]

[0291] Using 4,6-dichloro-2-methylpyrimidine-5-carboxylic acid and 4-fluorobicyclo[2.2.2]octane-1-amine as raw materials, the product 4,6-dichloro-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidine-5-carboxamide was obtained in the second step of Reference Example 5.

[0292] MS m / z(ESI): 332.2 [M+H] +

[0293] Step 2: (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidine-5-carboxamide

[0294]

[0295] Using 4,6-dichloro-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidine-5-carboxamide as a raw material, the product (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidine-5-carboxamide was obtained by referring to the third step of Example 5.

[0296] MS m / z (ESI): 485.2 [M+H] +

[0297] Step 3: (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrimidine-5-carboxamide

[0298]

[0299] Using (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methylpyrimidine-5-carboxamide as a raw material, the product (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methylpyrimidine-5-carboxamide was obtained by referring to the fourth step of Example 5.

[0300] MS m / z(ESI): 521.2 [M+H] +

[0301] Step 4: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0302]

[0303] Using (R,E)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-ethoxyvinyl)-N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methylpyrimidin-5-carboxamide as a raw material, the product (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one was obtained by referring to step 5 of Example 5.

[0304] MS m / z (ESI): 475.2 [M+H] +

[0305] Example 7

[0306] (R)-1-Cyclopropyl-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[4,3-d]pyrimidin-7-yl)pyridin-2(1H)-one

[0307]

[0308] Step 1: 1-Cyclopropyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2(1H)-one

[0309]

[0310] 4-Bromo-1-cyclopropylpyridin-2(1H)-one (5.0 g, 23.4 mmol) was dissolved in dioxane (150 mL), and pinacol borate ester (6.5 g, 25.7 mmol) and potassium acetate (3.4 g, 35.0 mmol) were added. Pd2(dba)3 (1.1 g, 1.2 mmol) and tricyclohexylphosphine (0.79 g, 2.8 mmol) were added to the reaction solution under nitrogen protection. The reaction was stirred at 85 °C for 3 hours. The reaction solution was filtered and concentrated. The crude product was purified by column chromatography to give 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2(1H)-one.

[0311] MS m / z(ESI): 262.2 [M+H] +

[0312] Step 2: Methyl 6-bromo-4-((4-methoxybenzyl)amino)nicotinic acid

[0313]

[0314] 4,6-Dibromonicotinic acid methyl ester (5.0 g, 17.0 mmol) was dissolved in DMF (100 mL), and (4-methoxyphenyl)methylamine (2.8 g, 20.3 mmol) and DIEA (6.6 g, 50.9 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 6-bromo-4-((4-methoxybenzyl)amino)nicotinic acid methyl ester.

[0315] MS m / z (ESI): 351.2 [M+H] +

[0316] Step 3: Methyl 1'-cyclopropyl-4-((4-methoxybenzyl)amino)-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid ester

[0317]

[0318] Using methyl 6-bromo-4-((4-methoxybenzyl)amino)nicotinic acid and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine-2(1H)-one as raw materials, refer to the fourth step of Example 5 to obtain the product methyl 1'-cyclopropyl-4-((4-methoxybenzyl)amino)-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid.

[0319] MS m / z (ESI): 406.2 [M+H] +

[0320] Step 4: Methyl 4-amino-1'-cyclopropyl-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid

[0321]

[0322] Methyl 1'-cyclopropyl-4-((4-methoxybenzyl)amino)-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid (3 g, 7.4 mmol) was dissolved in methanol, and Pd / C (500 mg) was added. The reaction was carried out under hydrogen atmosphere at room temperature with stirring for 5 hours, followed by filtration. The filtrate was evaporated to dryness to give methyl 4-amino-1'-cyclopropyl-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid.

[0323] MS m / z(ESI): 286.2 [M+H] +

[0324] Step 5: 7-(1-Cyclopropyl-2-carbonyl-1,2-dihydropyridin-4-yl)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

[0325]

[0326] Using methyl 4-amino-1'-cyclopropyl-2'-carbonyl-1',2'-dihydro-[2,4'-bipyridine]-5-carboxylic acid as a raw material, refer to step six of Example 1 to obtain the product 7-(1-cyclopropyl-2-carbonyl-1,2-dihydropyridin-4-yl)-2-methylpyrido[4,3-d]pyrimidine-4(3H)-one.

[0327] MS m / z(ESI): 295.2 [M+H]+

[0328] Step 6: 4-(4-chloro-2-methylpyridino[4,3-d]pyrimidin-7-yl)-1-cyclopropylpyridin-2(1H)-one

[0329]

[0330] Using 7-(1-cyclopropyl-2-carbonyl-1,2-dihydropyridin-4-yl)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a starting material, the product 4-(4-chloro-2-methylpyrido[4,3-d]pyrimidin-7-yl)-1-cyclopropylpyridin-2(1H)-one was obtained by referring to step 8 of Example 1.

[0331] MS m / z (ESI): 313.2 [M+H] +

[0332] Step 7: (R)-1-Cyclopropyl-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[4,3-d]pyrimidin-7-yl)pyridin-2(1H)-one

[0333]

[0334] Using 4-(4-chloro-2-methylpyridino[4,3-d]pyrimidin-7-yl)-1-cyclopropylpyridin-2(1H)-one and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine as raw materials, refer to Example 1, step nine to obtain the product (R)-1-cyclopropyl-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[4,3-d]pyrimidin-7-yl)pyridin-2(1H)-one.

[0335] MS m / z (ESI): 480.2 [M+H] +

[0336] Example 8

[0337] (R)-3-Methyl-2-(2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)phenol

[0338]

[0339] Step 1: Methyl 6-(2-methoxy-6-methylphenyl)-4-((4-methoxybenzyl)amino)nicotinic acid

[0340]

[0341] Using methyl 6-bromo-4-((4-methoxybenzyl)amino)nicotinic acid and (2-methoxy-6-methylphenyl)boronic acid as raw materials, refer to the fourth step of Example 5 to obtain the product methyl 6-(2-methoxy-6-methylphenyl)-4-((4-methoxybenzyl)amino)nicotinic acid.

[0342] MS m / z(ESI): 393.2 [M+H] +

[0343] Step 2: Methyl 4-amino-6-(2-methoxy-6-methylphenyl)nicotinic acid

[0344]

[0345] Using methyl 6-(2-methoxy-6-methylphenyl)-4-((4-methoxybenzyl)amino)nicotinic acid as a raw material, refer to step four of Example 7 to obtain the product methyl 4-amino-6-(2-methoxy-6-methylphenyl)nicotinic acid.

[0346] MS m / z(ESI): 273.2 [M+H] +

[0347] Step 3: 7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

[0348]

[0349] Using methyl 4-amino-6-(2-methoxy-6-methylphenyl)nicotinic acid as a raw material, the product 7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidine-4(3H)-one was obtained in step 6 of Example 1.

[0350] MS m / z(ESI): 282.2 [M+H] +

[0351] Step 4: 4-Chloro-7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidine

[0352]

[0353] Using 7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidine-4(3H)-one as a raw material, the product 4-chloro-7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidine was obtained in step 8 of Example 1.

[0354] MS m / z(ESI): 300.2 [M+H] +

[0355] Step 5: (R)-7-(2-methoxy-6-methylphenyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidine-4-amine

[0356]

[0357] Using 4-chloro-7-(2-methoxy-6-methylphenyl)-2-methylpyrido[4,3-d]pyrimidine and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, refer to Example 1, step nine to obtain the product (R)-7-(2-methoxy-6-methylphenyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidine-4-amine.

[0358] MS m / z (ESI): 467.2 [M+H] +

[0359] Step 6: (R)-3-methyl-2-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)phenol

[0360]

[0361] (R)-7-(2-methoxy-6-methylphenyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4-amine (200 mg, 0.43 mmol) was dissolved in 1,2-dichloroethane (10 mL), and aluminum trichloride (0.29 g, 2.2 mmol) was slowly added. The reaction mixture was stirred overnight at 80 °C. Excess sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred for 1 hour, then filtered. The filtrate was evaporated to dryness and purified by prep-HPLC to give (R)-3-methyl-2-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)phenol.

[0362] MS m / z (ESI): 453.2 [M+H] +

[0363] Example 9

[0364] (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidin-8(7H)-one

[0365]

[0366] Step 1: 5-((1,3-dioxopentane-2-yl)methyl)-4,6-dichloro-2-methylpyrimidine

[0367]

[0368] A mixed solution of 2-(4,6-dichloro-2-methylpyrimidin-5-yl)acetaldehyde (6.0 g, 30 mmol), ethylene glycol (2.7 g, 45 mmol), p-toluenesulfonic acid (516 mg, 3 mmol), and toluene (50 mL) was refluxed for 24 hours. The reaction system was cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate (100 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 5-((1,3-dioxopentane-2-yl)methyl)-4,6-dichloro-2-methylpyrimidinium (5.0 g).

[0369] MS m / z(ESI): 249.0 [M+H] + .

[0370] Step 2: (R)-5-((1,3-dioxopentane-2-yl)methyl)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrimidin-4-amine

[0371]

[0372] Referring to step nine of Example 1, (R)-5-((1,3-dioxopentane-2-yl)methyl)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrimidin-4-amine (3.9 g) was obtained.

[0373] MS m / z (ESI): 416.1 [M+H] + .

[0374] Step 3: (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-vinylpyrimidin-4-amine

[0375]

[0376] In a 100 mL round-bottom flask, (R)-5-((1,3-dioxopentane-2-yl)methyl)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrimidin-4-amine (1.0 g, 2.4 mmol), bis(triphenylphosphine)palladium dichloride (85 mg, 0.12 mmol), tributylvinyltin (0.9 g, 2.8 mmol), and triethylamine (1.2 g, 12 mmol) were dissolved in 40 mL of dioxane. The reaction mixture was purged with nitrogen. The reaction was carried out at 80 °C and stirred overnight under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature, quenched with 1N HCl, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography to obtain (R)-5-((1,3-dioxapentane-2-yl)methyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-vinylpyrimidin-4-amine (700 mg).

[0377] MS m / z (ESI): 408.1 [M+H] + .

[0378] Step 4: (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxaldehyde

[0379]

[0380] In a 100 mL round-bottom flask, (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-vinylpyrimidine-4-amine (700 mg, 1.7 mmol) was dissolved in 30 mL of dichloromethane / methanol (4:1 / v:v). Ozone was bubbled in at -78 °C for 5 h. The reaction was quenched with dimethyl sulfide and evaporated to dryness to give (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxaldehyde (700 mg).

[0381] MS m / z (ESI): 410.1 [M+H] + .

[0382] Step 5: (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid

[0383]

[0384] In a 100 mL round-bottom flask, (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-carboxaldehyde (700 mg, 1.7 mmol) and 2-methyl-2-butene (775 mg, 11 mmol) were dissolved in 30 mL of tert-butanol. A 5 mL aqueous solution of sodium chlorite (200 mg, 2.2 mmol) and sodium dihydrogen phosphate monohydrate (303 mg, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature for 18 h, evaporated to dryness, and then 1 N was added. Adjust the pH to 2 with HCl, add water (20 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated brine (30 mL), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid (500 mg).

[0385] MS m / z(ESI): 426.1 [M+H] + .

[0386] Step 6: (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-N-(1-methylcyclopropyl)pyrimidin-4-carboxamide

[0387]

[0388] Referring to the second step of Example 5, we obtained: (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-N-(1-methylcyclopropyl)pyrimidine-4-carboxamide (300 mg).

[0389] MS m / z (ESI): 479.2 [M+H] + .

[0390] Step 7: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidin-8(7H)-one

[0391]

[0392] (R)-5-((1,3-dioxopentane-2-yl)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-N-(1-methylcyclopropyl)pyrimidin-4-carboxamide (200 mg, 0.42 mmol) was dissolved in isopropanol (3 mL) and 5N HCl (1 mL) was added. The reaction was stirred at 50 °C for 2 hours under sealed conditions. NaHCO3 aqueous solution was added to adjust the pH to 7-8, and then ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was subjected to prep-HPLC to obtain (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidin-8(7H)-one (150 mg).

[0393] MS m / z (ESI): 417.1 [M+H] + .

[0394] Example 10

[0395] (R)-6-(1-(fluoromethyl)cyclopropoxy)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine

[0396]

[0397] Step 1: 2-(4,6-Dichloro-2-methylpyrimidin-5-yl)acetic acid

[0398]

[0399] 2-(4,6-dichloro-2-methylpyrimidin-5-yl)acetic acid was obtained by referring to step 5 of Example 9.

[0400] MS m / z(ESI): 220.9 [M+H] + .

[0401] Step 2: 2-(4,6-dichloro-2-methylpyrimidin-5-yl)acetamide

[0402]

[0403] 2-(4,6-dichloro-2-methylpyrimidin-5-yl)acetamide was obtained by referring to the second step of Example 5.

[0404] MS m / z(ESI): 220.0 [M+H] + .

[0405] Step 3: (R)-2-(4-chloro-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide

[0406]

[0407] Referring to step nine of Example 1, (R)-2-(4-chloro-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide was obtained.

[0408] MS m / z (ESI): 387.1 [M+H] + .

[0409] Step 4: (R)-2-(4-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide

[0410]

[0411] Referring to the third and fourth steps of Example 9, (R)-2-(4-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide was obtained.

[0412] MS m / z(ESI): 381.1 [M+H] + .

[0413] Step 5: (R)-2-(4-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide

[0414]

[0415] Referring to Example 9, step 1 yielded (R)-2-(4-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)acetamide.

[0416] MS m / z (ESI): 425.1 [M+H] + .

[0417] Step 6: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6(7H)-one

[0418]

[0419] Referring to step 7 of Example 9, (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidine-6(7H)-one was obtained.

[0420] MS m / z(ESI): 363.1 [M+H] + .

[0421] Step 7: (R)-6-(1-(fluoromethyl)cyclopropoxy)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidine-4-amine

[0422]

[0423] In a 50 mL round-bottom flask, (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6(7H)-one (100 mg, 0.28 mmol) was dissolved in 10 mL of THF. 1-(fluoromethyl)cyclopropyl 4-methylbenzenesulfonate (101 mg, 0.41 mmol) was added at -78 °C, and the mixture was stirred for 5 h at room temperature after cooling from -78 °C. Add water (20 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases and wash with saturated brine (30 mL), dry the organic phase with anhydrous sodium sulfate, filter, evaporate to dryness, and separate the crude product by column chromatography to obtain (R)-6-(1-(fluoromethyl)cyclopropoxy)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidine-4-amine (10 mg).

[0424] MS m / z (ESI): 435.1 [M+H] + .

[0425] Example 11

[0426] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1-methylcyclobutoxy)pyrido[3,4-d]pyrimidin-4-amine

[0427]

[0428] Referring to step 7 of Example 10, (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1-methylcyclobutoxy)pyrido[3,4-d]pyrimidine-4-amine was obtained.

[0429] MS m / z(ESI): 417.11 [M+H] + .

[0430] Example 12

[0431] (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidin-6(7H)-one

[0432]

[0433] Step 1: 2-(4,6-Dichloro-2-methylpyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide

[0434]

[0435] 2-(4,6-dichloro-2-methylpyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide (3.5 g) was obtained by referring to the second step of Example 5.

[0436] MS m / z(ESI): 274.0 [M+H] + .

[0437] Step 2: (R)-2-(4-chloro-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide

[0438]

[0439] Referring to step nine of Example 1, (R)-2-(4-chloro-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide (2.1 g) was obtained.

[0440] MS m / z(ESI): 441.1 [M+H] + .

[0441] Step 3: (R)-2-(4-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide

[0442]

[0443] Refer to the third and fourth steps of Example 9: (R)-2-(4-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide (1.5g).

[0444] MS m / z (ESI): 435.1 [M+H] +.

[0445] Step 4: (R)-2-(4-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide

[0446]

[0447] Referring to Example 9, step 1 yielded (R)-2-(4-(1,3-dioxapentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-5-yl)-N-(1-methylcyclopropyl)acetamide (800 mg).

[0448] MS m / z (ESI): 479.2 [M+H] + .

[0449] Step 5: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidin-6(7H)-one

[0450]

[0451] Referring to step 7 of Example 9, (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidine-6(7H)-one (350 mg) was obtained.

[0452] MS m / z (ESI): 417.1 [M+H] + .

[0453] Example 13

[0454] 8-Cyclopropyl-N-((R)-1-(3-(1,1-difluoroethyl)-2-methylphenyl)ethyl)-2-methyl-9,9a-dihydroimidazo[1',2':1,6]pyrido[4,3-d]pyrimidin-4-amine

[0455] Step 1: S-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide

[0456]

[0457] Tetraethyl titanate (16.9 g, 74.25 mmol) was added dropwise to a solution of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one (5.0 g, 24.75 mmol), (R)-2-methylpropane-2-sulfinamide (6.0 g, 45.5 mmol), and tetrahydrofuran (60 mL). The mixture was then refluxed at 70 °C for 24 hours. The reaction system was cooled to room temperature, quenched with water, filtered, and the filtrate was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain S-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (6 g, crude product).

[0458] MS m / z (ESI): 306.1 [M+H] + .

[0459] Step 2: (R)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide

[0460]

[0461] Sodium borohydride (728 mg, 19.67 mmol) was added to a tetrahydrofuran (100 mL) solution of R-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinamide (6 g, 19.67 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow oil (R)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (5.2 g, yield: 86%).

[0462] MS m / z (ESI): 308.1 [M+H] + .

[0463] Step 3: (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine

[0464]

[0465] Add 10 mL of dioxane hydrochloride to a solution of (R)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (5.2 g, 16.94 mmol) and dioxane (60 mL), and stir at room temperature for 3 hours. A solid precipitates out. Filter the solution and dry the filter cake to obtain a white solid (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (3.5 g, crude product).

[0466] MS m / z(ESI): 204.1 [M+H] + .

[0467] Step 4: 4,6-Dichloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine

[0468]

[0469] A mixed solution of 4,6-dichloro-2-methylpyrimidin-5-carboxaldehyde (10.0 g, 52.36 mmol), ethylene glycol (3.2 g, 78.53 mmol), p-toluenesulfonic acid (894 mg, 5.2 mmol), and toluene (150 mL) was refluxed for 24 hours. The reaction system was cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 4,6-dichloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidinium (11.0 g, yield: 89%).

[0470] 1 H NMR (400MHz, CDCl3) δ6.34 (s, 1H), 4.31 (t, J = 6.9Hz, 2H), 4.09 (dd, J = 8.3, 5.5Hz, 2H), 2.70 (s, 3H).

[0471] Step 5: Dimethyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)malonate

[0472]

[0473] A mixture of 4,6-dichloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine (11.0 g, 46.81 mmol), diethyl malonate (6.2 g, 46.81 mmol), cesium carbonate (30.4 g, 9.62 mmol), and dimethyl sulfoxide (150 mL) was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give dimethyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-yl)malonate (12.0 g, yield: 78%).

[0474] 1 H NMR (400MHz, CDCl3) δ6.11(s,1H),5.35(s,1H),4.20(dd,J=8.8,5.4Hz,2H),4.03(dd,J=8.7,5.3Hz,2H),3.77(s,6H),2.71(s,3H).

