Fused heterocyclic compounds as modulators of RAS signaling

Abstract

The present invention provides, inter alia, fused heterocyclic compounds of formula (I) or tautomers, stereoisomers, or pharma- ceutically acceptable salts thereof.These compounds and compositions containing them are useful for treating cancer and other diseases associated with RAS dysfunction in subjects. JPEG2025504495000115.jpg80170

Description

[Background technology]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to International Application No. PCT / CN2022 / 073235, filed January 21, 2022, and U.S. Application No. 63 / 310,765, filed February 16, 2022, the contents of which are incorporated by reference in their entireties herein.

[0002] BACKGROUND OF THEINVENTION Rat sarcoma virus (RAS) is one of the most validated cancer targets. However, despite the clinical importance of targeting RAS, discovering potent inhibitors of RAS has been difficult. RAS proteins have long had a reputation of being "undruggable."

[0003] In human cells, three closely related RAS genes, termed HRAS, KRAS, and NRAS, encode four highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). These RAS proteins are guanosine triphosphate degrading enzymes (GTPases) that are involved in a wide range of important molecular and cellular activities, including proliferation, differentiation, and cell death (Front. Oncol., October 18, 2019). RAS proteins constantly cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state to relay cellular signals in response to extracellular stimuli. Activation of Ras proteins is also controlled by guanine nucleotide exchange factors (GEFs), which catalyze nucleotide exchange, and GTPase-activating proteins (GAPs), which aid in GTP hydrolysis. Upon activation, RAS directly interacts with and activates several downstream effector pathways, including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. However, mutations in RAS typically render it GAP-independent and "lock" RAS in an active GTP-bound state, inhibiting the guanine exchange cycle, thereby activating downstream signaling pathways leading to tumor cell proliferation (PNAS, March 4, 2014 111 (9) 3401-3406; Nat Rev. Drug Discov., 2020 Aug; 19(8): 533-552).

[0004] Mutations in RAS genes occur frequently in solid and hematological malignancies, with at least one isoform mutation present in approximately 20% of all tumors. Most oncogenic mutations in RAS isoforms are missense gain-of-function mutations at codons G12, G13, or Q61, although their frequency of such mutations varies among RAS isoforms (Genes 2021 Jun; 12(6): 899). Mutations at amino acids G12, G13, Q61, and A146 are found in a variety of human cancers, including lung, colon, and pancreatic cancers (Cox et al., Nat. Rev. Drug Discov., 2014, 13(1): 828-51). However, recent biochemical analyses have demonstrated that these mutant proteins still require nucleotide cycling for activation, based on their intrinsic GTPase activity and / or partial sensitivity to exogenous GTPases. Therefore, mutant RAS proteins are sensitive to inhibition of upstream factors such as SOS or SHP2, upstream signaling proteins required for RAS activation (Nat Rev Drug Discov. 2020 Aug; 19(8): 533-552).

[0005] Son of Sevenless (SOS) has two homologous genes, SOS1 and SOS2. SOS1 encodes a protein that is a guanine nucleotide exchange factor (GEF) for RAS proteins. The product of this gene plays a key role in the activation of RAS proteins by mediating the exchange of GDP for GTP. SOS2 is the homolog of SOS1 in mammalian cells. It also functions as a GEF for the activation of RAS family proteins. SOS1 and SOS2 are approximately 70% identical in amino acid sequence. SOS2 knockouts in mice are viable, whereas SOS1 knockouts are embryonic lethal. Using a tamoxifen-inducible SOS1 knockout mouse model to investigate the role of SOS1 and SOS2 in adult mice, we demonstrated that while SOS1 knockout mice are viable, SOS1 and SOS2 (SOS1 / 2) double knockouts are lethal, suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1-RAS activated diseases (Mol Cell Biol., 2013 Nov; 33(22): 4562-4578).

[0006] SOS proteins bind to RAS not only through a catalytic binding site that promotes nucleotide exchange, but also through an allosteric site that binds to GTP-bound RAS family proteins that enhance the catalytic function of SOS (PNAS, November 7, 2006, 103 (45) 16692-16697). Binding to the allosteric site relieves steric blockage of the catalytic site and is therefore required for full activation of the catalytic site. Retention of the active conformation at the catalytic site after interaction with the allosteric site is maintained in isolation, as interactions of the key domains are strengthened in the active state. Selective pharmacological inhibition of the interaction between SOS1 and RAS is expected to prevent activation of RAS signaling via SOS1.

[0007] In the present invention, the applicant provides novel compounds that inhibit the interaction between SOS1 and RAS proteins, thereby preventing KRAS from recycling to its active GTP-bound form. These novel compounds provide therapeutic benefits for a wide range of cancers, particularly RAS protein-associated cancers.

[0008] (Summary of the invention) In one aspect, the present invention provides a fused heterocyclic compound of formula (I), and tautomers or stereoisomers thereof, or pharma- ceutically acceptable salts thereof. Formula (I) represents: [ka] [In the formula, X 1 is N or CR 11 and; X 2 and X 3 are independently N, CR 11 or O, but not both at the same time;X 2 or X 3 When O, X 2 and X 3 are linked by a single bond; R 11 is H, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, amine, cyano, alkynyl, or alkenyl; X 4 is N or CR 12 and R 12 is H, halo, haloalkyl or alkyl; R 1 is H, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, amine, cyano, alkynyl, or alkenyl; R 2 and R 3are each independently H, halo, alkyl, haloalkyl, alkoxyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, acyl, alkoxycarbonyl, or amine; A is a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or an 8-13 membered fused bicyclic ring, each A being optionally substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, acyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, cyano, amine, alkylamino, or dialkylamino; the 8-13 membered fused bicyclic ring contains at least one aromatic ring; M is an amine, alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, alkoxycarbonyl, aminocarbonyl, carboxyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or bridged cycloalkyl or heterocycloalkyl; M is 1 to 5 R 10 groups; each R 10 The groups are independently oxo, acyl, hydroxylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, -C(O)-(CH 2 )n-OR, -S(O) 2 -R,alk-S(O) 2 -R, alk-C(O)-R, alk-C(O)-NRR', -(CH 2 ) n -OR, CD 3-O-, cyano, alkoxyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, alkyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; optionally, two R 10 the groups, together with the atom to which they are both attached, form a cycloalkyl or heterocycloalkyl; Optionally, M may be -(CH) in the fused tricyclic heterocyclic moiety in formula (I). 2 -, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -NR-(CH 2 ) n -, -(CH 2 ) n -C(O)-O-(CH 2 ) n -, -(CH 2 ) n -OC(O)-(CH 2 ) n -, -(CH 2 ) n -C(O)-(CH 2 ) n -, -NR-C(O)-, or -C(O)-NR-; Each R is independently H or alkyl; each R' is independently H or alkyl; n is 0, 1, 2, or 3; each substituent is optionally further substituted; ring-forming carbon atoms or heteroatoms in cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are optionally substituted with one or two oxo groups; Any hydrogen (H) may be optionally replaced with deuterium (D)].

[0009] In formula (I), X 2 and X 3 If there is a dashed line and a solid line (shown as "--") between2 and X 3 The connection with X 2 and X 3 This means that depending on the definition of , it can be a double bond (=) or a single bond (-).

[0010] In some embodiments, A in formula (I) is an aryl, heteroaryl, or an 8-13 membered fused bicyclic ring, optionally substituted with one or more substituents that are each independently halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, acyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, cyano, amine, alkylamino, or dialkylamino.

[0011] In some embodiments, A is phenyl or fused phenyl, and A is optionally substituted with 1-5 substituents selected from halo, haloalkyl, alkyl, and amine. Preferably, halo is F.

[0012] Examples of suitable A's are: [ka] Including, but not limited to:

[0013] In some embodiments, X 1 is N.

[0014] In some embodiments, X 4 is N.

[0015] In some embodiments, X 2 and X 3 are each independently CH or N.