[0475] Step 6: Methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate

[0476]

[0477] A mixture of 12.0 g (36.36 mmol) of dimethyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)malonate, 6.1 g (145.4 mmol) of lithium chloride, and 120 mL of dimethyl sulfoxide was stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (100 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 7.0 g (71%) of methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate.

[0478] MS m / z(ESI): 273.1 [M+H] + .

[0479] Step 7: Methyl(R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate

[0480]

[0481] A mixture of methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate (7.0 g, 25.74 mmol), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (6.27 g, 30.88 mmol), N,N-diisopropylethylamine (6.6 g, 51.48 mmol), and dimethyl sulfoxide (80 mL) was stirred at 100 °C for 6 hours. The reaction system was then cooled. The reaction was quenched with water at room temperature, extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (6.0 g, yield: 53%).

[0482] MS m / z (ESI): 440.2 [M+H] + .

[0483] Step 8: Methyl(R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate

[0484]

[0485] To a methanol solution of (R)-2-(5-(1,3-dioxopentyl-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (3.0 g, 6.83 mmol), dilute hydrochloric acid (30 mL, 2N) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (2.6 g, crude product).

[0486] MS m / z(ESI): 396.2 [M+H] + .

[0487] Step 9: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0488]

[0489] (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (1.0 g, 2.53 mmol) and ammonia-methanol solution (20 mL) were stirred at 80 °C for 16 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to dryness, and then extracted with water and ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 15 / 1) to give (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (700 mg, yield: 77%).

[0490] MS m / z(ESI): 363.1 [M+H] + .

[0491] Step 10: (R)-7-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4-amine

[0492]

[0493] A mixed solution of (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (700 mg, 1.93 mmol) and phosphorus oxychloride (10 mL) was stirred at 80 °C for 8 hours. The reaction system was cooled to room temperature, and the reaction was quenched by slowly adding water. A solid precipitated out. The solid was filtered, and the filter cake was dried to give a white solid (R)-7-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4-amine (610 mg, yield: 83%).

[0494] MS m / z(ESI): 381.1 [M+H] + .

[0495] Step 11: (R)-2-methyl-N4-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidine-4,7-diamine

[0496]

[0497] A mixture of (R)-7-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4-amine (610 mg, 1.61 mmol) and ammonia-methanol (10 mL) was stirred at 100 °C for 1 hour under microwave conditions. The reaction system was cooled to room temperature, and water was slowly added. A solid precipitated out. The mixture was filtered, and the filter cake was dried to give a white solid (R)-2-methyl-N4-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4,7-diamine (520 mg, yield: 89%).

[0498] MS m / z(ESI): 362.2 [M+H] + .

[0499] Step 12: 8-Cyclopropyl-N-((R)-1-(3-(1,1-difluoroethyl)-2-methylphenyl)ethyl)-2-methyl-9,9a-dihydroimidazo[1',2':1,6]pyrido[4,3-d]pyrimidin-4-amine

[0500]

[0501] A mixture of (R)-2-methyl-N4-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[4,3-d]pyrimidin-4,7-diamine (52 mg, 0.14 mmol), 2-bromo-1-cyclopropylethane-1-one (35 mg, 0.2 mmol), and ethanol (3 mL) was stirred at 80 °C for 16 hours. The reaction system was cooled to room temperature, and water was added. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then separated by preparative chromatography to give 8-cyclopropyl-N-((R)-1-(3-(1,1-difluoroethyl)-2-methylphenyl)ethyl)-2-methyl-9,9a-dihydroimidazo[1',2':1,6]pyrido[4,3-d]pyrimidin-4-amine (12 mg, yield: 20%).

[0502] MS m / z(ESI): 426.2 [M+H] + .

[0503] Example 14

[0504] 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-methylcyclopropyl)imino)-6,7-dihydro-5H-6l4-thieno[3,4-d]pyrimidine-6-oxide

[0505]

[0506] Step 1: 2-Methyl-5,7-dihydrothiopheno[3,4-d]pyrimidin-4(3H)-one

[0507]

[0508] A mixture of methyl 4-carbonyltetrahydrothiophene-3-carboxylate (5.0 g, 31.25 mmol), acetylamidine hydrochloride (5.9 g, 62.5 mmol), sodium ethoxide (6.4 g, 93.75 mmol), and ethanol was stirred at 100 °C for 16 hours. The reaction system was cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give 2-methyl-5,7-dihydrothiopheno[3,4-d]pyrimidin-4(3H)-one (3.9 g, yield: 74%).

[0509] MS m / z(ESI): 169.0 [M+H] +

[0510] Step 2: 4-Chloro-2-methyl-5,7-dihydrothiopheno[3,4-d]pyrimidine

[0511]

[0512] A mixed solution of 2-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4(3H)-one (3.9 g, 23.21 mmol), triethylamine (4.7 g, 46.46 mmol), and phosphorus oxychloride (50 mL) was stirred at 140 °C for 2 hours. The reaction system was cooled to room temperature, concentrated to dryness under reduced pressure, and then slowly extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-2-methyl-5,7-dihydrothieno[3,4-d]pyrimidin (3.2 g, yield: 74%).

[0513] MS m / z(ESI): 187.0 [M+H] + .

[0514] Step 3: (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5,7-dihydrothiopheneno[3,4-d]pyrimidin-4-amine

[0515]

[0516] A mixture of 4-chloro-2-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (3.2 g, 17.1 mmol), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (3.47 g, 17.1 mmol), N,N-diisopropylethylamine (6.6 g, 51.3 mmol), and dimethyl sulfoxide (50 mL) was stirred at 100 °C for 24 hours. The reaction system was then cooled. The reaction was quenched with water at room temperature, extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5,7-dihydrothieno[3,4-d]pyrimidine-4-amine (3.6 g, yield: 59%).

[0517] MS m / z (ESI): 354.1 [M+H] + .

[0518] Step 4: 6-Imine-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dihydro-5H-6l4-thiopheno[3,4-d]pyrimidine-6-oxide

[0519]

[0520] A mixed solution of (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-amine (3.6 g, 10.17 mmol), [di(acetoxy)iodide]benzene (3.27 g, 10.17 mmol), ammonium carbamate (1.59 g, 20.34 mmol), and methanol (50 mL) was stirred at room temperature for 2 hours, and the reaction was quenched with water. Extracted with dichloromethane (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give 6-imino-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dihydro-5H-6l4-thieno[3,4-d]pyrimidine-6-oxide (2.3 g, yield: 59%).

[0521] MS m / z (ESI): 385.1 [M+H] + .

[0522] Step 5: 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-methylcyclopropyl)imino)-6,7-dihydro-5H-6l4-thieno[3,4-d]pyrimidine-6-oxide

[0523]

[0524] The following were added: 6-imino-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dihydro-5H-6l4-thieno[3,4-d]pyrimidine-6-oxide (100 mg, 0.26 mmol), [2,2]bipyridyl (4 mg, 0.026 mmol), copper acetate (5 mg, 0.026 mmol), (1-methylcyclopropyl)boronic acid (52 mg, 0.52 mmol), and triethylamine (53 mg, 0.52 mmol). The mixture of dichloromethane (5 mL) and dichloromethane was stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with dichloromethane (15 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Preparative chromatography was used to purify the mixture to give 2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-methylcyclopropyl)imino)-6,7-dihydro-5H-6l4-thieno[3,4-d]pyrimidine-6-oxide (25 mg, yield: 22%).

[0525] MS m / z(ESI): 439.2 [M+H] + .

[0526] Example 15

[0527] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0528]

[0529] Step 1: (R)-2-(5-(((1-(fluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0530]

[0531] A mixture of (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (300 mg, 0.76 mmol), 1-(fluoromethyl)cyclopropane-1-amine (101 mg, 1.14 mmol), sodium triacetoxyborohydride (322 mg, 1.52 mmol), and 1,2-dichloroethane (10 mL) was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with dichloromethane (30 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give (R)-2-(5-(((1-(fluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid methyl ester (210 mg, yield: 59%).

[0532] MS m / z (ESI): 469.2 [M+H] + .

[0533] Step 2: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-5,8-dihydropyridino[4,3-d]pyrimidin-7(6H)-one

[0534]

[0535] A mixture of (R)-2-(5-(((1-(fluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (100 mg, 0.21 mmol), p-toluenesulfonic acid (74 mg, 0.42 mmol), and toluene (5 mL) was stirred at 100 °C for 12 hours. The mixture was concentrated under reduced pressure to obtain the residue, which was then extracted with water and dichloromethane (15 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by preparative chromatography to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one (25 mg, yield: 27%).

[0536] MS m / z (ESI): 437.2 [M+H] + .

[0537] Example 16

[0538] (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0539]

[0540] Step 1: (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-(((1-methylcyclopropyl)amino)methyl)pyrimidin-4-yl)methyl acetate

[0541]

[0542] Using (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate and 1-methylcyclopropane-1-amine as raw materials, refer to Example 15 for the first step to obtain (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-(((1-methylcyclopropyl)amino)methyl)pyrimidin-4-yl)methyl acetate.

[0543] MS m / z (ESI): 451.2 [M+H] + .

[0544] Step 2: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-5,8-dihydropyridino[4,3-d]pyrimidin-7(6H)-one

[0545]

[0546] Using (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-(((1-methylcyclopropyl)amino)methyl)pyrimidin-4-yl)acetate as a starting material, refer to Example 15. In the second step, (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one is obtained.

[0547] MS m / z (ESI): 419.2 [M+H] + .

[0548] Example 17

[0549] (R)-6-(2-chlorophenyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0550]

[0551] Step 1: (R)-2-(5-(((2-chlorophenyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0552]

[0553] Using (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate as a starting material, refer to Example 15 for the first step to obtain (R)-2-(5-(((2-chlorophenyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate.

[0554] MS m / z (ESI): 507.2 [M+H] + .

[0555] Step 2: (R)-6-(2-chlorophenyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0556]

[0557] Using (R)-2-(5-(((2-chlorophenyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate as a starting material, refer to Example 15. In the second step, (R)-6-(2-chlorophenyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one is obtained.

[0558] MS m / z (ESI): 475.1 [M+H] + .

[0559] Example 18

[0560] (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0561]

[0562] Step 1: (R)-2-(5-(((1-(difluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0563]

[0564] Using (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate and 1-(difluoromethyl)cyclopropane-1-amine as raw materials, refer to Example 15 to obtain (R)-2-(5-(((1-(difluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate in the first step.

[0565] MS m / z (ESI): 487.2 [M+H] + .

[0566] Step 2: (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

[0567]

[0568] Using (R)-2-(5-(((1-(difluoromethyl)cyclopropyl)amino)methyl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate as a starting material, refer to Example 15. In the second step, (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one is obtained.

[0569] MS m / z (ESI): 455.2 [M+H] + .

[0570] Example 19

[0571] (S)-4-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0572]

[0573] Step 1: 2-Fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one

[0574]

[0575] 1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one (10.0 g, 49.5 mmol) was dissolved in methanol (80 mL), and Selectfluor (1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octanetetrafluoroborate, 35.0 g, 98.9 mmol) was added in portions. The reaction mixture was stirred in a microwave at 110 °C for 3 hours. Water (10 mL) was added to the reaction mixture, and the mixture was stirred in a microwave at 110 °C for another hour. The mixture was extracted with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one.

[0576] MS m / z(ESI): 221.2 [M+H] +

[0577] Step 2: (Z)-N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfonamide

[0578]

[0579] Using 2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one as a raw material, the product (Z)-N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfonamide was obtained in step 3 of Example 1.

[0580] MS m / z (ESI): 340.2 [M+H] +

[0581] Step 3: N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfonamide

[0582]

[0583] Using (Z)-N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfonamide as a raw material, refer to the fourth step of Example 1 to obtain the product N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfonamide.

[0584] MS m / z (ESI): 342.2 [M+H] +

[0585] Step 4: (S)-2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine

[0586]

[0587] Using N-(2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfonamide as a raw material, the product (S)-2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was obtained by referring to step 5 of Example 1.

[0588] MS m / z(ESI): 222.2 [M+H] +

[0589] Step 5: (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)methyl acetate

[0590]

[0591] 2-(6-chloro-5-(1,3-dioxopentyl-2-yl)-2-methylpyrimidin-4-yl)methyl acetate (1.0 g, 3.7 mmol) was dissolved in DMSO (20 mL), and (S)-2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (0.97 g, 4.4 mmol) and DIEA (1.9 g, 14.7 mmol) were added. The reaction mixture was stirred at 120 °C for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give (S)-2-(5-(1,3-dioxopentyl-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)methyl acetate.

[0592] MS m / z (ESI): 458.2 [M+H] +

[0593] Step 6: (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)acetic acid

[0594]

[0595] (S)-2-(5-(1,3-dioxopentyl-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)acetic acid methyl ester (500 mg, 1.1 mmol) was dissolved in DMSO (10 mL) and 2N NaOH (20 mL) was added. The reaction was stirred overnight at 80 °C. 1N HCl was added to adjust the pH to 5-6, and then ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness to give (S)-2-(5-(1,3-dioxopentyl-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)acetic acid.

[0596] MS m / z (ESI): 444.2 [M+H] +

[0597] Step 7: (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide

[0598]

[0599] Using (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)acetic acid and 1-(fluoromethyl)cyclopropane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide.

[0600] MS m / z (ESI): 515.2 [M+H] +

[0601] Step 8: (S)-4-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridano[4,3-d]pyrimidin-7(6H)-one

[0602]

[0603] (S)-2-(5-(1,3-dioxopentane-2-yl)-6-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide (200 mg, 0.39 mmol) was dissolved in isopropanol (0.5 mL), and 5N HCl (1 mL) was added. The reaction was stirred at 50 °C for 2 hours under sealed conditions. NaHCO3 aqueous solution was added to adjust the pH to 7-8, and then ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was subjected to prep-HPLC to obtain (S)-4-((2-fluoro-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridano[4,3-d]pyrimidin-7(6H)-one.

[0604] MS m / z (ESI): 453.2 [M+H] +

[0605] Example 20

[0606] 4-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0607]

[0608] Step 1: 1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-one

[0609]

[0610] Using 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one as a raw material, the product 1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-one was obtained in the first step of Reference Example 19.

[0611] MS m / z(ESI): 207.2 [M+H] + .

[0612] Step 2: (Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfonamide

[0613]

[0614] Using 1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-one as a raw material, the product (Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfonamide was obtained in step 3 of Example 1.

[0615] MS m / z(ESI): 326.2 [M+H] + .

[0616] Step 3: N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfonamide

[0617]

[0618] Using (Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfonamide as a raw material, the product N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfonamide was obtained by referring to the fourth step of Example 1.

[0619] MS m / z(ESI): 328.2 [M+H] + .

[0620] Step 4: (S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-amine

[0621]

[0622] Using N-(1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfonamide as a raw material, refer to step 5 of Example 1 to obtain the product (S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-amine.

[0623] MS m / z(ESI): 208.2 [M+H] + .

[0624] Step 5: (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)methyl acetate

[0625]

[0626] Using (S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethane-1-amine and methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, refer to Example 19, step 5 to obtain the product (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate.

[0627] MS m / z (ESI): 458.2 [M+H] + .

[0628] Step 6: (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid

[0629]

[0630] Using (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid methyl ester as the raw material, refer to Example 19, step 6 to obtain the product (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid.

[0631] MS m / z (ESI): 430.2 [M+H] + .

[0632] Step 7: 2-(6-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(3-(trifluoromethyl)tetrahydrofuran-3-yl)acetamide

[0633]

[0634] Using (S)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid and 3-(trifluoromethyl)tetrahydrofuran-3-amine as raw materials, refer to Example 5, step 2 to obtain the product 2-(6-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(3-(trifluoromethyl)tetrahydrofuran-3-yl)acetamide.

[0635] MS m / z (ESI): 567.2 [M+H] + .

[0636] Step 8: 4-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0637]

[0638] Using 2-(6-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(3-(trifluoromethyl)tetrahydrofuran-3-yl)acetamide as a raw material, refer to Example 19, step 8 to obtain the product 4-(((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2-fluoroethyl)amino)-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one.

[0639] MS m / z (ESI): 505.2 [M+H] +

[0640] Example 21

[0641] (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0642]

[0643] Step 1: 1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-ol

[0644]

[0645] 2-Methyl-3-(trifluoromethyl)benzaldehyde (10 g, 53.2 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL), and magnesium acetylene bromide (26.6 mL, 3 M, 79.7 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the temperature was raised to -20 °C, and stirring was continued for 3 hours. An aqueous solution of ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-ol.

[0646] MS m / z (ESI): 215.2 [M+H] + .

[0647] Step 2: N-(1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)acetamide

[0648]

[0649] 1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-ol (5.0 g, 23.3 mmol) was dissolved in anhydrous acetonitrile (100 mL), and anhydrous sodium sulfate (3.3 g, 23.3 mmol) was added. The reaction solution was cooled to -20 °C, and a mixture of concentrated sulfuric acid (11.45 g, 116.7 mmol) dissolved in anhydrous acetonitrile (50 mL) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was heated to room temperature and stirred overnight. The reaction solution was concentrated and poured into ice water, and then extracted with dichloromethane. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give N-(1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)acetamide.

[0650] MS m / z(ESI): 256.2 [M+H] + .

[0651] Step 3: 1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-ynyl-1-amine

[0652]

[0653] N-(1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)acetamide (3.0 g, 11.8 mmol) was dissolved in 3N HCl (30 mL), heated to 70 °C, and stirred for 6 hours. NaHCO3 was added to adjust the pH to 7-8, and then dichloromethane was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine.

[0654] MS m / z(ESI): 214.2 [M+H] + .

[0655] Step 4: (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-ynyl-1-amine

[0656]

[0657] (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine was prepared chirally.

[0658] MS m / z(ESI): 214.2 [M+H] + .

[0659] Step 5: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)methyl acetate

[0660]

[0661] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, refer to Example 19, step 5 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetate.

[0662] MS m / z (ESI): 450.2 [M+H] + .

[0663] Step 6: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid

[0664]

[0665] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid ester as the raw material, refer to Example 19, step 6 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid.

[0666] MS m / z (ESI): 436.2 [M+H] + .

[0667] Step 7: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide

[0668]

[0669] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid and 1-(fluoromethyl)cyclopropane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide.

[0670] MS m / z (ESI): 507.2 [M+H] + .

[0671] Step 8: (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0672]

[0673] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide as a raw material, refer to Example 19, step 8 to obtain the product (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one.

[0674] MS m / z (ESI): 445.2 [M+H] + .

[0675] Example 22

[0676] (R)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0677]

[0678] Step 1: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-methylcyclopropyl)acetamide

[0679]

[0680] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid and 1-methylcyclopropane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-methylcyclopropyl)acetamide.

[0681] MS m / z (ESI): 489.2 [M+H] + .

[0682] Step 2: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyridino[4,3-d]pyrimidin-7(6H)-one

[0683]

[0684] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-methylcyclopropyl)acetamide as a raw material, refer to Example 19, step 8 to obtain the product (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyridino[4,3-d]pyrimidin-7(6H)-one.

[0685] MS m / z (ESI): 427.2 [M+H] + .

[0686] Step 3: (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0687]

[0688] (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (300 mg, 0.70 mmol) was dissolved in acetic acid (10 mL), and NBS (0.14 g, 0.77 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 1 hour. The reaction mixture was poured into water, and NaHCO3 was added to adjust the pH to 7-8. Then dichloromethane was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one.

[0689] MS m / z (ESI): 505.2 [M+H] + .

[0690] Step 4: (R)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0691]

[0692] Using (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one and methylboronic acid as raw materials, refer to the fourth step of Example 5 to obtain the product (R)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one.

[0693] MS m / z (ESI): 441.2 [M+H] + .

[0694] Example 23

[0695] (R)-6-(bicyclo[2.2.2]octane-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0696]

[0697] Step 1: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(bicyclo[2.2.2]octane-1-yl)acetamide

[0698]

[0699] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid and bicyclo[2.2.2]octane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(bicyclo[2.2.2]octane-1-yl)acetamide.

[0700] MS m / z (ESI): 543.2 [M+H] +

[0701] Step 2: (R)-6-(bicyclo[2.2.2]octane-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0702]

[0703] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(bicyclo[2.2.2]octan-1-yl)acetamide as a raw material, the product (R)-6-(bicyclo[2.2.2]octan-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in step eight of Example 19.

[0704] MS m / z (ESI): 481.2 [M+H] +

[0705] Example 24

[0706] (R)-4-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0707]

[0708] Step 1: Cyclopropyl (2-methyl-3-(trifluoromethyl)phenyl) ketone

[0709]

[0710] Using 2-methyl-3-(trifluoromethyl)benzaldehyde as a raw material, the product cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl) ketone was obtained in the first step of Example 21.

[0711] Step 2: (R)-Cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methylamine

[0712]

[0713] Using cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl) methyl ketone as a raw material, product (R)-cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl) methylamine was obtained by referring to steps three to five of Example 1.

[0714] MS m / z(ESI): 230.1 [M+H] + .

[0715] Step 3: (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)methyl acetate

[0716]

[0717] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, refer to Example 19, step 5 to obtain the product (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate.

[0718] MS m / z (ESI): 466.1 [M+H] +

[0719] Step 4: (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid

[0720]

[0721] Using (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid ester as the raw material, refer to Example 19, step 6 to obtain the product (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid.

[0722] MS m / z (ESI): 452.1 [M+H] +

[0723] Step 5: (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide

[0724]

[0725] Using (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid and 1-(fluoromethyl)cyclopropane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide.

[0726] MS m / z (ESI): 523.3 [M+H] + .

[0727] Step 6: (R)-4-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0728]

[0729] Using (R)-2-(6-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-5-(1,3-dioxapentane-2-yl)-2-methylpyrimidin-4-yl)-N-(1-(fluoromethyl)cyclopropyl)acetamide as a raw material, refer to Example 19, step 8 to obtain the product (R)-4-((cyclopropyl(2-methyl-3-(trifluoromethyl)phenyl)methyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridino[4,3-d]pyrimidin-7(6H)-one.

[0730] MS m / z(ESI): 461.1 [M+H] + .

[0731] Example 25

[0732] (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(1-methylcyclobutyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0733]

[0734] Step 1: 1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-one

[0735]

[0736] Using 1-bromo-2-methyl-3-(trifluoromethyl)benzene as a raw material, the product 1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-one was obtained by referring to the second step of Example 1.

[0737] MS m / z(ESI): 217.1 [M+H] + .

[0738] Step 2: (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine

[0739]

[0740] Using 1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-one as a raw material, the product (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine was obtained by referring to steps three to five of Example 1.

[0741] MS m / z(ESI): 218.1 [M+H] + .

[0742] Step 3: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)methyl acetate

[0743]

[0744] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine and methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, refer to Example 19, step 5 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)acetate.

[0745] MS m / z (ESI): 454.1 [M+H] +

[0746] Step 4: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)acetic acid

[0747]

[0748] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)acetic acid ester as the raw material, refer to Example 19, step 6 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)acetic acid.

[0749] MS m / z (ESI): 440.1 [M+H] +

[0750] Step 5: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)-N-(1-methylcyclobutyl)acetamide

[0751]

[0752] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)acetic acid and 1-methylcyclobutane-1-amine as raw materials, refer to Example 5, step 2 to obtain the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)-N-(1-methylcyclobutyl)acetamide.

[0753] MS m / z (ESI): 507.2 [M+H] +

[0754] Step 6: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(1-methylcyclobutyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0755]

[0756] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)pyrimidin-4-yl)-N-(1-methylcyclobutyl)acetamide as a raw material, refer to Example 19, step 8 to obtain the product (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(1-methylcyclobutyl)pyridino[4,3-d]pyrimidin-7(6H)-one.

[0757] MS m / z (ESI): 445.2 [M+H] +

[0758] Example 26

[0759] (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[0760]

[0761] Step 1: (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0762]

[0763] Using methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, the product (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate was obtained by referring to step 5 of Example 19.

[0764] MS m / z (ESI): 440.1 [M+H] +

[0765] Step 2: (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0766]

[0767] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid as a raw material, the product (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to the first to third steps of Example 22.

[0768] MS m / z(ESI): 495.0 [M+H] + .

[0769] Step 3: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-carbonyl-6,7-dihydropyridino[4,3-d]pyrimidin-8-carboxynitrile

[0770]

[0771] In a 50 mL reaction flask, (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (495 mg, 1 mmol) and CuCN (890 mg, 10 mmol) were dissolved in N-methylpyrrolidone (10 mL), and the mixture was stirred at 140 °C for 8 hours under nitrogen protection. The reaction was stopped, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (dichloromethane / methanol: 20 / 1) to give (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidine-8-carboxynitrile (260 mg, 53%).

[0772] MS m / z(ESI): 442.1 [M+H] + .

[0773] Example 27

[0774] (R)-6-(bicyclo[1.1.1]pentan-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[0775]

[0776] Step 1: (R)-6-(bicyclo[1.1.1]pentan-1-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0777]

[0778] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid as a raw material and replacing 1-methylcyclopropane-1-amine with bicyclo[1.1.1]pentane-1-amine, the product (R)-6-(bicyclo[1.1.1]pentane-1-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to steps one to three of Example 22.

[0779] MS m / z (ESI): 507.0 [M+H] + .

[0780] Step 2: (R)-6-(bicyclo[1.1.1]pentan-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[0781]

[0782] Using (R)-6-(bicyclo[1.1.1]pentan-1-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-6-(bicyclo[1.1.1]pentan-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile was obtained by referring to the third step of Example 26.

[0783] MS m / z (ESI): 454.1 [M+H] + .

[0784] Example 28

[0785] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-ethynylpyridino[4,3-d]pyrimidin-7(6H)-one

[0786]

[0787] Step 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0788]

[0789] Using 4,6-dichloro-5-pyrimidinecarboxaldehyde and (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-amine as raw materials, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidine-7(6H)-one (500 mg) was obtained with reference to Example 19.

[0790] MS m / z (ESI): 425.1 [M+H] + .

[0791] Step 2: (R)-2-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0792]

[0793] In a 50 mL round-bottom flask, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (500 mg, 1.2 mmol) was dissolved in 30 mL of acetonitrile. NBS (210 mg, 1.2 mmol) was added at 0 °C, and the mixture was stirred for 16 h from 0 °C to room temperature. Water (20 mL) was then added. Extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography to obtain (R)-2-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (320 mg).

[0794] MS m / z(ESI): 503.0 [M+H] + .

[0795] Step 3: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-((trimethylsilyl)ethynyl)pyridino[4,3-d]pyrimidin-7(6H)-one

[0796]

[0797] (R)-2-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (300 mg, 0.6 mmol) was dissolved in 20 mL of triethylamine, and trimethylethynylsilane (88 mg, 0.9 mmol), Pd(PPh3)2Cl2 (42 mg, 0.06 mmol), and CuI (11 mg, 0.06 mmol) were added. The reaction was carried out overnight at 65 °C under nitrogen protection. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter, evaporate to dryness, and separate the crude product by column chromatography to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-((trimethylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-7(6H)-one (210 mg).

[0798] MS m / z(ESI): 521.1 [M+H] + .

[0799] Step 4: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-ethynylpyridino[4,3-d]pyrimidin-7(6H)-one

[0800]

[0801] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-((trimethylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-7(6H)-one (100 mg, 0.19 mmol) was dissolved in 10 mL of methanol, and potassium carbonate (125 mg, 0.95 mmol) was added. The mixture was reacted at room temperature for 6 h. The product was evaporated to dryness, and the crude product was separated by column chromatography to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-ethynylpyrido[4,3-d]pyrimidin-7(6H)-one (40 mg).

[0802] MS m / z (ESI): 449.1 [M+H] + .

[0803] Example 29

[0804] (R)-6-(1-(fluoromethyl)cyclopropyl)-2,5-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0805]

[0806] Step 1: N-(1-(fluoromethyl)cyclopropyl)formamide

[0807] Step 1: N-(1-(fluoromethyl)cyclopropyl)formamide

[0808]

[0809] Acetic anhydride (1.7 g, 16.85 mmol) was added dropwise to a formic acid (10 mL) solution of 1-(fluoromethyl)cyclopropane-1-amine (1.0 g, 11.24 mmol), and the mixture was stirred at room temperature for 2 days. The mixture was then extracted with water and dichloromethane (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give N-(1-(fluoromethyl)cyclopropyl)formamide (1.2 g, crude product).

[0810] MS m / z (ESI): 118.1 [M+H] + .

[0811] Step 2: Methyl 2-(5-(1-hydroxyethyl)-2-methyl-6-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate

[0812]

[0813] Methyl magnesium bromide solution (0.84 mL, 2.53 mmol, 3 M) was added dropwise to a tetrahydrofuran (15 mL) solution of (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (1.0 g, 2.53 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with dichloromethane (30 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give methyl 2-(5-(1-hydroxyethyl)-2-methyl-6-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (700 mg, 67%).

[0814] MS m / z(ESI): 412.2 [M+H] + .

[0815] Step 3: (R)-2-(5-acetyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0816]

[0817] To a solution of methyl 2-(5-(1-hydroxyethyl)-2-methyl-6-((((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (700 mg, 1.7 mmol) in dichloromethane (10 mL), Dys-Martin oxidant (1.4 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 10 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give (R)-2-(5-acetyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (620 mg, yield: 89%).

[0818] MS m / z (ESI): 410.2 [M+H] + .

[0819] Step 4: (R)-6-(1-(fluoromethyl)cyclopropyl)-2,5-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0820]

[0821] A mixture of (R)-2-(5-acetyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (100 mg, 0.24 mmol), N-(1-(fluoromethyl)cyclopropyl)formamide (43 mg, 0.37 mmol), and glacial acetic acid (5 mL) was stirred at 100 °C for 8 hours, concentrated under reduced pressure to obtain a residue, and saturated... Extracted with sodium bicarbonate solution and dichloromethane (15 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by preparative chromatography to obtain (R)-6-(1-(fluoromethyl)cyclopropyl)-2,5-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (18 mg, yield: 16%).

[0822] MS m / z (ESI): 449.2 [M+H] + .

[0823] Example 30

[0824] (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-5-ethynyl-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0825]

[0826] Step 1: N-(1-methylcyclopropyl)formamide,

[0827]

[0828] Using methylcyclopropane-1-amine as a raw material, N-(1-methylcyclopropyl)formamide was obtained in the first step of Example 29.

[0829] MS m / z (ESI): 100.1 [M+H] + .

[0830] Step 2: 2-(5-(1-hydroxypropyl-2-yn-1-yl)-2-methyl-6-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate

[0831]

[0832] Using (R)-2-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate and methyl magnesium bromide as raw materials, refer to Example 29 for step 2 to obtain 2-(5-(1-hydroxyprop-2-yn-1-yl)-2-methyl-6-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)methyl acetate.

[0833] MS m / z(ESI): 422.2 [M+H] + .

[0834] Step 3: (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-propynylpyrimidin-4-yl)methyl acetate

[0835]

[0836] Using methyl 2-(5-(1-hydroxyprop-2-yn-1-yl)-2-methyl-6-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate as a raw material, refer to Example 29, step 3 to obtain (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-propynylpyrimidin-4-yl)acetate.

[0837] MS m / z (ESI): 420.2 [M+H] + .

[0838] Step 4: (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-5-ethynyl-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0839]

[0840] Using (R)-2-(2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5-propynylpyrimidin-4-yl)acetate and N-(1-methylcyclopropyl)formamide as raw materials, refer to Example 29, step four to obtain (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-5-ethynyl-2-methyl-6-(1-methylcyclopropyl)pyridino[4,3-d]pyrimidin-7(6H)-one

[0841] MS m / z (ESI): 441.2 [M+H] + .

[0842] Example 31

[0843] N-((S)-1-(3-amino-5-(trifluoromethyl)phenyl)-2-fluoroethyl)-7-methoxy-6-(((R)-tetrahydrofuran-3-

[0844] 4-methylquinazolin-4-amine

[0845]

[0846] Step 1: 6-Hydroxy-7-methoxy-2-methylquinazoline-4(3H)-one

[0847]

[0848] 6,7-Dimethoxy-2-methylquinazoline-4(3H)-one (2.0 g, 9.1 mmol) was dissolved in 10 mL of methanesulfonic acid, and DL-methionine (2.0 g, 13.6 mmol) was added. The reaction was carried out at 80 °C for 16 h. The reaction was quenched with ice water, and 2N sodium hydroxide aqueous solution was added. The mixture was filtered to obtain 6-hydroxy-7-methoxy-2-methylquinazoline-4(3H)-one (1.5 g).

[0849] MS m / z(ESI): 207.0 [M+H] + .

[0850] Step 2: (R)-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)quinazolin-4(3H)-one

[0851]

[0852] 1.5 g (7.3 mmol) of 6-hydroxy-7-methoxy-2-methylquinazoline-4(3H)-one was dissolved in 30 mL of acetonitrile, and potassium carbonate (1.5 g, 10.9 mmol) was added. The mixture was reacted at 80 °C for 16 h. The product was evaporated to dryness, and the crude product was separated by column chromatography to give (R)-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)quinazoline-4(3H)-one (1.6 g).

[0853] MS m / z(ESI): 277.1 [M+H] + .

[0854] Step 3: (R)-4-chloro-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)quinazolin

[0855]

[0856] (R)-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)quinazoline-4(3H)-one (1.0 g, 3.6 mmol) was dissolved in 10 mL of PCl3 and reacted at 90 °C for 4 h. The solution was evaporated to dryness, 5 mL of water was added, and the mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography to give (R)-4-chloro-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)quinazoline (700 mg).

[0857] MS m / z(ESI): 295.0 [M+H] + .

[0858] Step 4: 1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one

[0859]

[0860] Following the second step of Example 1, 1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one (5.0 g) was obtained.

[0861] Step 5: 2-Fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one

[0862]

[0863] Referring to Example 19, step 1 yielded 1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one (2.0 g).

[0864] Step 6: (R,Z)-N-(2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide

[0865]

[0866] Following the third step of Example 1, 1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one (2.0 g) was obtained.

[0867] Step 7: (R)-N-((S)-2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0868]

[0869] Referring to the fourth step of Example 1, (R)-N-((S)-2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide was obtained.

[0870] Step 8: (S)-2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine

[0871]

[0872] (S)-2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine was obtained by referring to step 5 of Example 1.

[0873] Step 9: (S)-3-(1-amino-2-fluoroethyl)-5-(trifluoromethyl)aniline

[0874]

[0875] (S)-2-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine (500 mg) was dissolved in 20 mL of methanol, and 50 mg of Pd / C catalyst was added. The reaction was carried out overnight at room temperature under H2 atmosphere. After filtration and evaporation, (S)-3-(1-amino-2-fluoroethyl)-5-(trifluoromethyl)aniline (530 mg) was obtained.

[0876] MS m / z(ESI): 223.0 [M+H] + .

[0877] Step 10: N-((S)-1-(3-amino-5-(trifluoromethyl)phenyl)-2-fluoroethyl)-7-methoxy-6-(((R)-tetrahydrofuran-3-yl)methyl)quinazolin-4-amine

[0878]

[0879] Referring to step 7 of Example 13, N-((S)-1-(3-amino-5-(trifluoromethyl)phenyl)-2-fluoroethyl)-7-methoxy-6-(((R)-tetrahydrofuran-3-yl)methyl)quinazolin-4-amine (200 mg) was obtained.

[0880] MS m / z (ESI): 465.1 [M+H] + .

[0881] Example 32

[0882] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)-7-methoxy-6-(((R)-tetrahydrofuran-3-yl)methyl)quinazolin-4-amine

[0883]

[0884] Step 1: 1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-ol

[0885]

[0886] Using 3-nitro-5-(trifluoromethyl)benzaldehyde as a raw material, 1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-ol was obtained in the first step of Example 21.

[0887] Step 2: N-(1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)acetamide

[0888]

[0889] Referring to the second step of Example 21, N-(1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)acetamide was obtained.

[0890] Step 3: (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-ynyl-1-amine

[0891]

[0892] Referring to the third and fourth steps of Example 21, (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-amine was obtained.

[0893] Step 4: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)-7-methoxy-6-(((R)-tetrahydrofuran-3-yl)methyl)quinazolin-4-amine

[0894]

[0895] Referring to Example 31, N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)-7-methoxy-6-(((R)-tetrahydrofuran-3-yl)methyl)quinazolin-4-amine was obtained.

[0896] MS m / z (ESI): 457.1 [M+H] + .

[0897] Example 33

[0898] (S)-2-((6-(bicyclo[2.2.1]heptane-1-yl)-2-methyl-7-carbonyl-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)-2-(2-methyl-3-(trifluoromethyl)phenyl)acetonitrile

[0899]

[0900] Starting with (S)-2-amino-2-(2-methyl-3-(trifluoromethyl)phenyl)acetonitrile, (S)-2-((6-(bicyclo[2.2.1]heptane-1-yl)-2-methyl-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)-2-(2-methyl-3-(trifluoromethyl)phenyl)acetonitrile was obtained by referring to steps five to eight of Example 21.

[0901] MS m / z (ESI): 468.1 [M+H] + .

[0902] Example 34

[0903] N-((S)-1-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[0904]

[0905] Step 1: (S)-N-(1-(2-methyl-4-carbonyl-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[0906]

[0907] In a 50 mL round-bottom flask, 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (197 mg, 1 mmol), (S)-N-(pyrrolidine-3-yl)acetamide (258 mg, 2 mmol), potassium fluoride (58 mg, 1 mmol), DMSO (2 mL), and N,N-diisopropylethylamine (390 mg, 3 mmol) were added sequentially under nitrogen protection. The reaction mixture was stirred at 130 °C for 48 hours, concentrated, dissolved in ethyl acetate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 10 / 1) to obtain (S)-N-(1-(2-methyl-4-carbonyl-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide (150 mg, yield: 51.8%).

[0908] MS m / z(ESI): 288.1 [M+H] + .