[0016] In some embodiments, M in formula (I) is alkoxycarbonyl, alkoxyalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, acyl, [ka] [ka] [ka] It is. R 13 is H, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, acyl, -C(O)-NR 17 R 18 , -S(O) 2 -R,alk-S(O) 2 -R, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, oxo, alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkyl, or heterocycloalkyl; R 13 may be further optionally substituted with halo, alkyl, hydroxyl, haloalkyl or alkoxy; R 14 , R 15 , and R 16 are each independently H, halo, hydroxyl, hydroxyalkyl, haloalkyl, alkyl, amine, alkoxyalkyl, or alkoxy; and optionally, R 14 and R 15 together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; or optionally, R 15 and R 16 together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R 17 and R 18 are each independently H, cycloalkyl, heterocycloalkyl, or alkyl; optionally, R 17 and R 18 together with the nitrogen atom (N) to which they are both attached form a heterocycloalkyl; R 19 and R' 19are each independently H, alkyl, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, halo, haloalkyl, oxo, acyl, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, cyano, -S(O) 2 -R,alk-S(O) 2 -R, -C(O)-NR 17 R 18 , cycloalkenyl, heterocycloalkenyl, cycloalkyl, or heterocycloalkyl; optionally, R 19 and R' 19 together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R 20 is H, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, acyl, oxo, -S(O) 2 -R,alk-S(O) 2 -R, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, -C(O)-NR 17 R 18 -, cycloalkenyl, heterocycloalkenyl, cycloalkyl, heterocycloalkyl, or [ka] and; R 21 is H, alkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, halo, haloalkyl, haloalkyloxy, CF 3 O-, CHF 2 O-, CD 3 -O-, -NR-C(O)-R, or -(CH 2 ) n -C(O)-NR R'; R 22 , R' 22 , R 23 and R' 23are each independently H, alkyl, alkoxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, halo, haloalkyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, amine, oxo, -S(O) 2 -R,alk-S(O) 2 -R, -NR-C(O)-R, -C(O)-NR 17 R 18 , or -(CH 2 ) n -C(O)-NR'; optionally, R 22 and R' 22 together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; or optionally, R 23 and R' 23 together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R 24 is H, alkyl, haloalkyl, haloalkyloxy, hydroxy, hydroxyalkyl, alkoxyl, alkoxyalkyl, or cyano; R 25 and R 26 are each independently H, alkyl, halo, haloalkyl, alkoxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, or heterocycloalkyl; optionally, R 25 and R 26 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl; Each R is independently H or alkyl; each R' is independently H or alkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, 5, or 6; Optionally, M is a -(CH 2 ) n -O-(CH 2 ) n-, -NR-, -(CH 2 ) n -C(O)-O-(CH 2 ) n -, -(CH 2 ) n -OC(O)-(CH 2 ) n -, -(CH 2 ) n -C(O)-(CH 2 ) n -, -NR-C(O)- or -C(O)-NR-.

[0017] Preferably, M in formula (I) is [ka] [ka] can be, Optionally, M is attached to the fused triheterocyclic moiety of formula (I) via a linker C(O)-.

[0018] In some further embodiments, R 1 is H or alkyl, and R 2 is alkyl, R 3 is H.

[0019] Examples of compounds of formula (I) include: JPEG2025504495000010.jpg200170JPEG2025504495000011.jpg221170JPEG202 5504495000012.jpg221170JPEG2025504495000013.jpg221170JPEG20255044950 00014.jpg216170JPEG2025504495000015.jpg227170JPEG2025504495000016.j pg216170JPEG2025504495000017.jpg216170JPEG2025504495000018.jpg221170 JPEG2025504495000019.jpg216170JPEG2025504495000020.jpg216170JPEG202 5504495000021.jpg210170JPEG2025504495000022.jpg216170JPEG20255044950 00023.jpg221170JPEG2025504495000024.jpg227170JPEG2025504495000025.j pg227170JPEG2025504495000026.jpg221170JPEG2025504495000027.jpg133170

[0020] In some embodiments, preferred compounds are selected from the following: [ka] [ka]

[0021] Another aspect of the invention includes pharmaceutical compositions comprising the compounds described and a pharma- ceutically acceptable carrier or excipient, respectively.

[0022] Yet another aspect of the present invention provides for treating a disorder associated with RAS dysfunction in a subject in need of such treatment. The method comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described above. In some embodiments, the disorder is cancer. Cancer may refer to a type of tissue or organ, or may metastasize from one tissue or organ to another. Cancer may occur in any cell of any type, including breast, prostate, skin, lung, pancreas, stomach, brain, kidney, uterus, ovary, testis, endothelium, colon, bladder, bone, or even blood cells, and may cause various types of leukemia. Preferably, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC), colon cancer (CRC), or pancreatic cancer.

[0023] Yet another aspect of the invention provides the use of a compound or pharmaceutical composition as described for the manufacture of a medicament for treating a disorder associated with RAS dysfunction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description of the Invention The inventors of the present invention design and synthesize novel fused heterocyclic compounds, and their tautomers, stereoisomers, or pharma- ceutically acceptable salts, as regulators of RAS signal transduction.The compounds and compositions of the present invention are useful for treating cancer and other diseases associated with RAS dysfunction in subjects.The subjects are mammals or humans.

[0025] The present invention may be understood more readily by reference to the following detailed description of the invention and the examples included therein.

[0026] Unless the context requires otherwise, references to formula (I) in all sections of this document (including the uses, methods and other aspects of the invention) include references to all other sub-formulas, sub-groups, options, embodiments and examples defined herein.

[0027] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0028] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes mixtures of two or more such functional groups, alkyls, or residues, etc.

[0029] As used herein, the term "modulate" can refer to enhancing an activity or inhibiting an activity.

[0030] As used herein, the term "subject" refers to the subject of administration. In the present invention, the subject may be a mammal or a human.

[0031] As used herein, the term "administer" and "administration" refer to any method of providing a pharmaceutical preparation to a subject.Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, intranasal administration, topical administration, intravaginal administration, intraocular administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injection, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent.

[0032] Throughout this specification, "C(O)" is an abbreviation for a carbonyl group, i.e., C=O, and "SO 2 " or "S(O) 2 "teeth [ka] is an abbreviation for.

[0033] As used herein, "-SH" is a thiol group. The term "alkylthio" refers to alkyl-S-.

[0034] The compounds described herein may contain one or more double bonds, which may result in cis / trans isomers and other conformational isomers.Unless otherwise stated, the present invention includes all such possible isomers, as well as mixtures of such isomers.Furthermore, the present invention also includes all possible optical isomers, as well as mixtures of optical isomers.

[0035] As used herein, the term "alkyl" refers to an alkyl group that is free of unsaturation and has a specified number of carbon atoms (e.g., C 1 -C 10 or C 1 - 10 "alkyl" refers to a saturated straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms having a cyclic alkyl group (alkyl). Whenever a numerical range such as "1-10" is used in this specification, it refers to each integer in the specified range, for example, "1-10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to 10 carbon atoms, but this definition also covers occurrences of the term "alkyl" when no numerical range is specified. Examples include methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, etc. The term "substituted alkyl" refers to an alkyl substituted with one or more substituents.

[0036] As used herein, the term "alkylene" by itself or as part of another molecule means a divalent radical derived from an alkane, which may be straight or branched. In this context, the prefixes (e.g., C 1-4 , C 1-7 , C 1-20 , C 2-7 , C 3-7 etc.) indicates the number of carbon atoms, or a range of numbers of carbon atoms. For example, as used herein, the term "C 1 - 4"Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0037] As used herein, the term "cyano" or the formula "-CN" refers to -C≡N, where the carbon atom and nitrogen atom are joined by a triple bond.

[0038] As used herein, the term "alkoxy" or "alkoxyl" refers to a saturated straight or branched chain hydrocarbon bonded to an oxygen atom. Examples include methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, iso-butoxy, tert-butoxy, pentoxy, hexoxy, etc., preferably methoxy, ethoxy, propoxy, or 2-propoxy. Representative saturated straight chain alkoxy includes methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, etc., while saturated branched alkoxy includes isopropoxy, sec-butoxy, iso-butoxy, tert-butoxy, isopentoxy, etc. Cyclic alkoxy is referred to herein as "cycloalkoxy". Alkoxy can be attached to the molecule by one or two attachment points.

[0039] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0040] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain hydrocarbon and contains at least one C=C double bond. Examples include ethenyl and propenyl. Alkenyl can be substituted with one or more alkyl group(s). Alkenyl can be attached to the molecule by one or two points of attachment.

[0041] As used herein, the term "carbonyl" refers to -C(=O)-.

[0042] The term "alkoxycarbonyl," as used herein, refers to a group of the formula (alkoxy)(C=O)-, which is attached to the parent molecular moiety through the carbonyl carbon.

[0043] As used herein, the term "alk" as a prefix (e.g., in "alkoxy") includes alkyl, alkenyl, and alkynyl, unless specifically defined or chemically required, e.g., to be exclusively alkyl, alkenyl, or alkynyl.

[0044] The term "hydroxyalkylcarbonyl," as used herein, refers to a group of the formula (hydroxyalkyl)(C=O)-- attached to the parent molecular moiety through the carbonyl carbon.

[0045] As used herein, the term "aminocarbonyl" as used herein refers to the group -C(=O)-NRR', where R and R' are each independently H, alkyl, optionally substituted cycloalkyl or heterocycloalkyl. The term "alkylaminocarbonyl" refers to the group -C(=O)-NH-alkyl.

[0046] As used herein, the term "carboxyl" or "carboxy" as used herein refers to -C(O)-OH.

[0047] The term "acyl" refers to the groups HC(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, heterocycloalkyl-C(O)-, each of which is optionally further substituted.

[0048] As used herein, the term "amide" or "amido" refers to a -C(=O)-NR that contains either a carbonyl group or an amino group as the linking atom.2 (i.e., aminocarbonyl) and RC(=O)-NR-.