[0909] Step 2: N-((S)-1-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[0910]

[0911] Add trichlorophosphazene (146 mg, 0.42 mmol) to a mixture of (S)-N-(1-(2-methyl-4-carbonyl-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide (100 mg, 0.35 mmol), potassium phosphate (222 mg, 1.05 mmol), and acetonitrile (5 mL), then stir at room temperature for 1 hour, followed by the addition of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (85 mL). The reaction was stirred at room temperature for 16 hours (mg, 0.42 mmol), quenched with water, extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by preparative chromatography to obtain N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide (50 mg, yield: 30%).

[0912] MS m / z(ESI): 474.2 [M+H] + .

[0913] Example 35

[0914] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(3-Fluorobico[1.1.1]pentan-1-yl)-N 6 2-Dimethylpyrido[3,4-d]pyrimidine-4,6-diamine

[0915]

[0916] Step 1: 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0917]

[0918] Using 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one as a raw material, the product 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one was obtained in the first step of Example 34.

[0919] MS m / z(ESI): 275.1 [M+H] + .

[0920] Step 2: (R)-N 4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(3-Fluorobico[1.1.1]pentan-1-yl)-N 6 2-Dimethylpyrido[3,4-d]pyrimidine-4,6-diamine

[0921]

[0922] Using 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one as a starting material, product (R)-N was obtained in step 2 of Example 34. 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(3-Fluorobico[1.1.1]pentan-1-yl)-N 6 ,2-Dimethylpyrido[3,4-d]pyrimidine-4,6-diamine.

[0923] MS m / z (ESI): 461.2 [M+H] + .

[0924] Example 36

[0925] N-((S)-1-(8-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methylpyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide

[0926]

[0927] Step 1: 2-Methyl-6-(methylthio)pyrimidino[5,4-d]pyrimidin-4(3H)-one

[0928]

[0929] A mixture of 5-amino-2-(methylthio)pyrimidine-4-carboxylic acid (2 g, 10.8 mmol), acetamidine hydrochloride (4.06 g, 43.2 mmol), sodium acetate (2.66 g, 32.4 mmol), and 2-methoxyethanol (30 mL) was stirred at 120 °C for 12 hours. The reaction system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane (60 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 15 / 1) to give 2-methyl-6-(methylthio)pyrimidino[5,4-d]pyrimidine-4(3H)-one (mg, mmol) (1.5 g, yield: 67%).

[0930] MS m / z(ESI): 209.0 [M+H] + .

[0931] Step 2: 2-Methyl-6-(methanesulfonyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one

[0932]

[0933] To a solution of 1.5 g (7.2 mmol) of 2-methyl-6-(methylthio)pyrimido[5,4-d]pyrimidin-4(3H)-one in dichloromethane (20 mL), m-chloroperoxybenzoic acid (3.7 g, 21.6 mmol) was added. The mixture was stirred at room temperature for 12 hours, and the reaction was quenched with water. The mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 12 / 1) to give 2-methyl-6-(methanesulfonyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (1.2 g, yield: 71%).

[0934] MS m / z(ESI): 241.0 [M+H] + .

[0935] Step 3: (S)-N-(1-(6-methyl-8-carbonyl-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide

[0936]

[0937] A mixture of 2-methyl-6-(methanesulfonyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one (300 mg, 1.25 mmol), (S)-N-(pyrrolidone-3-yl)acetamide (320 mg, 2.5 mmol), N,N-diisopropylethylamine (484 mg, 3.75 mmol), and dioxane (10 mL) was stirred at 100 °C for 2 hours. The reaction system was then cooled to room temperature. The reaction was quenched with water at room temperature, extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give (S)-N-(1-(6-methyl-8-carbonyl-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide (300 mg, yield: 83%).

[0938] MS m / z(ESI): 289.1[M+H]+.

[0939] Step 4: N-((S)-1-(8-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methylpyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide

[0940]

[0941] Add trichlorophosphazene (146 mg, 0.42 mmol) to a mixture of (S)-N-(1-(6-methyl-8-carbonyl-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide (100 mg, 0.35 mmol), potassium phosphate (222 mg, 1.05 mmol), and acetonitrile (5 mL), then stir at room temperature for 1 hour, followed by the addition of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (8 mL). 5 mg (0.42 mmol) was stirred at room temperature for 16 hours, the reaction was quenched with water, extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was separated by preparative chromatography to obtain N-((S)-1-(8-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methylpyrimidino[5,4-d]pyrimidin-2-yl)pyrrolidine-3-yl)acetamide (12 mg, yield: 7%).

[0942] MS m / z(ESI): 475.2[M+H]+.

[0943] Example 37

[0944] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-ethoxy-2-methylpyrimidino[5,4-d]pyrimidin-4-amine

[0945]

[0946] Step 1: 6-ethoxy-2-methylpyrimidino[5,4-d]pyrimidin-4(3H)-one

[0947]

[0948] Sodium ethoxide (425 mg, 6.24 mmol) was added to an ethanol (15 mL) solution of 2-methyl-6-(methanesulfonyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (300 mg, 1.25 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, extracted with dichloromethane (50 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 15 / 1) to give 6-ethoxy-2-methylpyrimido[5,4-d]pyrimidin-4(3H)-one (210 mg, yield 81%).

[0949] MS m / z(ESI): 207.1[M+H]+.

[0950] Step 2: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-ethoxy-2-methylpyrimidino[5,4-d]pyrimidin-4-amine

[0951]

[0952] Using 6-ethoxy-2-methylpyrimidino[5,4-d]pyrimidin-4(3H)-one and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline as starting materials, (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-ethoxy-2-methylpyrimidino[5,4-d]pyrimidin-4-amine (8 mg, yield: 10%) was obtained by referring to step 4 of Example 36.

[0953] MS m / z(ESI): 392.3[M+H]+.

[0954] Example 38

[0955] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(((R)-tetrahydrofuran-3-yl)oxo)pyrido[4,3-d]pyrimidin-4-amine

[0956]

[0957] Step 1: 7-Chloro-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

[0958]

[0959] Using 4-amino-6-chloronicotinic acid as a starting material, 7-chloro-2-methylpyridano[4,3-d]pyrimidin-4(3H)-one (300 mg, yield: 15%) was obtained in the first step of Example 36 (referring to Example 36).

[0960] MS m / z(ESI): 196.0[M+H]+.

[0961] Step 2: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-chloro-2-methylpyrido[4,3-d]pyrimidin-4-amine

[0962]

[0963] Using 7-chloro-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a starting material, (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-chloro-2-methylpyrido[4,3-d]pyrimidin-4-amine (220 mg, yield: 70%) was obtained by referring to step 4 of Example 36.

[0964] MS m / z(ESI): 382.1 [M+H] + .

[0965] Step 3: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(((R)-tetrahydrofuran-3-yl)oxo)pyrido[4,3-d]pyrimidin-4-amine

[0966]

[0967] Add sodium hydroxide (40 mg, 1.04 mmol, 60%) to a 5 mL solution of (R)-(-)-3-hydroxytetrahydrofuran (46 mg, 0.52 mmol), stir at room temperature for 30 minutes, and then add (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-chloro-2-methylpyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol). Then, the mixture was stirred at 70°C for 24 hours, cooled, and quenched with water. It was extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. Preparative chromatography was used to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(((R)-tetrahydrofuran-3-yl)oxo)pyrido[4,3-d]pyrimidin-4-amine (10 mg, yield: 9%).

[0968] MS m / z(ESI): 434.2 [M+H] + .

[0969] Example 39

[0970] N-((S)-1-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7-yl)pyrrolidine-3-yl)acetamide

[0971]

[0972] Step 1: N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[4,3-d]pyrimidin-7-yl)pyrrolidine-3-yl)acetamide

[0973]

[0974] Using (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-chloro-2-methylpyrido[4,3-d]pyrimidin-4-amine and (S)-N-(pyrrolidine-3-yl)acetamide as raw materials, refer to step 3 of Example 36 to obtain N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7-yl)pyrrolidine-3-yl)acetamide (7 mg, yield: 10%).

[0975] MS m / z(ESI): 474.2 [M+H] + .

[0976] Example 40

[0977] (R)-6-Cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one

[0978]

[0979] Step 1: 2-Amino-5-bromo-4-methoxybenzoic acid

[0980]

[0981] 2-Amino-4-methoxybenzoic acid (5.0 g, 30 mmol) was dissolved in DMF (50 mL), and NBS (6.4 g, 36 mmol) was added at 0 °C. The mixture was slowly heated to room temperature and stirred for one hour. Saturated sodium sulfite solution was added and stirred for 5 min. The pH was adjusted to 3, and then ethyl acetate was added for extraction. The mixture was evaporated to dryness to obtain the crude product 2-amino-5-bromo-4-methoxybenzoic acid (7.3 g).

[0982] MS m / z(ESI): 168.0 [M+H]+

[0983] Step 2: 6-Bromo-7-methoxy-2-methylquinazolin-4(3H)-one

[0984]

[0985] Referring to Example 36, the first step yields the product 6-bromo-7-methoxy-2-methylquinazoline-4(3H)-one.

[0986] MS m / z(ESI): 268.9 [M+H] +

[0987] Step 3: 6-(cyclobutylamino)-7-methoxy-2-methylquinazolin-4(3H)-one

[0988]

[0989] A mixture of 6-bromo-7-methoxy-2-methylquinazoline-4(3H)-one (1 g, 3.7 mmol), cyclobutylamine (300 mg, 4.5 mmol), cesium carbonate (3.6 g, 11.1 mmol), and toluene (30 mL) was added to tris(dibenzylideneacetone)dipalladium (338 mg, 0.37 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (427 mg, 0.74 mmol). After nitrogen purging, the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to obtain 6-(cyclobutylamino)-7-methoxy-2-methylquinazoline-4(3H)-one (570 mg, yield 60%).

[0990] MS m / z(ESI): 260.1 [M+H] +

[0991] Step 4: 6-(cyclobutylamino)-7-hydroxy-2-methylquinazoline-4(3H)-one

[0992]

[0993] Refer to step 6 of Example 8 to obtain the product: 6-(cyclobutylamino)-7-hydroxy-2-methylquinazoline-4(3H)-one.

[0994] MS m / z(ESI): 246.1 [M+H] +

[0995] Step 5: 6-Cyclobutyl-2-methyl-3,6-dihydro-4H-[1,4]oxohexaazinyl[3,2-g]quinazolin-4,7(8H)-dione

[0996]

[0997] 6-(cyclobutylamino)-7-hydroxy-2-methylquinazolin-4(3H)-one (300 mg, 1.2 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (363 mg, 3.6 mmol) and 2-chloroacetyl chloride (161 mg, 1.44 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was dissolved in... Potassium carbonate (496 mg, 3.6 mmol) was added to DMF (30 mL), and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to obtain 6-cyclobutyl-2-methyl-3,6-dihydro-4H-[1,4]oxadiazono[3,2-g]quinazolin-4,7(8H)-dione (86 mg, yield 25%).

[0998] MS m / z(ESI): 286.1 [M+H] +

[0999] Step 6: (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one

[1000]

[1001] Referring to steps eight and nine of Example 1, the product (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one is obtained.

[1002] MS m / z (ESI): 457.1 [M+H] +

[1003] Example 41

[1004] (R)-6-Cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one

[1005]

[1006] (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one (100 mg, 0.22 mmol) was dissolved in THF (10 mL), and lithium aluminum hydride (10 mg, 0.26 mmol) was added at -78 °C. The mixture was stirred for two hours after the temperature was lowered from -78 °C to room temperature. After the reaction was complete, water (20 mL) was added. Extracted with ethyl acetate (50 mL x 3), the combined organic phases were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by high performance liquid chromatography to obtain (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one (24 mg, yield 25%).

[1007] MS m / z (ESI): 443.4 [M+H] +

[1008] Example 42

[1009] (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-cyclobutyl-2,2-dimethyl-6H-2l5-[1,4]oxazo[3,2-g]quinazolin-7(8H)-one

[1010]

[1011] Referring to Example 40, the product (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-cyclobutyl-2,2-dimethyl-6H-2l5-[1,4]oxadiazono[3,2-g]quinazolin-7(8H)-one was obtained.

[1012] MS m / z(ESI): 472.1 [M+H] +

[1013] Example 43

[1014] (R)-3-Cyclopentyl-7-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidino[4,5-d]pyrimidin-2(3H)-one

[1015]

[1016] Step 1: 7-Methylpyrimido[4,5-d]pyrimidin-2,5(3H,6H)-dione

[1017]

[1018] Referring to Example 36, the first step yields the product 7-methylpyrimido[4,5-d]pyrimidin-2,5(3H,6H)-dione.

[1019] MS m / z (ESI): 179.1 [M+H] +

[1020] Step 2: 3-Cyclopentyl-7-methylpyrimidino[4,5-d]pyrimidin-2,5(3H,6H)-dione

[1021]

[1022] 7-Methylpyrimido[4,5-d]pyrimidin-2,5(3H,6H)-dione (500 mg, 2.8 mmol) was dissolved in THF (30 mL), and triphenylphosphine (1.1 g, 4.2 mmol), diethyl azodicarbonate (730 mg, 4.2 mmol), and cyclopentanol (481 mg, 5.6 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to obtain 3-cyclopentyl-7-methylpyrimido[4,5-d]pyrimidin-2,5(3H,6H)-dione (358 mg, 52% yield).

[1023] MS m / z(ESI): 247.1 [M+H] +

[1024] Step 3: (R)-3-cyclopentyl-7-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidino[4,5-d]pyrimidin-2(3H)-one

[1025]

[1026] Referring to steps eight and nine of Example 1, the product (R)-3-cyclopentyl-7-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidino[4,5-d]pyrimidin-2(3H)-one is obtained.

[1027] MS m / z(ESI): 432.1 [M+H] +

[1028] Example 44

[1029] (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-cyclopentyl-7-methylpyrimidino[4,5-d]pyrimidin-2(3H)-one

[1030]

[1031] Referring to Example 44, the product (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-cyclopentyl-7-methylpyrimidino[4,5-d]pyrimidin-2(3H)-one was obtained.

[1032] MS m / z(ESI): 433.1 [M+H] +

[1033] Example 45

[1034] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine

[1035]

[1036] Step 1: Methyl 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[1037]

[1038] A mixture of 2-amino-1H-pyrrolo-3-onitrile (10 g, 93.36 mmol), tin tetrachloride (33 g, 93.36 mmol), methyl 3-carbonylpropionate (11.44 g, 112.03 mmol), and anhydrous toluene (150 mL) was stirred at room temperature for half an hour, then refluxed for 12 hours. The reaction system was cooled to room temperature, and the reaction was quenched with water and saturated sodium carbonate solution. The mixture was extracted with dichloromethane (100 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 15 / 1) to give methyl 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2 g, yield: 11%).

[1039] MS m / z(ESI): 192.1 [M+H] + .

[1040] Step 2: Methyl 4-amino-7-cyclobutyl-7H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ester

[1041]

[1042] A mixture of methyl 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2 g, 10.46 mmol), cyclobutyl bromide (2.12 g, 15.69 mmol), cesium carbonate (6.82 g, 20.92 mmol), and anhydrous N,N-dimethylformamide (30 mL) was stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with dichloromethane (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (dichloromethane / methanol = 10 / 1) to give methyl 4-amino-7-cyclobutyl-7H-pyrrolo[2,3-b]pyridine-5-carboxylate (300 mg, yield: 12%).

[1043] MS m / z(ESI): 246.1 [M+H] + .

[1044] Step 3: 6-Cyclobutyl-2-methyl-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one

[1045]

[1046] Using methyl 4-amino-7-cyclobutyl-7H-pyrrolo[2,3-b]pyridine-5-carboxylic acid as a raw material, 6-cyclobutyl-2-methyl-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one was obtained by referring to step 6 of Example 1.

[1047] MS m / z (ESI): 255.1 [M+H] + .

[1048] Step 4: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine

[1049]

[1050] Using 6-cyclobutyl-2-methyl-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one as a starting material, (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine was obtained by referring to step 4 of Example 36.

[1051] MS m / z (ESI): 441.2 [M+H] + .

[1052] Example 46

[1053] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine

[1054]

[1055] Step 1: Methyl 4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[1056]

[1057] Using methyl 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylate and 3-bromotetrahydrofuran as raw materials, methyl 4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxylate was obtained in step 2 of Example 45.

[1058] MS m / z(ESI): 262.1 [M+H] + .

[1059] Step 2: 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one

[1060]

[1061] Using methyl 4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxylic acid as a starting material, 2-methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyridolo[4,3-d]pyrimidin-4-one was obtained by referring to step 6 of Example 1.

[1062] MS m / z(ESI): 271.1 [M+H] + .

[1063] Step 3: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine

[1064]

[1065] Using 2-methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine as raw materials, refer to step 4 of Example 36 to obtain N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-amine

[1066] MS m / z(ESI): 442.2 [M+H] + .

[1067] Example 47

[1068] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin-4-amine

[1069]

[1070] Step 1: Dimethyl 4-hydroxy-6-(2-methoxy-2-carbonylethoxy)isophthalate

[1071]

[1072] Dimethyl 4,6-dihydroxyisophthalate (5 g, 22.1 mmol) was dissolved in acetone (100 mL), and methyl bromoacetate (3.4 g, 22.1 mmol) and potassium carbonate (4.6 g, 33.2 mmol) were added. The reaction mixture was refluxed overnight. The reaction solution was filtered and evaporated to dryness. The crude product was purified by column chromatography to give dimethyl 4-hydroxy-6-(2-methoxy-2-carbonylethoxy)isophthalate (4 g, yield: 60.7%).

[1073] MS m / z(ESI): 299.2 [M+H] + .

[1074] Step 2: 6-Hydroxy-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid ester

[1075]

[1076] Dimethyl 4-hydroxy-6-(2-methoxy-2-carbonylethoxy)isophthalate (4 g, 13.4 mmol) was dissolved in DMF (5 mL), and potassium phosphate (8.5 g, 40.2 mmol) and methanol (5 mL) were added. The reaction was carried out under microwave conditions at 150 °C for half an hour. The reaction solution was concentrated and then purified directly by column chromatography to give 6-hydroxy-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid ester (1.5 g, yield 53.7%).

[1077] MS m / z(ESI): 209.2 [M+H] + .

[1078] Step 3: Methyl 3-carbonyl-6-(toluenesulfonyloxy)-2,3-dihydrobenzofuran-5-carboxylic acid ester

[1079]

[1080] 6-Hydroxy-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid ester (1.5 g, 7.2 mmol) was dissolved in anhydrous dichloromethane (30 mL), and TsCl (1.5 g, 7.9 mmol) and pyridine (1.1 g, 14.4 mmol) were added. The reaction was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give methyl 3-carbonyl-6-(toluenesulfonyloxy)-2,3-dihydrobenzofuran-5-carboxylic acid ester (2.3 g, yield 88.1%).

[1081] MS m / z(ESI): 363.2 [M+H] + .

[1082] Step 4: Methyl 6-acetamido-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid

[1083]

[1084] Methyl 3-carbonyl-6-(toluenesulfonyloxy)-2,3-dihydrobenzofuran-5-carboxylic acid (2.3 g, 6.4 mmol) was dissolved in 1,4-dioxane (50 mL), and acetamide (0.94 g, 15.9 mmol) and potassium phosphate (5.4 g, 25.4 mmol) were added. [Pd(cinnamyl)Cl]₂ (328 mg, 0.64 mmol) and XantPhos (741 mg, 1.3 mmol) were added under nitrogen protection. The reaction was refluxed overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give methyl 6-acetamido-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid (1 g, yield 63.2%).

[1085] MS m / z (ESI): 250.2 [M+H] + .

[1086] Step 5: 2-Methylfurano[3,2-g]quinazolin-4,6(3H,7H)-dione

[1087]

[1088] Methyl 6-acetamido-3-carbonyl-2,3-dihydrobenzofuran-5-carboxylic acid (1 g, 4.0 mmol) was dissolved in 4NNH3 / MeOH (30 mL). The reaction was stirred under closed conditions for 4 hours. The reaction mixture was evaporated to dryness. The crude product was purified by column chromatography to give 2-methylfurano[3,2-g]quinazolin-4,6(3H,7H)-dione (700 mg, yield 80.7%).

[1089] MS m / z (ESI): 217.2 [M+H] + .

[1090] Step 6: 6-Hydroxy-2-methyl-6,7-dihydrofurano[3,2-g]quinazolin-4(3H)-one

[1091]

[1092] 2-Methylfurano[3,2-g]quinazoline-4,6(3H,7H)-dione (700 mg, 3.2 mmol) was dissolved in methanol, and Pd / C (100 mg) was added. The reaction was stirred under hydrogen atmosphere for 2 hours. The reaction solution was filtered to give 6-hydroxy-2-methyl-6,7-dihydrofurano[3,2-g]quinazoline-4(3H)-one (650 mg, 92.0% yield).

[1093] MS m / z(ESI): 219.2 [M+H] + .

[1094] Step 7: 2-Methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin-4(3H)-one

[1095]

[1096] 6-Hydroxy-2-methyl-6,7-dihydrofurano[3,2-g]quinazolin-4(3H)-one (650 mg, 3.0 mmol) was dissolved in acetonitrile (20 mL), and 1-methylcyclobutyl-4-methylbenzenesulfonate (931 mg, 3.9 mmol) and potassium carbonate (823 mg, 6.0 mmol) were added. The reaction was stirred overnight at 90 °C. The reaction solution was directly concentrated and purified by column chromatography to give 2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin-4(3H)-one (400 mg, yield 46.9%).

[1097] MS m / z(ESI): 287.2 [M+H] + .

[1098] Step 8: 4-Chloro-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin

[1099]

[1100] Using 2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin-4(3H)-one as a raw material, the product 4-chloro-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin was obtained by referring to step 8 of Example 1.

[1101] MS m / z (ESI): 305.2 [M+H] + .

[1102] Step 9: 2-Methyl-6-(1-methylcyclobutoxy)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6,7-dihydrofurano[3,2-g]quinazolin-4-amine

[1103]

[1104] Using 4-chloro-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazoline and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, the product 2-methyl-6-(1-methylcyclobutoxy)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6,7-dihydrofurano[3,2-g]quinazoline-4-amine was obtained by referring to step nine of Example 1.

[1105] MS m / z (ESI): 503.2 [M+H] + .

[1106] Step 10: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazolin-4-amine

[1107]

[1108] 2-Methyl-6-(1-methylcyclobutoxy)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6,7-dihydrofurano[3,2-g]quinazoline-4-amine (100 mg, 0.20 mmol) was dissolved in methanol (10 mL), and Pd / C (15 mg) was added. The reaction was stirred under hydrogen atmosphere for 4 hours. The reaction solution was filtered and concentrated. The crude product was purified by prep-HPLC to give N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methylcyclobutoxy)-6,7-dihydrofurano[3,2-g]quinazoline-4-amine (12 mg, yield 12.3%).

[1109] MS m / z(ESI): 473.2 [M+H] + .

[1110] Example 48

[1111] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4-amine

[1112]

[1113] Step 1: Methyl 2-(tert-butylamino)-6-methoxynicotinic acid

[1114]

[1115] Using methyl 2-chloro-6-methoxynicotinic acid and 2-methylpropane-2-amine as raw materials, the product methyl 2-(tert-butylamino)-6-methoxynicotinic acid was obtained by referring to step nine of Example 1.

[1116] MS m / z(ESI): 239.2 [M+H] + .

[1117] Step 2: Methyl 2-(tert-butylamino)-5-chloro-6-methoxynicotinic acid

[1118]

[1119] 2-(tert-butylamino)-6-methoxynicotinic acid methyl ester (5 g, 21.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and NCS (2.9 g, 22.0 mmol) was added in portions. After the addition was complete, the reaction was heated to 70 °C overnight. Sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 2-(tert-butylamino)-5-chloro-6-methoxynicotinic acid methyl ester (3.5 g, yield 61.2%).

[1120] MS m / z(ESI): 273.2 [M+H] + .

[1121] Step 3: (S)-2-(tert-butylamino)-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)methyl nicotinate

[1122]

[1123] Using methyl 2-(tert-butylamino)-5-chloro-6-methoxynicotinic acid and (S)-tetrahydrofuran-3-ol as raw materials, the product (S)-2-(tert-butylamino)-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)nicotinic acid methyl ester was obtained by referring to the second step of Example 31.

[1124] MS m / z (ESI): 325.2 [M+H] + .

[1125] Step 4: (S)-2-amino-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)methyl nicotinic acid

[1126]

[1127] (S)-2-(tert-butylamino)-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)methyl nicotinate (1 g, 3.1 mmol) was dissolved in TFA (25 mL). The reaction mixture was refluxed overnight. The reaction solution was evaporated to dryness and then dissolved in dichloromethane. Sodium bicarbonate aqueous solution was added to adjust the pH to 7-8. The organic phase was dried and evaporated to dryness to give (S)-2-amino-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)methyl nicotinate (800 mg, yield 96.7%).

[1128] MS m / z(ESI): 269.2 [M+H] + .

[1129] Step 5: (S)-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4(3H)-one

[1130]

[1131] Using (S)-2-amino-6-methoxy-5-((tetrahydrofuran-3-yl)oxo)nicotinic acid methyl ester as a raw material, the product (S)-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4(3H)-one was obtained by referring to step 6 of Example 1.

[1132] MS m / z(ESI): 278.2 [M+H] + .

[1133] Step 6: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidine-4-amine

[1134]

[1135] Using (S)-7-methoxy-2-methyl-6-(((tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4(3H)-one and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline as raw materials, refer to the fourth step of Example 36 to obtain the product N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4-amine.

[1136] MS m / z (ESI): 464.2 [M+H] + .

[1137] Example 49

[1138] 7,7-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-(((S)-tetrahydrofuran-3-yl)oxo)-7λ 5 -Pyrimidino[4,5-c]pyridazine-5-amine

[1139]

[1140] Step 1: 3-Chloro-7,7-dimethyl-7λ 5 -Pyrimidino[4,5-c]pyridazine-5(6H)-one

[1141]

[1142] Using methyl 3-amino-6-chloropyridazine-4-carboxylate as a raw material, the product 3-chloro-7,7-dimethyl-7λ was obtained by referring to step 6 of Example 1.5 -Pyrimidino[4,5-c]pyridazine-5(6H)-one.

[1143] MS m / z(ESI): 212.0 [M+H] + .

[1144] Step 2: (S)-7,7-dimethyl-3-((tetrahydrofuran-3-yl)oxo)-7λ 5 -Pyrimidino[4,5-c]pyridazine-5(6H)-one

[1145]

[1146] In a 50 mL round-bottom flask, (S)-tetrahydrofuran-3-ol (175 mg, 2 mmol) and DMF (2 mL) were added sequentially, followed by sodium hydride (80 mg, 2 mmol, 60%). The reaction mixture was kept under nitrogen protection at room temperature for 2 hours, after which 3-chloro-7,7-dimethyl-7λ was added. 5 A DMF solution of pyrimidino[4,5-c]pyridazine-5(6H)-one (211 mg, 1 mmol) was prepared, and the reaction mixture was heated to 100 °C and reacted for 24 hours. The reaction mixture was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 20 / 1) to give (S)-7,7-dimethyl-3-((tetrahydrofuran-3-yl)oxo)-7λ 5 -Pyrimido[4,5-c]pyridazine-5(6H)-one (160 mg, yield: 61.0%).

[1147] MS m / z(ESI): 264.1 [M+H] + .

[1148] Step 3: 7,7-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-(((S)-tetrahydrofuran-3-yl)oxo)-7λ 5 -Pyrimidino[4,5-c]pyridazine-5-amine

[1149]

[1150] (S)-7,7-dimethyl-3-((tetrahydrofuran-3-yl)oxo)-7λ 5 Using pyrimidino[4,5-c]pyridazine-5(6H)-one as a starting material, the product 7,7-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-(((S)-tetrahydrofuran-3-yl)oxo)-7λ was obtained in step 2 of Example 34. 5 -Pyrimidino[4,5-c]pyridazine-5-amine.

[1151] MS m / z (ESI): 449.2 [M+H] + .

[1152] Example 50

[1153] N-((S)-1-(2,2,8-trimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-7,8-dihydro-2λ 5 -pterin-6-yl)pyrrolidine-3-yl)acetamide

[1154]

[1155] Step 1: 6-Chloro-2,2-Dimethyl-2λ 5 -Pteridine-4,7(3H,8H)-dione

[1156]

[1157] Using methyl 3-amino-6-chloro-5-hydroxypyrazine-2-carboxylic acid ester as a raw material, the product 6-chloro-2,2-dimethyl-2λ was obtained by referring to step 6 of Example 1. 5 -Pteridine-4,7(3H,8H)-dione

[1158] MS m / z(ESI): 228.0 [M+H] + .

[1159] Step 2: 6-Chloro-2,2,8-Trimethyl-2λ 5 -Pteridine-4,7(3H,8H)-dione

[1160]

[1161] 6-chloro-2,2-dimethyl-2λ was added sequentially to a 50 mL pear-shaped flask. 5 3-Pteridine-4,7(3H,8H)-dione (300 mg, 1.3 mmol) and acetone (10 mL) were added, followed by the addition of iodomethane (560 mg, 4 mmol) and potassium carbonate (360 mg, 2.6 mmol). The reaction mixture was reacted at 60 °C for 12 hours under nitrogen protection, then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 20 / 1) to give 6-chloro-2,2,8-trimethyl-2λ. 5 -Pteridine-4,7(3H,8H)-dione (140 mg, yield: 45.0%).

[1162] MS m / z(ESI): 242.0 [M+H] + .

[1163] Step 3: (S)-N-(1-(2,2,8-trimethyl-4,7-dicarbonyl-3,4,7,8-tetrahydro-2λ) 5 -pterin-6-yl)pyrrolidine-3-yl)acetamide

[1164]

[1165] 6-Chloro-2,2,8-trimethyl-2λ 5 Using -pteridine-4,7(3H,8H)-dione as a starting material, the first step of Example 34 yielded the product (S)-N-(1-(2,2,8-trimethyl-4,7-dicarbonyl-3,4,7,8-tetrahydro-2λ). 5 -pterin-6-yl)pyrrolidine-3-yl)acetamide.

[1166] MS m / z(ESI): 334.1 [M+H] + .

[1167] Step 4: N-((S)-1-(2,2,8-trimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-7,8-dihydro-2λ 5 -pterin-6-yl)pyrrolidine-3-yl)acetamide

[1168]

[1169] (S)-N-(1-(2,2,8-trimethyl-4,7-dicarbonyl-3,4,7,8-tetrahydro-2λ) 5 Using pteridine-6-yl)pyrrolidine-3-yl)acetamide as a raw material, refer to Example 34, step 2 yields the product N-((S)-1-(2,2,8-trimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-7,8-dihydro-2λ 5 -pterin-6-yl)pyrrolidine-3-yl)acetamide.

[1170] MS m / z (ESI): 519.2 [M+H] + .

[1171] Example 51

[1172] (R)-6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

[1173]

[1174] Step 1: Methyl 2-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid

[1175]

[1176] Methyl 2-chloro-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid (5 g, 26.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to 0 °C, and NaH (1.3 g, 32.0 mmol) was added in portions. The reaction mixture was stirred at 0 °C for half an hour, and iodomethane (5.7 g, 40.0 mmol) was added. The reaction was heated to room temperature and stirred overnight. Water was added, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give methyl 2-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid (3.8 g, yield 70.7%).

[1177] MS m / z(ESI): 202.2 [M+H] + .

[1178] Step 2: Methyl 2-(tert-butylamino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid ester

[1179]

[1180] Using methyl 2-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylate and 2-methylpropane-2-amine as raw materials, the product methyl 2-(tert-butylamino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylate was obtained by referring to step nine of Example 1.

[1181] MS m / z(ESI): 239.2 [M+H] + .

[1182] Step 3: Methyl 2-(tert-butylamino)-5-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid ester

[1183]

[1184] Using methyl 2-(tert-butylamino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid as a raw material, the product methyl 2-(tert-butylamino)-5-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid was obtained in step 2 of Example 48.

[1185] MS m / z(ESI): 273.2 [M+H] + .

[1186] Step 4: 2-(tert-butylamino)-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid methyl ester

[1187]

[1188] Using methyl 2-(tert-butylamino)-5-chloro-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid and 3-fluoro-N-methylbicyclo[1.1.1]pentane-1-amine as raw materials, the product methyl 2-(tert-butylamino)-5-((3-fluorobicyclo[1.1.1]pentane-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid was obtained in the second step of Example 31.

[1189] MS m / z(ESI): 352.2 [M+H] + .

[1190] Step 5: Methyl 2-amino-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid ester

[1191]

[1192] Using methyl 2-(tert-butylamino)-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid as the raw material, the product methyl 2-amino-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid was obtained by referring to the fourth step of Example 48.

[1193] MS m / z(ESI): 296.2 [M+H] + .

[1194] Step 6: 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

[1195]

[1196] Using methyl 2-amino-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid ester as the raw material, the product 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione was obtained by referring to step 6 of Example 1.

[1197] MS m / z (ESI): 305.2 [M+H] + .

[1198] Step 7: (R)-6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

[1199]

[1200] Using 6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethylpyrido[2,3-d]pyrimidin-4,7(3H,8H)-dione and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, the product (R)-6-((3-fluorobicyclo[1.1.1]pentan-1-yl)(methyl)amino)-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one was obtained by referring to step four of Example 36.

[1201] MS m / z(ESI): 490.2 [M+H] + .

[1202] Example 52

[1203] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4-amine

[1204]

[1205] Step 1: 6-Chloro-2-methylpyridano[3,2-d]pyrimidin-4(3H)-one

[1206]

[1207] Using 3-amino-6-chloro-o-pyridinecarboxylic acid as a raw material, the product 6-chloro-2-methylpyrido[3,2-d]pyrimidine-4(3H)-one was obtained in the first step of Example 36.

[1208] MS m / z (ESI): 196.2 [M+H] + .

[1209] Step 2: (S)-2-methyl-6-((tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4(3H)-one

[1210]

[1211] Using 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one and (S)-tetrahydrofuran-3-ol as raw materials, the product (S)-2-methyl-6-((tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4(3H)-one was obtained by referring to the second step of Example 31.

[1212] MS m / z(ESI): 248.2 [M+H] + .

[1213] Step 3: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4-amine

[1214]

[1215] Using (S)-2-methyl-6-((tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4(3H)-one and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline as raw materials, the product N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[3,2-d]pyrimidin-4-amine was obtained by referring to the fourth step of Example 36.

[1216] MS m / z(ESI): 434.2 [M+H] + .

[1217] Example 53

[1218] N-((S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -thieno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1219]

[1220] Step 1: (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-3-aminothiophene-2-carboxylic acid methyl ester

[1221]

[1222] Using 4-amino-5-(methyl ester <methoxycarbonyl>)thiophene-2-carboxylic acid as a raw material, the product (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-3-aminothiophene-2-carboxylic acid methyl ester was obtained by referring to the second step of Example 5.

[1223] MS m / z(ESI): 312.0 [M+H] + .

[1224] Step 2: (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) 5 -thieneno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1225]

[1226] Using (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-3-aminothiophene-2-carboxylic acid methyl ester as a raw material, the product (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) was obtained by referring to step 6 of Example 1. 5 -Thiopheno[3,2-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1227] MS m / z (ESI): 336.1 [M+H] + .

[1228] Step 3: N-((S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -thieneno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1229]

[1230] (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) 5 Using thieno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide as a raw material, refer to Example 34, step 2 yields the product N-((S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,2-dimethyl-2λ 5-Thiopheno[3,2-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1231] MS m / z (ESI): 507.1 [M+H] + .

[1232] Example 54

[1233] N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -thieneno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1234]

[1235] (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) 5 Using thieno[3,2-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide as a raw material, refer to Example 34, step 2 yields the product N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -Thiopheno[3,2-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1236] MS m / z(ESI): 522.1 [M+H] + .

[1237] Example 55

[1238] N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -thieno[2,3-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1239]

[1240] Step 1: (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-2-aminothiophene-3-carboxylic acid methyl ester

[1241]

[1242] Using 5-amino-4-(methyl ester <methoxycarbonyl>)thiophene-2-carboxylic acid as a raw material, the product (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-2-aminothiophene-3-carboxylic acid methyl ester was obtained by referring to the second step of Example 5.

[1243] MS m / z(ESI): 312.0 [M+H] + .

[1244] Step 2: (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) 5 -thieno[2,3-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1245]

[1246] Using (S)-5-(3-acetamidopyrrolidine-1-carbonyl)-2-aminothiophene-3-carboxylic acid methyl ester as a raw material, the product (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) was obtained by referring to step 6 of Example 1. 5 -Thiopheno[2,3-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1247] MS m / z (ESI): 336.1 [M+H] + .

[1248] Step 3: N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -thieno[2,3-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1249]

[1250] (S)-N-(1-(2,2-dimethyl-4-carbonyl-3,4-dihydro-2λ) 5 Using thieno[2,3-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide as a raw material, refer to Example 34, step 2 yields the product N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,2-dimethyl-2λ 5 -Thiopheno[2,3-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1251] MS m / z(ESI): 522.1 [M+H] + .

[1252] Example 56

[1253] (R)-(2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)(pyrrolid-1-yl)methyl ketone

[1254]

[1255] Starting with methyl 2-amino-5-(pyrrolidine-1-carbonyl)nicotinate, (R)-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)(pyrrolidine-1-yl) methyl ketone was obtained by referring to steps six and seven of Example 51.

[1256] MS m / z (ESI): 444.1 [M+H] + .

[1257] Example 60

[1258] (R)-N,N,2,7-Tetramethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carboxamide

[1259]

[1260] Step 1: 4-Chloro-5-(1,3-dioxopentane-2-yl)-6-(1-ethoxyvinyl)-2-methylpyrimidine

[1261]

[1262] 4,6-Dichloro-5-(1,3-dioxopentyl-2-yl)-2-methylpyrimidine (5 g, 21.28 mmol), tributyl(1-ethoxyethylene)tin (7.68 g, 21.28 mmol), and dioxane (60 mL) were added sequentially to a 50 mL pear-shaped flask. Under nitrogen protection, bis(triphenylphosphine)palladium chloride (442 mg, 0.63 mmol) was added. The reaction mixture was stirred at 100 °C for 2 hours, cooled to room temperature, and stirred for 1 hour with saturated potassium fluoride solution. The mixture was then filtered, and the filtrate was extracted with ethyl acetate (60 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 4-chloro-5-(1,3-dioxopentyl-2-yl)-6-(1-ethoxyethylene)-2-methylpyrimidine (4 g, yield: 70%).