[0049] As used herein, the term "amino" or "amine" refers to the group -NR'R", where each R' or R" can be the same or different and is hydrogen (-NH 2 (yielding alkylamino or dialkylamino), or another chemical moiety such as optionally substituted heterocycloalkyl and cycloalkyl. The term "alkylamino" refers to -NH-alkyl and the term "dialkylamino" refers to -NRR', where R and R' are the same or different alkyl.

[0050] As used herein, the term "alkamino" refers to an amino group bonded to an alkylene. Generally, when a compound is bonded to an alkamino group, the alkylene portion of the alkamino is bonded to the compound.

[0051] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring composed of at least three carbon atoms, either by itself or as part of another substituent. The term "cycloalkyl" includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl groups. In bridged cycloalkyl, the rings share at least two common non-adjacent atoms. In fused bicyclic cycloalkyl, the two rings share a covalent bond. In spirocyclic cycloalkyl, one atom is common to two different rings.

[0052] As used herein, the term "fused phenyl" refers to a phenyl group fused to another ring, such as an aryl, heteroaryl, cycloalkenyl, heterocycloalkenyl, cycloalkyl, or heterocycloalkyl. The fused phenyl may be optionally substituted on any atom within the fused system.

[0053] As used herein, the term "heterocycloalkyl" is a type of cycloalkyl group defined above and is included in the meaning of the term "cycloalkyl" in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted.

[0054] Additionally, ring-forming carbon atoms or heteroatoms of a cycloalkyl or heterocycloalkyl group can be optionally substituted with one or two oxo groups. For example, a ring-forming S atom can be substituted with one or two oxo (S(O) or S(O) 2 As another example, a C atom forming a ring may be substituted with oxo (forming a carbonyl).

[0055] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Cycloalkenyl does not belong to an aromatic series and includes monocyclic or polycyclic groups. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. Cycloalkenyl groups can be further substituted.

[0056] As used herein, the term "heterocycloalkenyl" refers to a cycloalkenyl having at least one heteroatom in the ring. Heteroatom refers to an atom other than C. Heteroatom is preferably N, O, S, or P, etc. Heterocycloalkyl can be substituted or unsubstituted.

[0057] Furthermore, ring-forming carbon atoms or heteroatoms of a cycloalkenyl or heterocycloalkenyl group can be optionally substituted with one or two oxo groups.

[0058] As used herein, the term "halogen" or "halo" refers to chlorine (Cl), bromine (Br), fluorine (F) or iodine (I). The term "halogen" or "halo" preceding the name of a group means that the group is partially or fully halogenated, that is, the group is substituted with any combination of F, Cl, Br, or I.

[0059] As used herein, the term "haloalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms are replaced with halogen independently selected from fluoro, chloro, bromo, and iodo. "Fluoroalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms are replaced with fluoro atoms. Unless otherwise specified by number, haloalkyl can contain as many halo atoms as chemically possible as substituents of the alkyl group. For example, fluoroethyl is -CH 2 CF 3 , -CHF-CH 3 , or -CH 2 CH 2 It could be F.

[0060] As used herein, the term "hydrogen" (or H) includes its isotope deuterium (D or 2 H) and tritium ( 3 H), and one or any hydrogen atom in the compounds of the invention may also be deuterium (D or 2 H) and tritium ( 3 H) can be substituted.

[0061] As used herein, the terms "hydroxyl" or "hydroxy" refer to an --OH group.

[0062] As used herein, the term "hydroxyalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more hydrogen atoms have been replaced with a hydroxyl substituent. Thus, the term "hydroxyalkyl" is meant to include monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and the like.

[0063] As used herein, the term "sulfonyl" refers to -S(O) 2 - refers to.

[0064] As used herein, the term "alkcycloalkyl" refers to a cycloalkyl group bonded to an alkylene group. Generally, when a compound is bonded to an alkcycloalkyl group, the alkylene portion of the alkcycloalkyl group is bonded to the compound.

[0065] As used herein, the term "alk-S(O) 2 -R" is -S(O) bonded to an alkylene. 2 -R group. Generally, compounds are alk-S(O) 2 When bonded to the -R group, alk-S(O) 2 The alkylene portion of -R is attached to the compound. In some embodiments, R is H or alkyl.

[0066] As used herein, the term "aromatic" or "aromatic ring" or similar terms refer to a planar ring having a delocalized pi-electron system containing 4n+2 pi-electrons, where n is a positive integer. An aromatic ring may be formed from 5, 6, 7, 8, 9, 10, or more than 10 atoms. An aromatic is optionally substituted. The term "aromatic" includes carbocyclic aryl ("aryl", e.g., phenyl) and "heteroaryl" (or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0067] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups can be further substituted.

[0068] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring (i.e., rings sharing adjacent pairs of atoms) of 5 to 12 ring atoms containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and further having a fully conjugated pi-electron system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzthiazole, indazole, and quinazoline. Heteroaryl groups can be substituted or unsubstituted. Examples of substituents are halo, alkyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, alkoxyl, amino, amine, cyano, alkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, carbonyl, alkoxycarbonyl, aminocarbonyl, hydrocarboxyl, alkylthio, -D(deuterium), oxo, -C(O)-(CH 2 )n-OR, -(CH 2 ) n -S(O) 2 -R, -C(O)-R, -C(O)-NR, -(CH 2 ) n -OR, -NR-C(O)-(CH 2 ) n -, CD 3 Includes, but is not limited to, -O-, and -CN (where R is H or alkyl).

[0069] As used herein, the term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent. When it is attached to a carbon atom it results in a carbonyl group, when it is attached to a sulfur atom it results in a sulfoxide or sulfone group, or when it is attached to a nitrogen atom it results in an N-oxide group. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo substituents.

[0070] The above defined groups may include prefixes and / or suffixes that form substituents commonly used and further understood in the art. As an example, the term "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "(haloalkyl)oxyalkyl" refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups. As another example, the term "hydroxyalkamino" refers to an amino group substituted with one or two hydroxyalkyl groups.

[0071] As used herein, the term "stereoisomer" refers to an isomer of identical constitution that differs in the arrangement of atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric species, which composition lacks optical activity. When a disclosed compound is named or depicted by structure without showing stereochemistry, it is understood that the name or structure includes all possible stereoisomers, geometric isomers, and combinations thereof, including essentially pure stereoisomers or geometric isomers.

[0072] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. When tautomerization can occur (e.g., in solution), a chemical equilibrium of tautomers can be reached. "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl may be present, but does not necessarily have to be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with an alkyl group.

[0073] As used herein, the phrase "optionally substituted" means that the substitution is optional, and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen of the specified atom or moiety can be replaced with one selected from the specified substituents, provided that the normal valence of the specified atom or moiety is not exceeded and the substitution produces a stable compound. For example, when a methyl group is optionally substituted, three hydrogen atoms on the carbon atom can be replaced with a substituent.

[0074] As used herein, the term "pharmaceutical acceptable" means suitable for use in humans or other mammals.

[0075] The term "pharmaceutical acceptable salt" used herein refers to salts with known cations or anions, and can be applied to the use in the field.Suitable salts with bases, for example, salts formed from compounds of formula (I) containing carboxyl groups, include salts of alkali metals (such as sodium, potassium), alkaline earth metals (such as calcium, magnesium), ammonium, and amines.Suitable salts with acid radical additives, for example, salts formed from compounds of formula (I) containing amino, include salts formed with inorganic acids such as hydrochloride, sulfate, sulfite, phosphate, hydrogen phosphate, and nitrate, and salts formed with organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, salicylic acid, oxalic acid, etc.

[0076] Furthermore, if a compound is obtained as an acid addition salt, the free alkali can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free alkali, the addition salt can be prepared by dissolving the free alkali in a suitable organic solvent and treating the solution with an acid, which is consistent with the conventional process of preparing an acid addition salt from an alkaline compound. Those skilled in the art will recognize the various synthetic methods that can be used to prepare acceptable addition salts without undue experimentation.

[0077] In addition, when the compound of the present invention has a carboxyl group, the compound can be converted to the corresponding alcohol (e.g., C 1-6 By reacting the carboxylic acid with an alcohol) a pharma- ceutically acceptable ester can be obtained by a conventional method (for example, a condensation reaction between a carboxylic acid and an alcohol).

[0078] As used herein, "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or their pharmaceutically acceptable salts or prodrugs, and other chemical components, such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0079] As used herein, the term " pharmaceutically acceptable excipient " refers to the inert substance added to pharmaceutical compositions to further facilitate the administration of compound.The examples of excipient include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oil and polyethylene glycol.

[0080] As used herein, the term "therapeutically effective amount" refers to the amount of compound administered that relieves to some extent one or more of the symptoms of the disorder being treated.With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reducing tumor size; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) relieving one or more symptoms associated with cancer.