[1263] MS m / z(ESI): 271.0 [M+H] + .

[1264] Step 2: Ethyl 6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-carboxylic acid ester

[1265]

[1266] To a solution of 4-chloro-5-(1,3-dioxopentane-2-yl)-6-(1-ethoxyvinyl)-2-methylpyrimidine (4 g, 14.81 mmol), potassium permanganate (468 mg, 2.96 mmol), and dioxane (40 mL), an aqueous solution of sodium periodate (6.3 g, 29.62 mmol) (10 mL) was added dropwise. The mixture was stirred at 90 °C for 12 hours, then cooled and filtered. The filtrate was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give ethyl 6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-carboxylic acid (3.5 g, 87%).

[1267] MS m / z(ESI): 273.1 [M+H] + .

[1268] Step 3: (R)-5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid ethyl ester

[1269]

[1270] Using ethyl 6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-carboxylic acid ester as the raw material, the product ethyl(R)-5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid ester was obtained by referring to step nine of Example 1.

[1271] MS m / z (ESI): 440.2 [M+H] + .

[1272] Step 4: (R)-5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid

[1273]

[1274] Sodium hydroxide solution (2 mol / mL, 10 mL) was added dropwise to an ethanol (40 mL) solution of ethyl(R)-5-(1,3-dioxopentyl-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid ester (3.5 g, 7.97 mmol). The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 5 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (R)-5-(1,3-dioxopentyl-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid (2.8 g, 85%).

[1275] MS m / z(ESI): 412.1 [M+H] + .

[1276] Step 5: Ethyl(R)-N-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carbonyl)-N-methylglycine ester

[1277]

[1278] Using (R)-5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carboxylic acid as the starting material, the product ethyl(R)-N-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carbonyl)-N-methylglycine ester was obtained by referring to the second step of Example 5.

[1279] MS m / z (ESI): 511.2 [M+H] + .

[1280] Step 6: Ethyl(R)-N-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carbonyl)-N-methylglycine ester

[1281]

[1282] To a solution of ethyl(R)-N-(5-(1,3-dioxopentyl-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carbonyl)-N-methylglycinate (1 g, 1.96 mmol) in ethanol (15 mL), dilute hydrochloric acid (0.5 mol / mL, 10 mL) was added dropwise. The mixture was stirred at room temperature for 8 hours, extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product ethyl(R)-N-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-4-carbonyl)-N-methylglycinate (400 mg, 44%).

[1283] MS m / z (ESI): 467.2 [M+H] + .

[1284] Step 7: (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid

[1285]

[1286] A mixture of ethyl(R)-N-(5-formyl-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-carbonyl)-N-methylglycine ester (400 mg, 0.858 mmol), cesium carbonate (558 mg, 1.72 mmol), and ethanol (15 mL) was stirred at 50 °C for 3 hours. The reaction system was cooled to room temperature, the reaction was quenched with water, and the pH was adjusted to 5 with dilute hydrochloric acid. A solid precipitated out. The solid was filtered, and the filter cake was dried to give a white solid (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carboxylic acid (250 mg, 60%).

[1287] MS m / z(ESI): 421.1 [M+H] +

[1288] Step 8: (R)-N,N,2,7-Tetramethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide

[1289]

[1290] Using (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid as a starting material, the product (R)-N,N,2,7-tetramethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide was obtained by referring to the second step of Example 5.

[1291] MS m / z (ESI): 448.2 [M+H] + .

[1292] Example 61

[1293] (R)-6-(3-(dimethylamino)acetidine-1-carbonyl)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one

[1294]

[1295] Using (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid as a starting material, the product (R)-6-(3-(dimethylamino)acetidine-1-carbonyl)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidine-8(7H)-one was obtained by referring to the second step of Example 5.

[1296] MS m / z (ESI): 503.2 [M+H] + .

[1297] Example 62

[1298] N-((S)-1-(2,7-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1299]

[1300] Using (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid as a raw material, the product N-((S)-1-(2,7-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide was obtained by referring to the second step of Example 5.

[1301] MS m / z (ESI): 531.2 [M+H] + .

[1302] Example 63

[1303] (R)-2,7-Dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-N-(quininyl-4-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6-carboxamide

[1304]

[1305] Using (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid as a starting material, the product (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-N-(quininecyclo-4-yl)-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide was obtained by referring to the second step of Example 5.

[1306] MS m / z (ESI): 529.3 [M+H] + .

[1307] Example 64

[1308] (R)-3-(1-((2-methyl-7-carbonyl-6-(quininyl-4-yl)-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile

[1309]

[1310] Step 1: (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide

[1311]

[1312] Using 1-(3-bromo-5-(trifluoromethyl)phenyl)ethane-1-one as a raw material, the product (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide was obtained by referring to the third step of Example 1.

[1313] MS m / z(ESI): 370.0 [M+H] + .

[1314] Step 2: (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[1315]

[1316] Using (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide as a raw material, the product (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide was obtained by referring to step four of Example 1.

[1317] MS m / z(ESI): 372.0 [M+H] + .

[1318] Step 3: (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[1319]

[1320] In a 50 mL reaction flask, (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.3 mmol), ZnCN (366 mg, 4 mmol), and Pd2(dna)3 (119 mg, 0.1 mmol) were dissolved in DMF (10 mL). Under nitrogen protection, the mixture was stirred at 120 °C for 8 hours. The reaction was stopped, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to obtain (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (189 mg, 46%).

[1321] MS m / z (ESI): 319.1 [M+H] + .

[1322] Step 4: (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile

[1323]

[1324] Using (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide as a raw material, refer to step 5 of Example 1 to obtain the product (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile.

[1325] MS m / z(ESI): 215.0 [M+H] + .

[1326] Step 5: Methyl(R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate

[1327]

[1328] Referring to Example 13, step seven yields the product methyl(R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxapentane-2-yl)-2-methylpyrimidin-4-yl)acetate.

[1329] MS m / z (ESI): 451.1 [M+H] + .

[1330] Step 6: (R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid

[1331]

[1332] Referring to Example 16, step 6 yields the product (R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid.

[1333] MS m / z (ESI): 437.1 [M+H] + .

[1334] Step 7: (R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(quinine-4-yl)acetamide

[1335]

[1336] Referring to Example 16, step 7 yields the product (R)-2-(6-((1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)-N-(quinine-4-yl)acetamide.

[1337] MS m / z (ESI): 545.2 [M+H] + .

[1338] Step 8: (R)-3-(1-((2-methyl-7-carbonyl-6-(quininecyclo-4-yl)-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile

[1339]

[1340] Referring to Example 16, step 8 yields the product (R)-3-(1-((2-methyl-7-carbonyl-6-(quininecyclo-4-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile.

[1341] MS m / z (ESI): 483.2 [M+H] + .

[1342] Example 65

[1343] 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1344]

[1345] Step 1: 8-Bromo-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione

[1346]

[1347] 2-Methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione (500 mg, 1.59 mmol) was dissolved in acetonitrile (20 mL), and NBS (296 mg, 1.67 mmol) was added. The reaction was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 8-bromo-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione (300 mg, 48% yield).

[1348] MS m / z(ESI): 394.0 [M+H] +

[1349] Step 2: 8-Bromo-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyridino[4,3-d]pyrimidin-7(6H)-one

[1350]

[1351] Using 8-bromo-2-methyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-4,7(3H,6H)-dione and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, the product 8-bromo-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 34.

[1352] MS m / z (ESI): 579.2 [M+H] + .

[1353] Step 3: 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-8-carboxynitrile

[1354]

[1355] 8-Bromo-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (100 mg, 0.173 mmol) was dissolved in anhydrous DMSO (3 mL), and zinc cyanide (61 mg, 0.518 mmol) was added. Pd₂(dba)₃ (3.2 mg, 0.00346 mmol) and dppf (3.8 mg, 0.00692 mmol) were added under nitrogen protection. The reaction was carried out at 150 °C for 3 hours under microwave conditions. The reaction solution was filtered and purified by prep-HPLC to obtain 2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6-(3-(trifluoromethyl)tetrahydrofuran-3-yl)-6,7-dihydropyrido[4,3-d]pyrimidine-8-carboxynitrile.

[1356] MS m / z(ESI): 526.2 [M+H] + .

[1357] Example 66

[1358] 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1359]

[1360] Step 1: 8-Bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione

[1361]

[1362] Using 2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione as a starting material, the product 8-bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione was obtained in the first step of Reference Example 65.

[1363] MS m / z (ESI): 340.2 [M+H] +

[1364] Step 2: 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyridino[4,3-d]pyrimidin-7(6H)-one

[1365]

[1366] Using 8-bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-4,7(3H,6H)-dione and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline as raw materials, the product 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 34.

[1367] MS m / z(ESI): 526.2 [M+H] +

[1368] Step 3: 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyridino[4,3-d]pyrimidin-8-carboxynitrile

[1369]

[1370] Using 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-bromo-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile was obtained in step 3 of Example 65.

[1371] MS m / z(ESI): 473.2 [M+H] +

[1372] Example 67

[1373] (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1374]

[1375] Step 1: 6-(1-azabicyclo[2.2.1]heptane-4-yl)-8-bromo-2-methylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione

[1376]

[1377] Using 6-(1-azabicyclo[2.2.1]heptan-4-yl)-2-methylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione as a starting material, the product 6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-2-methylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione was obtained in the first step of Reference Example 65.

[1378] MS m / z (ESI): 351.2 [M+H] +

[1379] Step 2: (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[1380]

[1381] Using 6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-2-methylpyrido[4,3-d]pyrimidin-4,7(3H,6H)-dione and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine as raw materials, the product (R)-6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 34.

[1382] MS m / z (ESI): 536.2 [M+H] +

[1383] Step 3: (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1384]

[1385] Using (R)-6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-6-(1-azabicyclo[2.2.1]heptan-4-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile was obtained in step 3 of Example 65.

[1386] MS m / z (ESI): 483.2 [M+H] + .

[1387] Example 68

[1388] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)propyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1389]

[1390] Step 1: (R)-3-(1-aminopropyl)-5-(trifluoromethyl)aniline

[1391]

[1392] Starting with 1-(3-nitro-5-(trifluoromethyl)phenyl)propane-1-one, (R)-3-(1-aminopropyl)-5-(trifluoromethyl)aniline was obtained by referring to steps six through nine of Example 31.

[1393] MS m / z(ESI): 219.1 [M+H] + .

[1394] Step 2: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)propyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1395]

[1396] Referring to the tenth step of Example 31, N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)propyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine was obtained.

[1397] MS m / z (ESI): 477.2 [M+H] + .

[1398] 1 H NMR(400MHz, Methanol-d4)δ7.66(s,1H),7.04(s,1H),7.01–6.93(m,2H),6.80(s,1H),5.42–5.34(m,1H),5.24–5.1 4(m,1H),4.08–3.99(m,4H),3.95(s,3H),2.47(s,3H),2.33–2.17(m,2H),2.09–1.97(m,2H),1.02(t,J=7.4Hz,3H).

[1399] Example 69

[1400] (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(quininocyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1401]

[1402] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine and methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, and replacing 1-(fluoromethyl)cyclopropane-1-amine with quininecyclo-4-amine, refer to steps five to eight of Example 21 to obtain the product (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(quininecyclo-4-yl)pyridino[4,3-d]pyrimidin-7(6H)-one.

[1403] MS m / z (ESI): 486.2 [M+H] + .

[1404] Example 70

[1405] (R)-3-(1-((2-methyl-7-carbonyl-6-(quininyl-4-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)propyl)-5-(trifluoromethyl)benzonitrile

[1406]

[1407] Step 1: (R)-3-(1-aminopropyl)-5-(trifluoromethyl)benzonitrile

[1408]

[1409] Starting with 3-propionyl-5-(trifluoromethyl)benzonitrile, (R)-3-(1-aminopropyl)-5-(trifluoromethyl)aniline was obtained by referring to steps six to eight of Example 31.

[1410] MS m / z(ESI): 229.0 [M+H] + .

[1411] Step 2: (R)-3-(1-((2-methyl-7-carbonyl-6-(quininyl-4-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)propyl)-5-(trifluoromethyl)benzonitrile

[1412]

[1413] Using (R)-3-(1-aminopropyl)-5-(trifluoromethyl)aniline and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)methyl acetate as raw materials, and replacing 1-(fluoromethyl)cyclopropane-1-amine with quinine-4-amine, refer to steps five to eight of Example 21 to obtain the product (R)-3-(1-((2-methyl-7-carbonyl-6-(quinine-4-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)propyl)-5-(trifluoromethyl)benzonitrile.

[1414] MS m / z (ESI): 497.2 [M+H] + .

[1415] Example 71

[1416] 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1417]

[1418] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, and replacing 1-(fluoromethyl)cyclopropane-1-amine with 8-methyl-8-azabicyclo[3.2.1]octane-3-amine, the product 2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained from steps five to eight of Example 21.

[1419] MS m / z (ESI): 500.2 [M+H] + .

[1420] Example 72

[1421] 3-((1R)-1-((2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile

[1422]

[1423] Step 1: (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide

[1424]

[1425] Using 1-(3-bromo-5-(trifluoromethyl)phenyl)ethane-1-one as a raw material, the product (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide was obtained by referring to the third step of Example 1.

[1426] MS m / z(ESI): 370.0 [M+H] + .

[1427] Step 2: (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[1428]

[1429] Using (R,E)-N-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide as a raw material, the product (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide was obtained by referring to step four of Example 1.

[1430] MS m / z(ESI): 372.0 [M+H] + .

[1431] Step 3: (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[1432]

[1433] In a 50 mL reaction flask, (R)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.3 mmol), ZnCN (366 mg, 4 mmol), and Pd2(dba)3 (119 mg, 0.1 mmol) were dissolved in DMF (10 mL). Under nitrogen protection, the mixture was stirred at 120 °C for 8 hours. The reaction was stopped, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to obtain (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (189 mg, 46%).

[1434] MS m / z (ESI): 319.1 [M+H] + .

[1435] Step 4: (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile

[1436]

[1437] Using (R)-N-((R)-1-(3-cyano-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide as a raw material, refer to step 5 of Example 1 to obtain the product (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile.

[1438] MS m / z(ESI): 215.0 [M+H] + .

[1439] Step 5: 3-((1R)-1-((2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile

[1440]

[1441] Using (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile as a raw material, product 3-((1R)-1-((2-methyl-6-(3-methyltetrahydrofuran-3-yl)-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile was obtained by referring to Example 19.

[1442] MS m / z (ESI): 458.1 [M+H] + .

[1443] Example 73

[1444] 3-((1R)-1-((2-methyl-7-carbonyl-6-(quininecyclo-3-yl)-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile

[1445]

[1446]

[1447] Using (R)-3-(1-aminoethyl)-5-(trifluoromethyl)benzonitrile and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetic acid methyl ester as raw materials, and replacing 1-(fluoromethyl)cyclopropane-1-amine with quinine-3-amine, refer to steps five to eight of Example 21 to obtain the product 3-((1R)-1-((2-methyl-7-carbonyl-6-(quinine-3-yl)-6,7-dihydropyridino[4,3-d]pyrimidin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzonitrile.

[1448] MS m / z (ESI): 483.2 [M+H] + .

[1449] Example 74

[1450] (R)-8-ethynyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininocyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1451]

[1452] Step 1: (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1453]

[1454] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid as a starting material, the product (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained from steps one to three of Example 22.

[1455] MS m / z (ESI): 550.1 [M+H] + .

[1456] Step 2: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininocyclo-4-yl)-8-((trimethylsilyl)ethynyl)pyridino[4,3-d]pyrimidin-7(6H)-one

[1457]

[1458] Using (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)-8-((trimethylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to the third step of Example 28.

[1459] MS m / z (ESI): 568.3 [M+H] + .

[1460] Step 3: (R)-8-ethynyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininocyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1461]

[1462] Using (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)-8-((trimethylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-8-ethynyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(quininecyclo-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to step four of Example 28.

[1463] MS m / z(ESI): 496.2 [M+H] + .

[1464] Example 75

[1465] (R)-8-(acetidin-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxobutylcyclo-3-yl)pyridino[4,3-d]pyrimidin-7(6H)-one

[1466]

[1467] Step 1: (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxobutan-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1468]

[1469] Using (R)-2-(5-(1,3-dioxopentane-2-yl)-2-methyl-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid as a raw material, the product (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxobutane-3-yl)pyridino[4,3-d]pyrimidin-7(6H)-one was obtained by referring to the first to third steps of Example 22.

[1470] MS m / z(ESI): 511.1[M+H]+.

[1471] Step 2: (R)-8-(acetidin-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxobutan-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1472]

[1473] The following ingredients were added: (R)-8-bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxobutylcyclo-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (30 mg, 0.058 mmol), aziridine hydrochloride (5 mg, 0.058 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (3 mg, 0.0058 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.0058 mmol), and cesium carbonate (38 mg, 0.116 mmol). The mixture of N,N-dimethylformamide (3 mL) and N,N-dimethylformamide (3 mL) was stirred at 120 °C for 12 hours under nitrogen protection, cooled, and then water (15 mL) was added. The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative chromatography to give a white solid (R)-8-(acadidin-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methyloxadicyclo-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (10 mg, 35%).

[1474] MS m / z (ESI): 488.2 [M+H] + .

[1475] Example 76

[1476] (R)-8-acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1477]

[1478] Step 1: 8-Bromo-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione

[1479]

[1480] Using 2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione as a starting material, the product 8-bromo-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione was obtained in the first step of Reference Example 65.

[1481] MS m / z (ESI): 310.2 [M+H] +

[1482] Step 2: 8-Acetyl-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione

[1483]

[1484] Using 8-bromo-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione as a raw material, the product 8-acetyl-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione was obtained in the second step of Example 1.

[1485] MS m / z(ESI): 274.2 [M+H] +

[1486] Step 3: (R)-8-acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1487]

[1488] Using 8-acetyl-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-4,7(3H,6H)-dione and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine as raw materials, the product (R)-8-acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 34.

[1489] MS m / z (ESI): 445.2 [M+H] +

[1490] Example 77

[1491] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-hydroxypropan-2-yl)-2-methyl-6-(1-methylcyclopropyl)pyridino[4,3-d]pyrimidin-7(6H)-one

[1492]

[1493] Step 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-hydroxypropane-2-yl)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1494]

[1495] Using (R)-8-acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-hydroxypropane-2-yl)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 29.

[1496] MS m / z (ESI): 461.2 [M+H] + .

[1497] Example 78

[1498] (R)-4-((1-(3-(difluoro-13-methyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)-8-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1499]

[1500] Step 1: Methyl(R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate

[1501]

[1502] Using (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine and 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, refer to Example 19, step 5 to obtain the product methyl(R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate.