[0081] An atom of a chemical group that is bonded to another atom, e.g. [ka] It is represented by a wavy line as follows. EXAMPLES

[0082] The following examples are presented so as to provide one of ordinary skill in the art with a more complete disclosure and description of how to make and use the compounds of the present invention, and are intended to be merely illustrative of the invention and are not intended to limit the scope of what the inventors regard as their invention. Example 1: Ethyl (R)-6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate [ka]

[0083] Step 1: To a solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (300 mg, 1.57 mmol, 1.0 equiv) in DCM (2.5 mL) was added a solution of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (367.8 mg, 1.57 mmol, 1.0 equiv) in DMSO (2.5 mL), followed by addition of Et 3 N (476.8 mg, 4.71 mmol, 3.0 equiv) was added at 0° C. The reaction was stirred at 26° C. for 10 min to give a red-purple solution. The mixture was extracted with DCM (3×) and the organic phase was concentrated to dryness under reduced pressure to give the crude product, (R)-4-chloro-2-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-5-carbaldehyde.

[0084] Step 2: To a solution of (R)-4-chloro-2-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-5-carbaldehyde (400 mg, 1.03 mmol, 1.0 equiv) in DMAc (5.0 mL) was added Cs 2 CO 3 (670.5 mg, 2.06 mmol, 2.0 equiv) and ethyl 2-(4H-1,2,4-triazol-3-yl)acetate (159.7 mg, 1.03 mmol, 1.0 equiv) were added. The reaction was stirred for 0.5 h at 100 °C to give a red-purple solution. The mixture was extracted with DCM (3 times) and the organic phase was concentrated to dryness under reduced pressure. The crude product was purified by flash column (SiO 2 , eluted with 0–100% EA in PE) to obtain compound ethyl (R)-8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate.

[0085] Step 3: To a solution of ethyl (R)-8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate (30 mg, 0.061 mmol, 1.0 equiv.) in EtOH (1.0 mL), add SnCl 2 2H 2 2H2O (69.2 mg, 0.31 mmol, 5.0 equiv) was added. The reaction was stirred for 0.5 h at 50 °C to give a red-purple solution. The reaction was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 2 O, 0–100%) to give the product ethyl (R)-6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate. JPEG2025504495000033.jpg76170 Example 2: Synthesis of (R)-(6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)(morpholino)methanone [ka]

[0086] Step 1: To a solution of methyl (R)-8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate (200 mg, 0.4 mmol, 1.0 equiv) in MeOH (5.0 mL) was added 10% aqueous LiOH (3.0 mL). The reaction was stirred at 25 °C for 10 min to give a yellow solution. The mixture was then adjusted to pH 3-4 by the addition of 1N HCl and extracted with DCM (3 times). The organic phase was concentrated to dryness under reduced pressure to give the product lithium (R)-8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate.

[0087] Step 2: To a solution of lithium (R)-8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate (60 mg, 0.15 mmol, 1.0 equiv.) in DMF (1.0 mL), add BOP (127.5 mg, 0.3 mmol, 2.0 equiv.) and stir for 30 min, then add Et 3 N (0.04 mL) and morpholine (80.0 mg, 0.4 mmol, 3.0 equiv.) were added. The mixture was stirred at 26° C. for 1.0 h to give a red solution. The mixture was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 2 OH, 0–100%) to give the product, (R)-(8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)(morpholino)methanone.

[0088] Step 3: To a solution of (R)-(8-methyl-6-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)(morpholino)methanone (20 mg, 0.03 mmol, 1.0 equiv.) in EtOH (1.0 mL), add SnCl 2 . 2H 2 O ( The reaction was stirred at 50 °C for 0.5 h to give a red solution. The mixture was then treated with NaHCO 3 The pH was adjusted to 7-8 by adding 500 ml of water, and the mixture was extracted with DCM (3 times). The organic phase was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 2 OH, 0–100%) to give the product, (R)-(6-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)(morpholino)methanone. JPEG2025504495000035.jpg205170JPEG2025504495000036.jpg216170JPEG2025504495000037.jpg227170JPEG2025504495000038.jpg210170JPEG2025504495000039.jpg155170Example 50: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide [ka]

[0089] Step 1: To a stirred solution of 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (1.61 g, 9.38 mmol, 1.0 equiv.) in dry DMSO (5 mL) was added (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (2.33 g, 10.32 mmol, 1.1 equiv.) and Et 3 N (2.85 g, 28.14 mmol, 3.0 equiv) was added. The reaction was heated at 80° C. for 5 h to give a deep red solution. The reaction was cooled to 5° C. for 1 h. 2 The mixture was diluted with 2×O (5 mL) and extracted with EtOAc (8×3 mL). The combined organic layers were washed with an aqueous solution of brine (10 mL×2) and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated to give the crude product which was used in the next step without further purification.

[0090] Step 2: To a suspension of 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (3.4 g, 9.38 mmol, 1.0 equiv) in EtOH (10 mL) was added diethyl malonate (3.0 g, 18.76 mmol, 2.0 equiv) and piperidine (0.80 g, 9.38 mmol, 1.0 equiv) at room temperature. The mixture was stirred at 75 °C for 2 h to give a pale yellow solution. The reaction was concentrated and diluted with H 2 The mixture was diluted with 2 mL of 2H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated to give the crude product, which was purified by flash column (SiO 2 The mixture was purified by elution with 0-80% PE in EA. The collected flow-through was concentrated to give ethyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate.

[0091] Step 3: Add ethyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate (221 mg, 0.53 mmol, 1.0 equiv.) and POCl to a vial. 3 (0.5 mL) was charged. To this mixture was added a catalytic amount of DMF (2 drops). The mixture was stirred at 90 °C under nitrogen atmosphere for 3 h to give a deep red solution. The reaction was cooled to 0 °C with ice-cold saturated NaHCO 3 The reaction mixture was poured into EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated to give ethyl (R)-7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine-6-carboxylate.

[0092] Step 4: A solution of ethyl (R)-7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine-6-carboxylate (90 mg, 0.51 mmol, 1.0 equiv.) in MeOH (1.0 mL) and THF (1.5 mL) was diluted with LiOH solution (51 mg in 0.5 mL of H 2 2H 2 O (0.54 mmol, 6.0 equiv.) was added. The mixture was stirred at room temperature for 4 h to give a pale yellow solution. The solvent was removed under reduced pressure to give 136 mg of crude lithium (R)-7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine-6-carboxylate, which was used in the next step without further purification.

[0093] Step 5: To a solution of lithium (R)-7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine-6-carboxylate (136 mg, 0.51 mmol, 1.0 equiv) in EtOH (2.0 mL), NH 2 NH 2 H 2 0 (0.5 mL) was added. The mixture was stirred at room temperature for 4 min to give a red solution. The reaction was concentrated to give the crude product of lithium (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-hydrazinyl-2-methylpyrido[2,3-d]pyrimidine-6-carboxylate, which was used in the next step without further purification.

[0094] Step 6: The crude product is reacted with CH(OEt) 3 (2.0 mL) was added and the reaction was stirred at room temperature overnight to give a red solution. The mixture was neutralized to pH 7-8 with 2N HCl solution and concentrated to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-carboxylic acid.

[0095] Step 7: To a mixture of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-carboxylic acid (20 mg, 0.048 mmol, 1.0 equiv.) and dimethylamine hydrochloride (9.8 mg, 0.120 mmol, 2.5 equiv.) in DCM (2.0 mL) was added Et 3 N (14.6 mg, 0.144 mmol, 3.0 equiv) and BOP (21.4 mg, 0.048 mmol, 1.0 equiv) were added. The mixture was stirred at room temperature overnight to give a deep red solution. The reaction was cooled to 5° C. for 1 hour. 2 The organic layer was washed with brine (8 mL) and diluted with 200 mL of anhydrous NaCl. 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated to give the crude product, which was purified by flash column (C18, H 2 O(0.5% HCO 2 The mixture was purified by elution with 0-80% MeCN in hexanes (H). The collected flow was concentrated and lyophilized to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide. JPEG2025504495000041.jpg121170 Example 54: Synthesis of (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)(morpholino)methanone [ka]

[0096] Step 1: To a solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (2.0 g, 8.7 mmol, 1.0 equiv.) in DMSO (10 mL) was added 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (1.9 g, 9.8 mmol, 1.1 equiv.) in DMSO (10 mL), followed by addition of Et 3 N (3.7 mL) was added portionwise. The reaction was stirred at 26° C. for 10 min to give a deep red solution. The mixture was extracted with DCM (3×) and the organic phase was concentrated to dryness under reduced pressure to give the compound (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrimidine-5-carbaldehyde.

[0097] Step 2: To a solution of (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrimidine-5-carbaldehyde (1.2 g, 3.5 mmol, 1.0 equiv.) in DMAc (12 mL), add K 2 CO 3(1.0 g, 7.0 mmol, 2.0 equiv) and ethyl 2-(1H-imidazol-2-yl)acetate (0.5 g, 3.5 mmol, 1.0 equiv) were added. The reaction was stirred at 100 °C for 2 h to give a red solution. The mixture was extracted with DCM (3 times) and the organic phase was concentrated to dryness under reduced pressure. The crude product was purified by flash column (SiO 2 , eluted with 0–100% EA in PE) to give ethyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxylate.

[0098] Step 3: To a solution of ethyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxylate (200 mg, 0.45 mmol, 1.0 equiv.) in MeOH (5 mL) was added 10% aqueous LiOH (3 mL). The reaction was stirred at 25 °C for 10 min to give a yellow solution. The mixture was then adjusted to pH 3-4 by adding 1N HCl and extracted with DCM (3 times). The organic phase was concentrated to dryness under reduced pressure to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxylic acid.

[0099] Step 4: To a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxylic acid (67.8 mg, 0.16 mmol, 1.0 equiv) in DMF (1 mL) was added BOP (144.4 mg, 0.33 mmol, 2.0 equiv) and stirred for 30 min, then added Et 3 N (0.045 mL) and morpholine (71.1 mg, 0.82 mmol, 2.0 equiv.) were added. The mixture was stirred at 25° C. for 1 h to give a red solution. The mixture was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 20, 0–100%) and purified to obtain the compound (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)(morpholino)methanone. JPEG2025504495000043.jpg91170 Example 55: (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,8-trimethyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxamide [ka]

[0100] Step 1: To a solution of (R)-4-chloro-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrimidine-5-carbaldehyde (3.5 g, 9.5 mmol, 1.0 equiv.) in ACN (30 mL), add K 2 CO 3 (2.6 g, 19.0 mmol, 2.0 equiv) and methyl 2-(1H-tetrazol-5-yl)acetate (1.5 g, 10.5 mmol, 1.0 equiv) were added. The reaction was stirred at 100 °C overnight to give a red solution. The mixture was extracted with DCM (3 times) and the organic phase was concentrated to dryness under reduced pressure. The crude product was purified by flash column (SiO 2 , eluted with 0–100% EA in PE) to obtain the compound methyl (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate.

[0101] Step 2: To a solution of methyl (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylate (732.7 mg, 1.7 mmol, 1.0 equiv.) in MeOH (5 mL) was added 10% aqueous NaOH (3 mL). The reaction was stirred at 24 °C for 10 min to give a yellow solution. The mixture was then adjusted to pH 3-4 by adding 1N HCl and extracted with DCM (3 times). The organic phase was concentrated to dryness under reduced pressure to give the compound (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylic acid.

[0102] Step 3: To a solution of (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxylic acid (100 mg, 0.24 mmol, 1.0 equiv.) in DMF (2 mL), BOP (212 mg, 0.48 mmol, 2.0 equiv.) was added and stirred for 30 min, then added Et 3 N (0.166 mL) and dimethylamine (108.0 mg, 2.4 mmol, 10 equiv.) were added. The mixture was stirred at 26 °C for 1 h to give a red solution. The mixture was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 2 0°C, 0–100%) to give (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,8-trimethyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidine-4-carboxamide. JPEG2025504495000045.jpg200170JPEG2025504495000046.jpg84170 Example 67: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one [ka]

[0103] Step 1: A solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (20.0 g, 105.8 mmol, 1.0 equiv) in THF (150 mL) was treated with NH 3 H 2 The reaction was then stirred at room temperature for 1 h to give an orange solution, which was filtered to give 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde.

[0104] Step 2: A solution of LiHMDS (4.4 mL, 4.37 mmol, 2.5 equiv, 1.0 M in THF) was added dropwise to a solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (764.1 mg, 2.62 mmol, 1.5 equiv) in THF (5 mL) at -78 °C, and the reaction was stirred at -78 °C for 30 min. A suspension of 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (300 mg, 1.75 mmol, 1.0 equiv) in THF (5 mL) was added to the above solution at -78 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h to give a yellow solution. The reaction was then heated to 50 °C overnight. Water was added dropwise to the reaction mixture, and the residue was partitioned into ethyl acetate (20 mL). The separated organic layer was washed with water and anhydrous Na 2 SO 4 The crude product was purified by silica gel chromatography (PE / EA, 0-50%) to give benzyl 4-(4-chloro-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate.

[0105] Step 3: To a solution of benzyl 4-(4-chloro-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (550.0 mg, 1.33 mmol, 1.0 equiv.) in DMSO (10 mL), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (360.7 mg, 1.60 mmol, 3.0 equiv.) and Et 3 N (0.56 mL, 4.0 mmol, 3.0 equiv) was added at room temperature, and then the reaction mixture was heated at 90° C. for 2 h. The mixture turned into a pale yellow solution. 2 O (10 mL) was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The crude product was purified by silica gel chromatography (PE / EA, 0-80%) to give benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate.

[0106] Step 4: Benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (1.5 g, 2.65 mmol), POCl 3 (5.0 mL), and DMF (1 drop) were combined and the resulting mixture was heated at 80° C. in a sealed tube. After 3.0 h, the mixture turned to a red-brown solution. The reaction was concentrated in vacuo and the residue, benzyl (R)-4-(7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate, was used in the next step without further purification.

[0107] Step 5: To a solution of the crude product benzyl (R)-4-(7-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (5.83 mmol) in EtOH (10.0 mL) was added hydrazine hydrate (2.0 mL) dropwise at room temperature and stirred at 100° C. for 1.0 h in a sealed tube. The mixture turned into a dark red solution. Most of the solvent was removed under reduced pressure and the residue benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-hydrazinyl-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate was used in the next step without further purification.

[0108] Step 6: CH(OEt) 3 A solution of the crude product benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-hydrazinyl-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (5.83 mmol) in 10 mL of 100 ml ... 2 OH, 0–100%) to give benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate.

[0109] Step 7: To a solution of benzyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (200 mg, 0.34 mmol, 1.0 equiv) in EtOH (2.0 mL) was added 12 M HCl (2.0 mL). The mixture was stirred at room temperature for 24 h to give a light brown solution. The reaction was poured into ice water and Na 2 CO 3 (aqueous) to pH=10-11 and extracted with EA. The combined organic layers were washed with brine and 2 SO 4 The residue was purified by flash column (C18, ACN / H2O containing 0.5% HCCOH). 2 The mixture was purified by elution with a gradient of 0.05% CO. The collected flow-through was lyophilized to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(piperidin-4-yl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine formate.

[0110] Step 8: To a solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(piperidin-4-yl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amineformate (50 mg, 0.11 mmol, 1.0 equiv) in THF (1 mL) was added Et 3 N (0.076 mL) was added, followed by the dropwise addition of acetyl chloride (8.6 mg, 0.11 mmol, 1.0 equiv). The reaction was stirred at 26 °C for 5 min to give a red solution. The mixture was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (MeCN / H 2OH, 0–100%) to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one. JPEG2025504495000048.jpg158170 Example 73: (R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)oxazol-4(5H)-one [ka]

[0111] Step 1: To a solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperidin-4-yl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (220 mg) in DCM (5.0 mL) was added 2-chloroacetyl isocyanate (60 mg, 0.50 mmol, 2.0 equiv) at 0° C. The mixture was then stirred at room temperature for 1 h to give a red-brown solution. The reaction was quenched with saturated NaHCO 3 The organic layer was washed with brine (5 mL) and diluted with anhydrous Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated to give (R)-N-(2-chloroacetyl)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxamide, which was used in the next step without further purification.

[0112] Step 2: The above crude product was dissolved in THF (5.0 mL) and DBU (76 mg, 0.5 mmol, 2.0 equiv.) was added. Stirring at room temperature for 2 h gave a brown suspension. The volatiles were removed and the crude product was purified by flash column (C18, H 2 0-80% MeCN (0.5% HCO 2 Purification by elution with HPLC (HPLC-HPLC)) to give (R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)oxazol-4(5H)-one. LC / MS: 525.20 (M+1) + 1 H NMR (400 MHz, CD 3 OD) δ 9.62 (s, 1H), 8.49 (s, 1H), 8.08 (d, J = 3.7 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.03 (t, J = 54.8 Hz, 1H), 5.87 (q, J = 6.9 Hz, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.68 (q, J = 6.6 Hz, 1H), 4.62 (s, 1H), 4.27 (d, J = 13.6 Hz, 1H), 3.67-3.55 (m, 1H), 3.40 (d, J = 13.6 Hz, 1H), 2.95 (t, J = 12.8 Hz, 1H), 2.34-2.17 (m, 2H), 1.92 (tt, J = 12.0, 6.3 Hz, 2H), 1.72 (d, J = 7.0 Hz, 3H), 1.40 (dd, J = 10.8, 6.6 Hz, 3H). Example 74: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-morpholino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine [ka]

[0113] Step 1: To a mixture of 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (3.0 g, 17.48 mmol, 1.0 equiv.) and EtOAc (2.56 mL, 26.23 mmol, 1.5 equiv.) in THF (30 mL) was added LiHMDS (43.7 mL, 43.71 mmol, 2.5 equiv.) at -20 °C, and the resulting mixture was stirred at room temperature for 2 h to give a red-brown suspension. 4 The reaction was quenched by dropwise addition of Cl(Sat.) and the suspension was concentrated to dryness. The residue was purified by FC(SiO 2 ) (PE / EA, 80%) to give 4-chloro-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

[0114] Step 2: To a solution of 4-chloro-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.45 g, 7.41 mmol, 1.0 equiv.) in DMSO (15.0 mL), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (1.67 g, 7.41 mmol, 1.0 equiv.) and TEA (3.09 mL, 22.24 mmol, 3.0 equiv.) were added at room temperature and the reaction mixture was heated at 90° C. for 2 h. The mixture turned into a pale yellow solution. After cooling to room temperature, H 2 O (10 mL) was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 Drying at rt and concentration in vacuo afforded (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one, which was used in the next step without purification.