[1503] MS m / z(ESI): 426.2 [M+H] + .

[1504] Step 2: ((R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1505]

[1506] Using methyl(R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as a starting material, refer to the first to third steps of Example 22 to obtain the product ((R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1507] MS m / z(ESI): 481.1 [M+H] + .

[1508] Step 3: (R)-4-((1-(3-(difluoro-13-methyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)-8-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1509]

[1510] Using (R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one and N-methylpiperazine as raw materials, the product (R)-4-((1-(3-(difluoro-13-methyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)-8-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained in step 2 of Example 90.

[1511] MS m / z (ESI): 500.2 [M+H] + .

[1512] Example 79

[1513] 6-(1-azabicyclo[2.2.1]heptan-4-yl)-2-methyl-4-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[1514]

[1515] Step 1: N-phenylmethyl-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine

[1516]

[1517] In a 100 mL reaction flask, 4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-one (1 g, 5 mmol), benzylamine (642 mg, 6 mmol), and Ti(OEt)4 (1.7 g, 7.5 mmol) were dissolved in THF (40 mL) and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (380 mg, 10 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to give N-phenylmethyl-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-amine (1 g, 70%).

[1518] MS m / z(ESI): 292.1 [M+H] + .

[1519] Step 2: 4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine

[1520]

[1521] In a 50 mL reaction flask, N-phenylmethyl-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-amine (1 g, 3.5 mmol) was dissolved in 20 mL of THF, and Pd / C (200 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solution was filtered and evaporated to dryness to give 4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-amine (700 mg).

[1522] MS m / z(ESI): 202.0 [M+H] + .

[1523] Step 3: 6-(1-azabicyclo[2.2.1]heptane-4-yl)-2-methyl-4-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[1524]

[1525] Referring to Example 73, the product 6-(1-azabicyclo[2.2.1]heptane-4-yl)-2-methyl-4-((4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained.

[1526] MS m / z (ESI): 456.2 [M+H] + .

[1527] Example 80

[1528] (R)-2-Methyl-6-(1-Methylcyclopropyl)-4-((8-(trifluoromethyl)trypan-4-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[1529]

[1530] Using (R)-8-(trifluoromethyl)trypan-4-amine as a raw material, the product (R)-2-methyl-6-(1-methylcyclopropyl)-4-((8-(trifluoromethyl)trypan-4-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to Example 19.

[1531] MS m / z(ESI): 431.1 [M+H] + .

[1532] Example 81

[1533] (R)-2-methyl-6-(quininocyclo-4-yl)-4-((8-(trifluoromethyl)trypan-4-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[1534]

[1535] Using (R)-8-(trifluoromethyl)trypan-4-amine as a raw material, the product (R)-2-methyl-6-(quininecyclo-4-yl)-4-((8-(trifluoromethyl)trypan-4-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one was obtained by referring to Example 73.

[1536] MS m / z (ESI): 486.2 [M+H] + .

[1537] Example 82

[1538] (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1539]

[1540] Step 1: (R)-6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[1541]

[1542] Using 6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-2-methylpyrido[4,3-d]pyrimidin-4,7(3H,6H)-dione and (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethane-1-amine as raw materials, the product (R)-6-(1-azabicyclo[2.2.1]heptan-4-yl)-8-bromo-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one was obtained in the second step of Example 34.

[1543] MS m / z (ESI): 532.2 [M+H] +

[1544] Step 3: (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile

[1545]

[1546] Using (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-8-bromo-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one as a starting material, the product (R)-6-(1-azabicyclo[2.2.1]heptane-4-yl)-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-7-carbonyl-6,7-dihydropyrido[4,3-d]pyrimidin-8-carboxynitrile was obtained in step 3 of Example 65.

[1547] MS m / z (ESI): 479.2 [M+H] +

[1548] Example 83

[1549] 2-Methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(quinanocyclo-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[1550]

[1551] Using (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propane-1-amine and methyl 2-(6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidin-4-yl)acetate as raw materials, and replacing 1-(fluoromethyl)cyclopropane-1-amine with quininecyclo-3-amine, refer to steps five to eight of Example 21 to obtain the product 2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)propyl)amino)-6-(quininecyclo-3-yl)pyridino[4,3-d]pyrimidin-7(6H)-one.

[1552] MS m / z (ESI): 486.2 [M+H] + .

[1553] Example 84

[1554] N-((S)-1-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethyl-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1555]

[1556] Step 1: Ethyl(R)-6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-carboxylic acid ester

[1557]

[1558] Using ethyl 6-chloro-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-carboxylic acid ester as the raw material, the product ethyl(R)-6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxopentane-2-yl)-2-methylpyrimidine-4-carboxylic acid ester was obtained by referring to step nine of Example 1.

[1559] MS m / z (ESI): 441.2 [M+H] + .

[1560] Step 2: N-((S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethyl-8-carbonyl-7,8-dihydropyridino[3,4-d]pyrimidin-6-carbonyl)pyrrolidine-3-yl)acetamide

[1561]

[1562] Using ethyl(R)-6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-5-(1,3-dioxapentane-2-yl)-2-methylpyrimidine-4-carboxylic acid ester as a raw material, refer to steps four to nine of Example 60 to obtain the product N-((S)-1-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethyl-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-3-yl)acetamide.

[1563] MS m / z (ESI): 532.2 [M+H] + .

[1564] Example 85

[1565] (R)-2,7-Dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(oxazol-2-yl)pyrido[3,4-d]pyrimidin-8(7H)-one

[1566]

[1567] Step 1: (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide

[1568]

[1569] Using (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxylic acid and ammonium chloride as raw materials, (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide was obtained by referring to the second step of Example 5.

[1570] MS m / z (ESI): 420.2 [M+H] + .

[1571] Step 2: (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(oxazol-2-yl)pyrido[3,4-d]pyrimidin-8(7H)-one

[1572]

[1573] A mixture of (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carboxamide (40 mg, 0.095 mmol), bromoacetaldehyde diethanolamide (28 mg, 0.14 mmol), and toluene (5 mL) was stirred at 110 °C for 12 hours, cooled, and water (15 mL) was added. The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative chromatography to give a white solid (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(oxazol-2-yl)pyrido[3,4-d]pyrimidin-8(7H)-one.

[1574] MS m / z (ESI): 444.2 [M+H] + .

[1575] Example 86

[1576] (R)-2,7-Dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidin-6-carboxynitrile

[1577]

[1578] Trifluoroacetic anhydride (0.5 mL) was added dropwise to a solution of (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (40 mg, 0.095 mmol), triethylamine (0.5 mL), and dichloromethane (3 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour, and water (20 mL) was added. The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative chromatography to give a white solid (R)-2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-carbonyl-7,8-dihydropyrido[3,4-d]pyrimidine-6-carboxynitrile.

[1579] MS m / z(ESI): 402.2 [M+H] + .

[1580] Example 87

[1581] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1582]

[1583] Step 1: (R)-4-chloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxo)quinazolin

[1584]

[1585] Referring to the second step of Example 31, (R)-4-chloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxo)quinazoline (600 mg) was obtained.

[1586] MS m / z(ESI): 281.0 [M+H] + .

[1587] Step 2: 7-Methoxy-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1588]

[1589] (R)-4-chloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxo)quinazoline (100 mg, 0.35 mmol) was dissolved in 10 mL of anhydrous ethanol, and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine (106 mg, 0.45 mmol) and 0.5 mL of DIPEA were added. The mixture was stirred overnight at 120 °C, and the reaction solution was evaporated to dryness. The crude product was purified by column chromatography to give 7-methoxy-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazoline-4-amine (45 mg).

[1590] Step 3: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1591]

[1592] Referring to the ninth step of Example 31, N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine was obtained.

[1593] MS m / z (ESI): 449.1 [M+H] + .

[1594] 1 H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.18(s,1H),7.09(s,1H),7.05(s, 1H),6.96(s,1H),6.81(t,J=1.9Hz,1H),6.00(s,1H),5.57(t,J=7.0Hz,1H),5. 15(q,J=4.2,3.2Hz,1H),4.09–4.03(m,2H),4.02–3.99(m,1H),3.99–3.96(m, 1H), 3.95 (s, 3H), 3.94–3.90 (m, 2H), 2.29–2.22 (m, 2H), 1.67 (d, J = 6.9Hz, 3H).

[1595] Example 88

[1596] N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-2,4-diamine

[1597]

[1598] Step 1: 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzoic acid methyl ester

[1599]

[1600] 5-Hydroxy-4-methoxy-2-nitro-benzoic acid methyl ester (2 g, 8.80 mmol), (3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate (2.13 g, 8.80 mmol) and DMF (20 mL) were added to a 100 mL flask. Cesium carbonate (5.74 g, 17.61 mmol) was added at 25 °C, and the reaction mixture was then reacted at 60 °C for 5 h. The reaction mixture was filtered, concentrated, and column-sected with PE / EA = 1 / 1 to obtain the product 4-methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzoic acid methyl ester (2.0 g, 6.73 mmol, 76.42% yield).

[1601] MS m / z(ESI): 298.0[M+H]+.

[1602] Step 2: 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzoic acid

[1603]

[1604] 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxobenzoic acid methyl ester (1 g, 3.36 mmol) and EtOH (10 mL) were added to a 25 mL flask. An aqueous solution of NaOH (403.66 mg, 10.09 mmol) (2 mL) was added at 25 °C, and the reaction mixture was allowed to react at room temperature for 2 h. The pH of the reaction mixture was adjusted to 5-6 with HCl (2 M), then concentrated. After dissolving in DCM / MeOH (20 / 10), the solution was filtered. The concentrated filtrate was used directly in the next reaction step.

[1605] MS m / z(ESI): 284.0[M+H]+.

[1606] Step 3: 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzamide

[1607]

[1608] 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzoic acid (900 mg, 3.18 mmol) and DCM (10 mL) were added to a 25 mL flask. Oxaloyl chloride (4.03 g, 31.78 mmol) and DMF (11.61 mg, 158.88 μmol, 12.30 μL) were added at 25 °C, and the reaction mixture was allowed to react at room temperature for 12 h. After concentration, ammonia water (10 mL) was added, resulting in the precipitation of a solid. The solid was filtered, dried, and the product 4-methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzoamide (600 mg, 2.13 mmol, 66.90% yield) was obtained.

[1609] MS m / z(ESI): 283.0[M+H]+.

[1610] Step 4: 2-Amino-4-methoxy-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzamide

[1611]

[1612] 4-Methoxy-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzamide (600 mg, 2.13 mmol) and MeOH (10 mL) were added to a 25 mL flask. Zinc powder (1.39 g, 21.26 mmol) and ammonium chloride (568.55 mg, 10.63 mmol) were added at 25 °C, and the reaction mixture was allowed to react at room temperature for 12 h. The reaction mixture was filtered and concentrated to dryness, and then used directly for the next reaction step.

[1613] MS m / z (ESI): 253.1 [M+H] + .

[1614] Step 5: 7-Methoxy-6-[(3S)-tetrahydrofuran-3-yl]oxo-1H-quinazolin-2,4-dione

[1615]

[1616] 2-Amino-4-methoxy-5-[(3S)-tetrahydrofuran-3-yl]oxo-benzamide (500 mg, 1.98 mmol) and THF (15 mL) were added to a 25 mL flask. CDI (482.08 mg, 2.38 mmol, 80% purity) was added at 25 °C, and the reaction mixture was allowed to react at room temperature for 12 h. LCMS showed that the reaction was complete. The reaction mixture was quenched with water, and a solid precipitated. After filtration and drying, the solid yielded the product 7-methoxy-6-[(3S)-tetrahydrofuran-3-yl]oxo-1H-quinazolin-2,4-dione (220 mg, 39.89% yield).

[1617] MS m / z(ESI): 279.0[M+H]+.

[1618] Step 6: 2,4-Dichloro-7-methoxy-6-[(3S)-tetrahydrofuran-3-yl]oxo-quinazolin

[1619]

[1620] 7-Methoxy-6-[(3S)-tetrahydrofuran-3-yl]oxo-1H-quinazolin-2,4-dione (220 mg, 790.63 μmol) and acetonitrile (10 mL) were added to a 25 mL flask. Phosphorus oxychloride (1.21 g, 7.91 mmol) was added at 25 °C, and the reaction mixture was then incubated at 80 °C for 3 h. LC-MS showed that the reaction was complete, and the reaction mixture was directly concentrated for the next step of the reaction.

[1621] MS m / z(ESI): 315.0 [M+H] + .

[1622] Step 7: 2-Chloro-7-methoxy-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-[(3S)-tetrahydrofuran-3-yl]oxo-quinazolin-4-amine

[1623]

[1624] Using 2,4-dichloro-7-methoxy-6-[(3S)-tetrahydrofuran-3-yl]oxo-quinazoline as a raw material, refer to Example 14, step 3 to obtain the product 2-chloro-7-methoxy-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-[(3S)-tetrahydrofuran-3-yl]oxo-quinazoline-4-amine.

[1625] MS m / z(ESI): 513.1[M+H]+.

[1626] Step 8: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-chloro-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine

[1627]

[1628] 2-Chloro-7-methoxy-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-[(3S)-tetrahydrofuran-3-yl]oxo-quinazolin-4-amine (30 mg, 58.49 μmol) and EtOH (10 mL) were added to a 25 mL flask. Stannous chloride (11.09 mg, 58.49 μmol) was added at 25 °C, and the reaction mixture was then reacted at 90 °C for 1 h. The reaction mixture was filtered, concentrated, and the product N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-chloro-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-4-amine was prepared by prep-HPLC.

[1629] MS m / z(ESI): 483.1[M+H]+.

[1630] Step 9: N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazolin-2,4-diamine

[1631]

[1632] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-chloro-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazoline-4-amine and an ammonia-ethanol solution were reacted in a sealed container at 100°C for 3 hours to obtain the product N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)quinazoline-2,4-diamine.

[1633] MS m / z (ESI): 464.1 [M+H]+ .

[1634] 1 H NMR(400MHz, Methanol-d4)δ7.55(s,1H),7.03–6.92(m,2H),6.84–6.74(m,2H),5.61–5.48(m,1H), 5.12–5.03(m,1H),4.07–3.94(m,3H),3.93–3.83(m,4H),2.28–2.13(m,2H),1.61(d,J=7.0Hz,3H).

[1635] Example 89

[1636] N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-2,4-diamine

[1637]

[1638] Using methyl 5-hydroxy-6-methoxy-2-nitronicotinic acid as a raw material, refer to Example 88. Steps 1 to 9 yielded the product N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidine-2,4-diamine.

[1639] MS m / z (ESI): 465.1 [M+H] + .

[1640] Example 90

[1641] N-((R)-1-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[1642]

[1643] Step 1: 6-Bromo-2-methylpyridano[2,3-d]pyrimidin-4(3H)-one

[1644]

[1645] Using 2-amino-5-bromonicotinic acid as a raw material, the product 6-bromo-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one was obtained in the first step of Example 36.

[1646] MS m / z(ESI): 240.1 [M+H]+ .

[1647] 1 H NMR (400MHz, DMSO) δ12.66(s,1H),8.99(d,J=2.6Hz,1H),8.56(d,J=2.6Hz,1H),2.40(s,3H).

[1648] Step 2: (R)-6-bromo-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[1649]

[1650] Using 2-amino-5-bromonicotinic acid and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride as raw materials, the product (R)-6-bromo-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine was obtained in step four of Example 36.

[1651] MS m / z (ESI): 425.1 [M+H] + .

[1652] Step 3: N-((R)-1-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[1653]

[1654] Using (R)-6-bromo-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and (R)-N-(pyrrolidine-3-yl)acetyl as raw materials, refer to Example 40, step 3 to obtain the product N-((R)-1-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)pyrrolidine-3-yl)acetamide

[1655] MS m / z(ESI): 473.2 [M+H] + .

[1656] Example 91

[1657] (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1658]

[1659]

[1660] Using (R)-6-bromo-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as raw materials, the product (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one was obtained by referring to step 7 of Example 1.

[1661] MS m / z (ESI): 470.2 [M+H] + .

[1662] 1 H NMR (400MHz, CDCl3) δ8.98(d,J=16.2Hz,1H),8.71-8.58(m,1H),7.81-7.74(m,1H),7.52(d,J=7.5Hz,1H),7.23(s,1H),6.28(d,J=29.1Hz,1H) ,5.91(s,1H),4.21(d,J=30.6Hz,2H),3.86–3.49(m,2H),2.77–2.44(m ,6H),2.14(d,J=8.4Hz,5H),1.80–1.65(m,2H),1.28(d,J=21.0Hz,2H).

[1663] Example 92

[1664] (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1665]

[1666] (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one (100 mg, 0.21 mmol) was dissolved in methanol (6 mL), and Pd / C (10 mg, 10%) was added. The reaction was stirred at room temperature under hydrogen atmosphere for 2 hours, then filtered, and the filtrate was evaporated to dryness. Preparative chromatography (alkaline) was then performed to obtain a white solid (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one (25 mg, yield: 25%).

[1667] MS m / z (ESI): 472.2 [M+H] + .

[1668] 1 H NMR (400MHz, CDCl3) δ8.78(s,1H),8.64(s,1H),7.75(s,1H),7.53(s,1H),7.23(s,1H),5.91(s,1H),4.75(dd,J=24.1,12.3H z,1H),3.93(d,J=13.3Hz,1H),3.19(d,J=8.0Hz,1H),2.94(s,1H),2.28–1.80(m,12H),1.68(s,4H),1.28(d,J=22.2Hz,2H).

[1669] Example 93

[1670] (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyridin-3-yl)pyridino[2,3-d]pyrimidin-4-amine

[1671]

[1672] Using (R)-6-bromo-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid as raw materials, refer to Example 5, step four to obtain the product (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine.

[1673] MS m / z (ESI): 424.2 [M+H] + .

[1674] 1H NMR (400MHz, DMSO) δ9.34(d,J=2.4Hz,1H),9.24(d,J=2.5Hz,1H),9.13(d,J=2.3Hz,1H),8.92(d,J=6.8Hz,1H),8.68(d,J=4.7Hz,1H),8.31(d,J= 7.7Hz,1H),7.80(d,J=7.9Hz,1H),7.63–7.54(m,2H),7.37(t,J=7.8Hz, 1H),5.81–5.70(m,1H),2.64(s,3H),2.41(s,3H),1.60(d,J=7.0Hz,3H).

[1675] Example 94

[1676] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1677]

[1678] Step 1: 6-Bromo-4-chloro-2-methylpyridano[2,3-d]pyrimidine

[1679]

[1680] 6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one (600 mg, 2.5 mmol) was dissolved in 20 mL of acetonitrile, and phosphorus oxychloride (1.9 g, 12.5 mmol) and DIPEA (960 mg, 7.5 mmol) were added. The reaction was carried out at 80 °C for 6 h. The solvent was evaporated to obtain the crude product (600 mg), which was directly added to the next step.

[1681] MS m / z (ESI): 257.9 [M+H] + .