[0115] Step 3: To a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7.41 mmol) in DMF (5.0 mL) was added NBS (1.32 g, 7.41 mmol, 1.0 equiv) at room temperature and the reaction mixture was heated at 50° C. for 2 h. The mixture turned into a pale yellow suspension. After cooling to room temperature, H 2 O (20 mL) was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 After drying at 40° C. and concentrating in vacuum, the crude product was purified by silica gel chromatography (PE / EA, 40%) to give (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

[0116] Step 4: (R)-6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.25 g, 2.93 mmol, 1.0 equiv.), POCl 3 (5.0 mL), and DMF (1 drop) were combined and the resulting mixture was heated at 90° C. in a sealed tube. After 2 h, the mixture turned into a red-brown solution. The reaction was slowly poured into ice water and then extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 and then concentrated in vacuo to give the crude product (R)-6-bromo-7-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine, which was used in the next step without purification.

[0117] Step 5: To a solution of the crude product (R)-6-bromo-7-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine (3.04 mmol) in EtOH (10.0 mL) was added hydrazine hydrate (1.0 mL) dropwise at room temperature and stirred at 100 °C for 1 h in a sealed tube. The mixture turned into a dark red solution. Most of the solvent was removed under reduced pressure and the residue (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-hydrazinyl-2-methylpyrido[2,3-d]pyrimidin-4-amine was used in the next step without further purification.

[0118] Step 6: CH(OEt) 3 A solution of the crude product (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-hydrazinyl-2-methylpyrido[2,3-d]pyrimidin-4-amine (3.04 mmol) in 10 mL of ethyl acetate was stirred at 100° C. for 12 h in a sealed tube to give a dark red solution. The reaction mixture was cooled to room temperature and then extracted with EtOAc. The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 After drying at 40° C. and concentrating in vacuum, the crude product was purified by silica gel chromatography (PE / EA, 0-40%-60%) to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine.

[0119] Step 7: To a solution of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (50 mg, 0.11 mmol, 1.0 equiv.) and morpholine (19.2 mg, 0.22 mmol, 2.0 equiv.) in dioxane (1.0 mL), XantPhos (12.8 mg, 0.022 mmol, 0.2 equiv.), Cs 2 CO3 (108.3 mg, 0.33 mmol, 3.0 equiv.) and Pd(OAc) 2 (2.5 mg, 0.011 mmol, 0.1 equiv.) 2 The reaction was stirred in a microwave at 110° C. for 2 h to give a black solution. The reaction was filtered through a pad of Celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (C18, ACN / H2O with 0.5% HCCOH). 2 The mixture was purified by elution with a gradient of 0.025 ml of 1000 ml of toluene (eluted with a gradient of 0.025 ml of 1000 ml of toluene). The collected flow-through was concentrated to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-morpholino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine. JPEG2025504495000051.jpg205170JPEG2025504495000052.jpg155170Example 90: Cis-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol and trans-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol [ka] [ka]

[0120] Step 1: 1,4-Dioxane / H 2(R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (2.0 g, 4.4 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.63 g, 9.9 mmol, 2.25 equiv.), Pd(dppf)Cl in 2O (42 mL, 5:1). 2 (0.64 mg, 0.88 mmol, 0.2 equiv.) and Na 2 CO 3 A mixture of (1.4 mg, 13.2 mmol, 3.0 equiv) was stirred at 80° C. for 2.5 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by flash column chromatography (eluted with DCM:MeOH=97:3) to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine. LC-MS [M+H] + = 511.2.

[0121] Step 2: To a solution of (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohex-3-en-1-one (1.8 g, 3.5 mmol) in THF (30 mL) was added HCl (10 mL, 3N) in portions. The reaction mixture was stirred at 25 °C for 1.5 h. The reaction was then quenched with NaHCO 3(aqueous) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by recrystallization with MeOH to give (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohex-3-en-1-one. LC-MS [M+H] + = 467.15.

[0122] Step 3: To a solution of (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohex-3-en-1-one (1.2 g, 3.2 mmol) in MeOH (200 mL), add PtO 2 was added. The reaction mixture was stirred under hydrogen at 25°C for 1.5 hours. The reaction was filtered. The filtrate was concentrated to give (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol (1.2g, >100%) as a yellow solid. 100mg of the crude product was purified by preparative HPLC (column: Gemini 5um C18 150*20mm; mobile phase: ACN-H 2 0 (0.1% TFA); gradient: 5-95) and lyophilization to give cis-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol and trans-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol. Isomer 1:90-P1 LC / MS: 471.15 (M+1) + . 1 H NMR (400 MHz, CD 3 OD) δ 8.18 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.14-6.87 (t, J = 54.4 Hz,1H), 5.86-5.81 (m, 1H), 3.70 (s, 1H), 3.23 (s, 1H), 2.50 (s, 3H), 2.16-2.14 (m, 4H), 1.81 (s, 2H), 1.69 (d, J = 7.2 Hz, 3H), 1.57-1.52 (m, 2H). LC / MS: 471.15 (M+1) + . Isomer 2:90-P2 1 H NMR (400 MHz, CD 3 OD) δ 9.67 (s, 1H), 8.19 (s, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 6.8 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.14-6.87 (m, 1H), 5.86 (q, J = 7.2 Hz, 1H), 4.15 (s, 1H), 3.24 (m, 1H), 2.51 (s, 3H), 2.12 (m, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.82 (m, 2H), 1.71 (d, J = 7.2 Hz, 3H). Example 91: Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-4-morpholinotetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine [ka]

[0123] Step 1: To a solution of (R)-6-bromo-7-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine (2 g, 4.5 mmol, 1.0 equiv.) in EtOH at 25 °C, NaN 3 (2.05 g, 31.5 mmol, 7.0 equiv) was added portionwise. The reaction mixture was stirred at 80° C. for 16 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (eluted with DCM:MeOH=98:2) to give (R)-4-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine. LC-MS [M+H] + = 452.5.

[0124] Step 2: To a solution of (R)-4-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyltetrazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine (50 mg, 0.11 mmol, 1.0 equiv.) and morpholine (19.2 mg, 0.22 mmol, 2.0 equiv.) in dioxane (1.0 mL), XantPhos (12.8 mg, 0.022 mmol, 0.2 equiv.), Cs 2 CO 3 (108.3 mg, 0.33 mmol, 3.0 equiv.) and Pd(OAc) 2 (2.5 mg, 0.011 mmol, 0.1 equiv.) 2 The reaction was stirred in a microwave at 110° C. for 2 h to give a black solution. The reaction was filtered through a pad of Celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (C18, ACN / H2O with 0.5% HCCOH). 2The mixture was purified by elution with a gradient of 0.025 ml of 1000 ml of 1000 ml of 1000 ml of 2 ... JPEG2025504495000056.jpg196170 Example 100: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one [ka]

[0125] Step 1: Dioxane (10.0 mL) and H 2 To a solution of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (1.0 g, 2.22 mmol, 1.0 equiv.) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)ethan-1-one (0.83 g, 3.32 mmol, 1.5 equiv.) in 2H2O (2.0 mL), was added 10 mL of KCl. 2 CO 3 (0.92 g, 6.65 mmol, 3.0 equiv.) and Pd(dppf)Cl 2 (81 mg, 0.11 mmol, 0.05 equiv.) 2 The reaction was stirred in a microwave at 100° C. for 0.5 h to give a brown solution. The residue was diluted with H 2 The mixture was diluted with O and extracted with EA (30 mL×2). The combined organic layers were washed with brine and 2 SO 4The mixture was dried at 40° C., filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography (DCM / MeOH, 5%~) to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one. JPEG2025504495000058.jpg177170 Example 107: Synthesis of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one [ka]

[0126] Step 1: 8.0 mL of DCM / i A solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (500 mg, 1.01 mmol, 1.0 equiv.) and cobalt TPP (67.8 mg, 0.101 mmol, 0.1 equiv.) in PrOH (1:1) was added to EtOH at 0 °C. 3 SiH (0.48 mL, 3.027 mmol, 2.0 equiv) was added. The reaction was then heated at room temperature for 2 h at 37 °C. 2The mixture was stirred at atmospheric pressure (balloon) for 2 hours to give a brown solution. The reaction was concentrated to dryness under vacuum. The crude product was purified by silica gel chromatography (DCM / MeOH, 0-5%) to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one. JPEG2025504495000060.jpg169170 Example 114: Synthesis of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one [ka]

[0127] Step 1: To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (300 mg, 0.584 mmol, 1.0 equiv) in 5.0 mL of DCM was added DAST (0.12 mL, 0.876 mmol, 1.5 equiv) at 0 °C. After stirring at 0 °C for 0.5 h, the reaction was stirred at room temperature for 1 h to give a brown solution. NaHCO 3 The reaction was quenched by the addition of (Sat.) and extracted with DCM. The combined organic layers were washed with brine and 2 SO 4 The crude product was purified by reverse phase column chromatography (MeCN / H 2OH, 0-50%) to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one. JPEG2025504495000062.jpg123170 Example 118: Synthesis of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methoxypiperidin-1-yl)ethan-1-one [ka]

[0128] Step 1: 5.4 mL of CH 3 CN / MeOH / H 2 To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (24.5 mg, 0.047 mmol, 1.0 equiv) in 2H2O (5:3:1) was added NaOMe (23.1 mg, 0.428 mmol, 9.0 equiv) at 0°C. The reaction was stirred at room temperature overnight to give a yellow solution. NH 4 The reaction was quenched by addition of Cl(Sat.) and extracted with DCM. The combined organic layers were washed with brine and 2 SO 4 The crude product was purified by reverse phase column chromatography (MeCN / H 2OH, 0-50%) to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methoxypiperidin-1-yl)ethan-1-one. JPEG2025504495000064.jpg206170 Example 127: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylpiperidin-1-yl)ethan-1-one [ka]

[0129] Step 1: To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (30 mg, 0.058 mmol, 1 equiv) in DCM (2 mL) was added Me 3 Al (2M in hexane, 0.1 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 2 h. The mixture was quenched with MeOH and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gemini 5um C18 150*21.2 mm, mobile phase: ACN-H 2 0 (0.1% TFA); gradient: 5-95) and lyophilization gave (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylpiperidin-1-yl)ethan-1-one. JPEG2025504495000066.jpg159170 Example 133: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-(methoxy-d3)piperidin-1-yl)ethan-1-one [ka]

[0130] Step 1: To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (150 mg, 0.3 mmol) in THF (2 mL) was added sodium hydride (10.8 mg, 0.45 mmol) in portions at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, followed by addition of CDCl. 3 I (42.6 mg, 0.3 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 50° C. for 2 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was analyzed by preparative TLC and preparative HPLC (column: Gemini 5um C18 150*21.2 mm, mobile phase: ACN-H 2 0 (0.05% TFA); gradient: 20-95) and lyophilized to give the final compound. LC / MS: 517.2 (M+1) + . Example 134: (R)-N-(1-acetyl-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-4-yl)acetamide [ka]

[0131] Step 1: Stirred under nitrogen at -15 °C in CH 3 To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (100 mg, 0.2 mmol, 1 equiv) in CN (1 mL) was added H 2 SO 4 (2 mL) was added dropwise. The reaction mixture was stirred at -15 °C for 8 h. The mixture was diluted with NaHCO 3 (20 mL) followed by extraction with DCM (3×10 mL). The combined organic layers were washed with brine, dried, filtered and concentrated. The residue was purified by preparative HPLC (column: Shim-pack Velox C18, 3.0×50 mm, 2.7 um, mobile phase: ACN-H 2 0 (0.05% HCOOH); gradient: 5-95) and lyophilized to give the final compound. LC / MS: 541.4 (M+1) + . Example 135: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-9-(trifluoromethyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one [ka]

[0132] Step 1: To a reaction tube equipped with a stir bar, AgOTf (77 mg, 0.3 mmol, 3 equiv.), Selectfluor (53 mg, 0.15 mmol, 1.5 equiv.), KF (23 mg, 0.4 mmol, 4 equiv.), (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (50 mg, 0.1 mmol, 1 equiv.) were added sequentially in a nitrogen-filled glove box. Then, ethyl acetate (2 mL), 2-fluoropyridine (29 mg, 0.3 mmol, 3.0 equiv.) and CF were added sequentially in a nitrogen-filled glove box. 3 TMS (43 mg, 0.3 mmol, 3.0 equiv.) was dissolved in N 2 The mixture was stirred at 25° C. for 12 hours. The mixture was filtered through a plug of silica. The filtrate was concentrated and the residue was purified by preparative HPLC (column: Shim-pack Velox C18, 3.0×50 mm, 2.7 um; mobile phase: ACN-H 2 O(0.05%NH 3 .H 2 O); gradient: 5-95) and lyophilized to give the final compound. LC / MS: 568.3 (M+1) + . Example 136: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one [ka]

[0133] Step 1: (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (40 mg, 83.1 μmol, 1.0 equiv.) and NiCl in MeOH (2 mL). 2 .6H 2 To a solution of 2.0 mg, 8.31 μmol, 0.1 equiv., NaBH 4 (9.4 mg, 249.2 μmol, 3.0 equiv) was added in portions. The reaction was stirred at room temperature for 0.5 h to give a dark brown solution. The reaction was cooled to 10° C. for 2 h. 2 The mixture was diluted with O and extracted with EA (10 mL × 3). The combined organic layers were washed with brine and 2 SO 4 The residue was purified by flash column (C18 column, ACN / H2O containing 0.5% HCOOH). 2 The mixture was purified by elution with a gradient of O at a flow rate of 30 mL / min. The collected flow was lyophilized to give (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one. JPEG2025504495000071.jpg202170JPEG2025504495000072.jpg79170 Example 149: 4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-thiopyran 1-oxide [ka]

[0134] Step 1: THF (2 mL) and H 2To a solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (80 mg, 170.0 μmol, 1 equiv.) in 2H2O (0.5 mL) was added oxone (52.3 mg, 85.0 μmol, 0.5 equiv.) at 0-5 °C. The reaction was stirred at room temperature for 0.5 h to give an off-white suspension. The residue was diluted with NaCl and concentrated in 50 mL of 1000 mL of 1H2O. 2 SO 3 The mixture was quenched with aqueous EA and extracted with EA (10 mL×3). The combined organic layers were washed with brine and 2 SO 4 The residue was purified by flash column (C18 column, ACN / H2O containing 0.5% HCOOH). 2 0 gradient) to give 4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-thiopyran 1-oxide. JPEG2025504495000074.jpg85170 Example 151: (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide [ka]

[0135] Step 1: THF (2 mL) and H 2To a solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-4-amine (10 mg, 21.3 μmol, 1.0 equiv.) in 2H2O (0.5 mL) was added oxone (13.1 mg, 21.3 μmol, 1.0 equiv.) at 0-5 °C. The reaction was stirred at room temperature for 0.5 h to give an off-white suspension. The residue was diluted with NaCl and concentrated in 50 mL of 1000 mL of 1H2O. 2 SO 3 The mixture was quenched with aqueous EA and extracted with EA (10 mL×3). The combined organic layers were washed with brine and 2 SO 4 The residue was purified by flash column (C18 column, ACN / H2O containing 0.5% HCOOH). 2 0 gradient) to give (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide. JPEG2025504495000076.jpg75170 Example 153: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-morpholino-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine [ka]

[0136] Step 1: 1,4-dioxane (40 mL) and NH in a sealed tube 3 H 2A solution of (R)-6-bromo-7-chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (3.6 g, 8.3 mmol, 1 equiv., synthesized according to the procedure in Example 74) in 30 mL of O was stirred at 120° C. for 4 h. The solution was concentrated under reduced pressure and purified by flash column chromatography (DCM:MeOH=95:5) to give (R)-6-bromo-N4-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidine-4,7-diamine as a light brown solid. LC-MS [M+H] + : 457.0; 459.1

[0137] Step 2: A solution of (R)-6-bromo-N4-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidine-4,7-diamine (3 g, 9.1 mmol, 1 equiv.) and dimethylformamide dimethyl acetal (5.78 g, 48.5 mmol, 5 equiv.) in 1,4-dioxane (40 mL) was stirred at 50° C. for 4 h. The solution was concentrated under reduced pressure to give the crude product (R,Z)-N'-(6-bromo-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7-yl)-N,N-dimethylformimidamide as a black solid, which was used directly in the next step. LC-MS [M+H] + : 512.2; 514.2