[1682] Step 2: (R)-6-bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[1683]

[1684] 6-Bromo-4-chloro-2-methylpyridano[2,3-d]pyrimidine (600 mg, 2.3 mmol) was dissolved in 20 mL of DMAc, and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine (650 mg, 2.8 mmol) and 1 mL of DIPEA were added. The mixture was reacted overnight at 80 °C. The reaction was quenched with water, extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give (R)-6-bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridano[2,3-d]pyrimidine-4-amine (420 mg).

[1685] MS m / z(ESI): 456.0 [M+H] + .

[1686] Step 3: (R)-1-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1687]

[1688] Referring to step 7 of Example 1, (R)-1-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one (90 mg) was obtained.

[1689] MS m / z (ESI): 501.1 [M+H] + .

[1690] Step 4: (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1691]

[1692] (R)-1-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one (90 mg, 0.18 mmol) was dissolved in 10 mL of ethanol, and stannous chloride (122 mg, 0.54 mmol) was added. The mixture was reacted at 90 °C for 2 h. The pH was adjusted to neutral by adding sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one (65 mg).

[1693] MS m / z (ESI): 471.2 [M+H] + .

[1694] Example 95

[1695] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridino[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1696]

[1697] Using (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as a starting material, (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained according to Example 92.

[1698] MS m / z(ESI): 473.2 [M+H] + .

[1699] Example 96

[1700] (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1701]

[1702] Step 1: 6-Bromo-7-methoxy-2-methylpyridano[2,3-d]pyrimidin-4(3H)-one

[1703]

[1704] Using 2-amino-5-bromo-6-methoxynicotinic acid as a raw material, the product 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidine-4(3H)-one was obtained in the first step of Example 36.

[1705] MS m / z(ESI): 270.0 [M+H] + .

[1706] 1 H NMR (400MHz, DMSO) δ12.54(s,1H),8.45(s,1H),4.02(s,3H),2.37(s,3H).

[1707] Step 2: (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[1708]

[1709] Using 6-bromo-7-methoxy-2-methylpyridano[2,3-d]pyrimidin-4(3H)-one and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride as raw materials, refer to Example 94 for the first and second steps to obtain the product (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyridano[2,3-d]pyrimidin-4-amine

[1710] MS m / z (ESI): 455.1 [M+H] + .

[1711] Step 3: (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1712]

[1713] Using (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as raw materials, the product (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one was obtained by referring to step 7 of Example 1.

[1714] MS m / z (ESI): 500.2 [M+H] + .

[1715] 1 H NMR (400MHz, DMSO) δ8.56(d,J=7.4Hz,2H),7.77(d,J=7.7Hz,1H),7.54(d,J=7.6Hz,1H),7.36(t,J=7.7Hz,1H),6.07(d,J=9.3Hz,1H),5.81–5.61(m,1 H),4.15(d,J=18.0Hz,2H),3.95(s,3H),3.63(t,J=5.8Hz,2H),3.36(s,2H ),2.62(s,3H),2.33(s,3H),2.08(d,J=10.8Hz,3H),1.54(d,J=6.8Hz,3H).

[1716] Example 97

[1717] (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1718]

[1719] Using (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as a starting material, the product (R)-1-(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained by referring to Example 92.

[1720] MS m / z (ESI): 502.2 [M+H] + .

[1721] 1 H NMR (400MHz, DMSO) δ8.48(d,J=8.6Hz,2H),7.74(d,J=7.9Hz,1H),7.54(d,J=7.7Hz,1H ),7.36(t,J=7.8Hz,1H),5.77–5.61(m,1H),4.61(d,J=12.2Hz,1H),3.97(s,3H),3.24 –2.99(m,2H),2.74–2.64(m,1H),2.62(s,3H),2.32(s,3H),2.05(s,3H),2.01-1.98(m ,1H),1.91-1.82(m,2H),1.66-1.61(m,1H),1.54(d,J=6.8Hz,3H),1.48–1.44(m,1H).

[1722] Example 98

[1723] (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1724]

[1725]

[1726] Using 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one as a raw material, the product (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one was obtained by referring to the second and third steps of Example 96.

[1727] MS m / z (ESI): 486.2 [M+H] + .

[1728] 1H NMR (400MHz, DMSO) δ8.49(s,1H),8.41(d,J=7.2Hz,1H),7.61(t,J=7.3Hz,1H),7.43(t,J=6.9Hz,1H),7.33–7.13(m,2H),6.01(d,J=8.8Hz,1H),5.72 (dd,J=14.1,7.1Hz,1H),4.08(d,J=18.0Hz,2H),3.89(s,3H),3.68–3.48( m,2H),2.48(s,2H),2.27(s,3H),2.07–1.87(m,3H),1.52(d,J=6.9Hz,3H).

[1729] Example 99

[1730] (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyridino[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1731]

[1732] Using (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as a starting material, the product (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained by referring to Example 92.

[1733] MS m / z (ESI): 488.2 [M+H] + .

[1734] Example 100

[1735] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1736]

[1737] Using 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one as a starting material, the product (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one was obtained by referring to the first to fourth steps of Example 94.

[1738] MS m / z (ESI): 501.2 [M+H] + .

[1739] Example 101

[1740] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyridino[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1741]

[1742] Using (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as a starting material, the product (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained by referring to Example 92.

[1743] MS m / z (ESI): 503.2 [M+H] + .

[1744] Example 102

[1745] (R)-1-(4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1746]

[1747] Step 1: 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one

[1748]

[1749] 2-Amino-5-bromonicotinic acid (1.0 g, 4.6 mmol) was dissolved in 7N NH3 / MeOH (10 mL), and trimethyl orthoformate (3 mL) was added. The reaction was stirred at 110 °C under microwave conditions for 6 hours. The reaction solution was evaporated to dryness and purified by column chromatography (DCM / MeOH = 9 / 1) to give 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (730 mg, 70% yield).

[1750] Step 2: (R)-6-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[1751]

[1752] Using 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one as the starting material, (R)-6-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine was obtained by referring to the second step of Example 34.

[1753] MS m / z (ESI): 410.8 [M+H] + .

[1754] Step 3: (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1755]

[1756] Starting with (R)-6-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was obtained by referring to step 7 of Example 1.

[1757] MS m / z(ESI): 514.0 [M+H] + .

[1758] Step 4: (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylic acid tert-butyl ester

[1759]

[1760] Starting with (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylic acid tert-butyl ester was obtained by referring to step nine of Example 31.

[1761] MS m / z (ESI): 516.2 [M+H] + .

[1762] Step 5: (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)pyrido[2,3-d]pyrimidin-4-amine

[1763]

[1764] (R)-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-carboxylic acid tert-butyl ester (130 mg, 252 μmol) was dissolved in 25% TFA / DCM (20 mL). The reaction was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to give trifluoroacetate of (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)pyrido[2,3-d]pyrimidin-4-amine (100 mg, trifluoroacetate).

[1765] MS m / z(ESI): 416.0 [M+H] + .

[1766] Step 6: (R)-1-(4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1767]

[1768] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)pyrido[2,3-d]pyrimidin-4-amine (50 mg, 94 μmol, TFA salt) was dissolved in DCM (10 mL), and DIPEA (61 mg, 472 μmol) was added. The mixture was stirred for 5 minutes. Acetyl chloride (8 mg, 103 μmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred for another 10 minutes. Water was added, followed by extraction with DCM. The organic phase was dried and then evaporated to dryness. The crude product was purified by prep-HPLC to give (R)-1-(4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one.

[1769] MS m / z(ESI): 458.0 [M+H] + .

[1770] Example 103

[1771] (R)-1-(4-(7-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1772]

[1773] Using (R)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride as a raw material, referring to the second and third steps of Example 96 and Example 97, the product (R)-1-(4-(7-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained.

[1774] MS m / z (ESI): 488.2 [M+H] + .

[1775] Example 104

[1776] (R)-Cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)methyl ketone

[1777]

[1778] Step 1: tert-Butyl(R)-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester

[1779]

[1780] Using (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester as raw materials, the product tert-butyl(R)-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester was obtained by referring to step 7 of Example 1.

[1781] MS m / z (ESI): 558.3 ​​[M+H] +

[1782] Step 2: (R)-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridino[2,3-d]pyrimidin-4-amine

[1783]

[1784] 100 mg (0.18 mmol) of tert-butyl(R)-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester (ethyl hydrochloride) (5 mL, 4 M) was added, and the mixture was stirred at room temperature for 2 hours until the reaction was complete. The mixture was then concentrated under reduced pressure to dryness to obtain crude (R)-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine (85 mg).

[1785] MS m / z (ESI): 458.2 [M+H] + .

[1786] Step 3: (R)-Cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)methyl ketone

[1787]

[1788] Triethylamine (52 mg, 0.51 mmol) was added to a tetrahydrofuran (4 mL) solution of (R)-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine (80 mg, 0.17 mmol) at 0 °C. Cyclopropylformyl chloride (36 mg, 0.34 mmol) was then added dropwise. The mixture was stirred at room temperature for 30 minutes, water was added to the reaction solution, and ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was separated by preparative chromatography to obtain (R)-cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl) methyl ketone.

[1789] MS m / z(ESI): 526.2 [M+H] + .

[1790] Step 4: (R)-Cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)methyl ketone

[1791]

[1792] Using (R)-cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl) methyl ketone as a starting material, the product (R)-cyclopropyl(4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl) methyl ketone was obtained by referring to Example 92.

[1793] MS m / z(ESI): 528.3 [M+H] + .

[1794] Example 105

[1795] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4-amine

[1796]

[1797] Step 1: 2-Amino-5-bromo-6-methylnicotinic acid

[1798]

[1799] 2-Amino-6-methylnicotinic acid (3.1 g, 20.0 mmol) and acetic acid (20 mL) were added to a 50 mL flask, and liquid bromine (3.8 g, 24.0 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 12 h. A solid precipitated out, which was filtered, washed with acetic acid, dried under vacuum, slurried with methanol, filtered, and dried to give a gray solid product, 2-amino-5-bromo-6-methylnicotinic acid (3.5 g, yield: 75%).

[1800] MS m / z(ESI): 231.0 [M+H] + .

[1801] Step 2: 6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one

[1802]

[1803] Using 2-amino-5-bromo-6-methylnicotinic acid as a raw material, the product 6-bromo-2,7-dimethylpyridino[2,3-d]pyrimidin-4(3H)-one was obtained in the first step of Reference Example 36.

[1804] MS m / z(ESI): 254.0 [M+H] + .

[1805] Step 3: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine

[1806]

[1807] Using 6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one as a starting material, the product (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine was obtained in step four of Example 36.

[1808] MS m / z(ESI): 440.0 [M+H] + .

[1809] Step 4: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidine-6-phenol

[1810]

[1811] The following solutions were prepared: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (100 mg, 0.24 mmol), potassium hydroxide (79 mg, 1.4 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.024 mmol), and dioxane (3 mL). After purging the mixture with water (3 mL) three times with nitrogen, the mixture was stirred at 100 °C for 12 hours under nitrogen protection, cooled, and the pH was adjusted to 2 with dilute hydrochloric acid (1N). The mixture was then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidine-6-phenol (80 mg, crude product).

[1812] MS m / z(ESI): 378.1 [M+H] + .

[1813] Step 5: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4-amine

[1814]

[1815] Using (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-phenol and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate as raw materials, refer to Example 31. In the second step, the product N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxo)pyrido[2,3-d]pyrimidin-4-amine is obtained.

[1816] MS m / z (ESI): 448.1 [M+H]+ .

[1817] 1 H NMR(400MHz, Methanol-d4)δ8.01(s,1H),7.01–6.94(m,2H),6.81(s,1H),5.69–5.59(m,1H),5.23–5.16(m,1 H),4.09–3.91(m,4H),2.57(s,3H),2.50(s,3H),2.40–2.31(m,1H),2.24–2.14(m,1H),1.65(d,J=7.0Hz,3H).

[1818] Example 106

[1819] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine

[1820]

[1821] Step 1: (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1822]

[1823] Using (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine as a starting material, refer to Example 1, step 7 to obtain the product (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[1824] MS m / z (ESI): 543.2 [M+H] + .

[1825] Step 2: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridino[2,3-d]pyrimidin-4-amine

[1826]

[1827] Using (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester as the starting material, refer to Example 102, step 5 to obtain the product (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(1,2,3,6-tetrahydropyridino-4-yl)pyridino[2,3-d]pyrimidin-4-amine.

[1828] MS m / z (ESI): 443.2 [M+H] + .

[1829] Example 107

[1830] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyridino[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1831]

[1832] Using (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as raw materials, refer to Example 1, step 7 to obtain the product (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[1833] MS m / z (ESI): 485.2 [M+H] + .

[1834] Example 108

[1835] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyridino[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1836]

[1837] Using (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one as a starting material, the product (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained by referring to Example 92.

[1838] MS m / z (ESI): 487.2 [M+H] + .

[1839] Example 109

[1840] (R)-1-(4-(2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1841]

[1842] Using (R)-6-bromo-2,7-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine as a starting material, the product (R)-1-(4-(2,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one was obtained by referring to steps three and four of section 102.

[1843] MS m / z (ESI): 486.2 [M+H] + .

[1844] Example 110

[1845] (R)-1-(4-fluoro-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1846]

[1847] Step 1: (R)-1-(4-hydroxy-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1848]

[1849] To a solution of (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.44 mmol) in tetrahydrofuran (5 mL), add 0.88 mL of isopropyl magnesium bromide solution (1 M), then stir at 0 °C for 30 minutes. Next, add 1-acetylpiperidin-4-one (93 mg, 0.66 mmol) and stir at room temperature for 12 hours. Finally, quench with saturated ammonium chloride solution. The organic phases were quenched (30 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative chromatography to give a white solid (R)-1-(4-hydroxy-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one (50 mg, yield: 22%).

[1850] MS m / z (ESI): 518.2 [M+H] +

[1851] Step 2: (R)-1-(4-fluoro-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one

[1852]

[1853] Diethylaminosulfur trifluoride (31 mg, 0.19 mmol) was added dropwise to a solution of (R)-1-(4-hydroxy-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one (50 mg, 0.097 mmol) in dichloromethane (5 mL) at -78 °C. The mixture was then stirred at room temperature for 2 hours, followed by quenching with saturated ammonium chloride solution (3... 0 mL), then extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative chromatography to give a white solid (R)-1-(4-fluoro-4-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethane-1-one (12 mg, yield: 24%).

[1854] MS m / z (ESI): 520.2 [M+H]+

[1855] Example 111

[1856] (R)-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)pyrido[2,3-d]pyrimidine-4-amine

[1857]

[1858] Using (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and 2-methyl-2,6-diazaspiro[3.3]heptane as raw materials, the product (R)-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)pyrido[2,3-d]pyrimidin-4-amine was obtained by referring to the third step of Example 40.

[1859] MS m / z (ESI): 487.2 [M+H] + .

[1860] Example 112

[1861] (R)-1-(6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-yl)ethane-1-one

[1862]

[1863] Step 1: tert-Butyl(R)-6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

[1864] (amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3,3]heptane-2-carboxylic acid ester

[1865]

[1866] Using (R)-6-bromo-7-methoxy-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine and tert-butyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester as raw materials, the product tert-butyl(R)-6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester was obtained by referring to the third step of Example 40.

[1867] MS m / z (ESI): 573.3 [M+H] + .

[1868] Step 2: (R)-1-(6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3,3]heptane-2-yl)ethane-1-one

[1869]

[1870] Using tert-butyl(R)-6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester as the raw material, refer to Example 104. The product (R)-1-(6-(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-yl)ethane-1-one is obtained in the second and third steps.

[1871] MS m / z (ESI): 515.2 [M+H] + .

[1872] Example 113

[1873] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxo)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine

[1874]

[1875] Step 1: Methyl 2-(tert-butylamino)-6-(trifluoromethyl)nicotinic acid

[1876]

[1877] Using methyl 2-chloro-6-(trifluoromethyl)nicotinic acid and 2-methylpropane-2-amine as raw materials, the product methyl 2-(tert-butylamino)-6-(trifluoromethyl)nicotinic acid was obtained by referring to step nine of Example 1.

[1878] MS m / z(ESI): 277.2 [M+H] + .

[1879] Step 2: Methyl 5-bromo-2-(tert-butylamino)-6-(trifluoromethyl)nicotinate

[1880]

[1881] Using methyl 2-(tert-butylamino)-6-(trifluoromethyl)nicotinic acid and N-bromosuccinimide as raw materials, the product methyl 5-bromo-2-(tert-butylamino)-6-(trifluoromethyl)nicotinic acid was obtained in step 2 of Example 48.

[1882] MS m / z (ESI): 355.2 [M+H] + .

[1883] Step 3: Methyl 2-(tert-butylamino)-5-hydroxy-6-(trifluoromethyl)nicotinate

[1884]

[1885] Using methyl 5-bromo-2-(tert-butylamino)-6-(trifluoromethyl)nicotinic acid as a raw material, the product methyl 2-(tert-butylamino)-5-hydroxy-6-(trifluoromethyl)nicotinic acid was obtained in the second step of Example 105.

[1886] MS m / z(ESI): 293.2 [M+H] + .

[1887] Step 4: (S)-2-(tert-butylamino)-5-((tetrahydrofuran...

Claims

1. Compounds of general formula (V), their stereoisomers, or pharmaceutically acceptable salts thereof: in: R1 is a methyl group; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R7 is trifluoromethyl; R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R a Selected from the following groups: , , or , Optional further additions include deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 It is replaced by one or more substituents in the alkyl group.

2. The compound of general formula (V) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R1 is a methyl group; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R7 is trifluoromethyl; R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R a Selected from the following groups: , , or , Optional further additions include deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 It is replaced by one or more substituents in a haloalkyl group.

3. The compound of general formula (V) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R1 is a methyl group; R6 is selected from hydrogen, halogen, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; R7 is trifluoromethyl; R8 is selected from hydrogen, halogen, amino, hydroxyl, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; R a Selected from the following groups: , , or , Optional further additions of deuterium, halogen, hydroxyl, or C 1-3 It is replaced by one or more substituents in the alkyl group.

4. The compound of general formula (V) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R1 is a methyl group; R6 is selected from hydrogen or amino groups; R7 is trifluoromethyl; R8 is selected from hydrogen or methyl; R a Selected from the following groups: , , or , Optional further deuterium or C 1-3 It is replaced by one of the substituents in the alkyl group.

5. The compound described below, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The structure of the compound is as follows: or .

6. A pharmaceutical composition comprising a therapeutically effective dose of the compound shown in any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

7. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of SOS1 inhibitors and RAS family protein and / or RAC1 inhibitors.

8. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6 in the preparation of a drug for the prevention and / or treatment of adenocarcinoma, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

9. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating RAS-related diseases, wherein the RAS-related diseases are selected from neurofibromatosis type I, Noonan syndrome, capillary malformation arteriovenous malformation syndrome, Costello syndrome, cardiofacial skin syndrome, and Legg's syndrome.

10. The use according to claim 9, wherein the RAS-related disease is a KRAS-related disease.

11. The use according to claim 10, wherein the KRAS-related disease is an SOS1 inhibitor-mediated disease.

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