[0138] Step 3: To a solution of (R,Z)-N'-(6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-7-yl)-N,N-dimethylformimidamide (3.00 g, 8.6 mmol, 1 equiv.) in MeOH (50 mL) was added hydroxylamine hydrochloride (2.99 g, 4.3 mmol, 5 equiv.). The mixture was stirred at 50 °C for 4 h. The mixture was concentrated under reduced pressure. The residue was dissolved in THF and filtered, and the filtrate was concentrated under reduced pressure to give the crude product (R,E)-N-(6-bromo-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7-yl)-N'-hydroxyformimidamide, which was used directly in the next step. LC-MS [M+H] + : 499.9; 501.9

[0139] Step 4: To a solution of (R,E)-N-(6-bromo-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7-yl)-N'-hydroxyformimidamide (3.00 g, 6.6 mmol, 1 equiv.) in THF (50 mL) was added propylphosphonic anhydride (50% in EtOAc, 4.2 g, 13.2 mmol, 2 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to 30 °C and cooled to 30 °C ... 3 The mixture was quenched with aqueous solution to adjust pH=8 and extracted with ethyl acetate (3x200mL). The combined organic phase was washed with brine (500mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (DCM:MeOH=97:3) to give (R)-4-bromo-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine as a light brown solid. LC-MS [M+H] + : 481.9 ; 483.9 1H NMR (400 MHz, DMSO) δ 13.90 (s, 1H), 9.38 (d, J = 7.4 Hz, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 5.86 - 5.69 (m, 1H), 1.65 (d, J = 7.0 Hz, 3H).

[0140] Step 5: 7-Bromo-N-[(1R)-1-{3-[(difluoromethyl)-$l^{2}-fluoranyl]-5-nitrophenyl}ethyl]-2,3,5,11,13-pentaazatricyclo[7.4.0.0^{2,6}]trideca-1(13),3,5,7,9,11-hexaen-10-amine [100 mg, 0.20 mmol, 1.0 equiv], morpholine [36.1 mg, 0.41 mmol, 2.05 equiv], Cs in 1,4-dioxane 2 CO 3 A solution of Pd-PEPPSI-IPENT [203.5 mg, 0.62 mmol, 3.1 equiv] and Pd-PEPPSI-IPENT [7.9 mg, 0.01 mmol, 0.05 equiv] was stirred at 100° C. under nitrogen for 14 h. The reaction was quenched with water (10 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The separated organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (DCM / MeOH=4%) to give the product as a yellow solid. LC-MS [M+H] + 489.4

[0141] Step 6: 7-(morpholin-4-yl)-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-2,3,5,11,13-pentaazatricyclo[7.4.0.0^{2,6}]trideca-1(13),3,5,7,9,11-hexaen-10-amine [63.4 mg, 0.13 mmol] in MeOH and PtO 2 [2.9 mg, 0.01 mmol] solution in H 2The mixture was stirred at 25° C. under reduced pressure. The reaction mixture was stirred at 25° C. for 2 h. The reaction was filtered. The filtrate was concentrated and the residue was purified by Genal-Prep-HPLC to give the product as a white solid. LC-MS [M+H] + = 459.4 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.30 (s, 1H), 7.52 (s, 1H), 6.82-6.79 (m, 3H), 6.71 (s, 1H), 5.58 (s, 2H), 5.51 (q, J = 7.7 Hz, 1H), 3.75 (t, J = 4.2 Hz, 4H), 3.17 (s, 4H), 1.55 (d, J = 7.0 Hz, 3H). JPEG2025504495000078.jpg221170JPEG2025504495000079.jpg103170 Example 169: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-4-(1-(trifluoromethyl)cyclopropyl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine [ka]

[0142] Step 1: To a mixture of 4-bromo-6-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2-methyl[1,2,4]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (100.0 mg, 0.22 mmol) and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (59.0 mg, 0.27 mmol) in dioxane (1 mL) and water (0.1 mL) was added potassium carbonate (92.0 mg, 0.666 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (18.0 mg, 0.02 mmol). The reaction mixture was stirred at 90 °C overnight to give a dark red suspension. LCMS indicated the desired mass was observed. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica column chromatography (DCM / MeOH: 0-6%) to give 6-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)[1,2,4]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine as a yellow oil. LCMS m / z (M+1) + : 467.2.

[0143] Step 2: To a solution of 6-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)[1,2,4]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (93.0 mg, 0.20 mmol) and methyl(diphenyl)sulfonium fluoroborate (149.1 mg, 0.52 mmol) in THF (2 mL) was added sodium bis(trimethylsilyl)amide (0.80 mL, 0.80 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 10 min and at room temperature overnight to give a dark red suspension. LCMS showed that the desired mass was observed. The mixture was quenched with MeOH and water, extracted with EA, dried over sodium sulfonate, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 6-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2-methyl-4-[(trifluoromethyl)cyclopropyl][1,2,4]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine as a white solid. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.75 (s, 1H), 8.56 (s, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 54.8 Hz, 1H), 5.89 (q, J = 7.0 Hz, 1H), 2.66 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H), 1.66 - 1.58 (m, 2H), 1.40 - 1.33 (m, 2H). Example 170: (R)-1-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)cyclopropane-1-carbonitrile [ka]

[0144] Step 1: Dioxane [10 mL] / H 2 (R)-4-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-6-amine [500.0 mg, 1.1 mmol, 1.0 equiv.], 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole [322.0 mg, 1.65 mmol, 1.2 equiv.] and Cs in O (2 ml). 2 CO 3 [1070.0 mg, 3.3 mmol, 3.0 equiv.] in suspension with N 2 CataCXium(R)A Pd G3 [80.0 mg, 0.1 equiv.] was added under the conditions below. The reaction mixture was stirred at 100° C. for 16 h and then heated at 120° C. for 6 h. The mixture was filtered. The filtrate was extracted with EA (30 ml), washed with brine (20 ml) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (mobile phase: MeOH / CH 2 Cl 2 , volume gradient: 0-10%), the desired product (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)acetonitrile was obtained as a brown solid. LCMS m / z (M+1) + : 412.0

[0145] Step 2: To a solution of (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)acetonitrile [100.0 mg, 0.24 mmol, 1.0 equiv] in DMSO [5 mL], DBU [0.11 ml, 3.0 equiv] and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (108.0 mg, 1.2 equiv) were added. The reaction mixture was stirred at room temperature for 3 h. Water (20 ml) was added. The solution was extracted with EA (30 ml), washed with brine (20 ml) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (mobile phase: MeOH / 0.1% NH 4 HCO 3 The solution, volume gradient: 40-80%, was then purified by preparative HPLC to give the product (R)-1-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)cyclopropane-1-carbonitrile as a brown solid. LCMS m / z (M+1) + : 437.8

[0146] The following examples were synthesized using the methods described above, except for example 174, which used the same method as example 159. JPEG2025504495000082.jpg159170

[0147] Biological Examples Example A. Protein-Protein Interaction (PPI) Assays This example demonstrates that exemplary compounds of the invention inhibit the interaction of SOS1 and KRAS proteins.

[0148] The ability of compounds of formula (I) to inhibit the interaction of SOS1 and KRAS was measured using the SOS1-KRAS Binding Assay Kit (CAT # 63ADK000CB16PEG, Cisbio). This assay utilizes HTRF (homogeneous time-resolved fluorescence) technology to allow simple and rapid characterization of compounds and antibody blockers in a high-throughput format. The interaction between Tag1-SOS1 and Tag2-KRAS-G12C is detected using anti-Tag1-Terbium antibody (HTRF donor) and anti-Tag2-XL665 antibody (HTRF acceptor). When the binding of SOS1 and KRAS-G12C brings the donor and acceptor antibodies into close proximity, excitation of the donor antibody induces fluorescence resonance energy transfer (FRET) to the acceptor antibody, which then emits light specifically at 665 nm. This specific signal is directly proportional to the extent of KRAS-G12C / SOS1 interaction.

[0149] The assay was performed according to the manufacturer's instructions. Compounds at an initial concentration of 10 mM in DMSO were first serially diluted in a 1:3 ratio using assay buffer on a 384-well plate to create a total of nine concentrations with 20 μL of each deposition. Blank buffer was included as a negative control. The final compound solution was a buffer solution containing 1% DMSO. Then, each well of the 384-well plate was incubated for 15 min with 2 μL of compound solution, 4 μL each of tagged SOS1 and KRAS(G12C) protein stocks, and a solution of 10 μM GTP. A mixture of 10 μL of anti-Tag1X665 and anti-Tag1-Terbium antibodies was introduced into each individual well. After 2 h of incubation at room temperature, fluorescence readings were measured using a PelkinElmer multiplate reader VICTOR Nivo.

[0150] Excitation was performed in the range of 245-395 nm, emission from the donor (emission 1) was detected at (657.5-672.5) nm, and emission from the acceptor (emission 2) was detected at (606.5-623.5) nm. The HTRF ratio was calculated using the following formula: (emission 1 @665 nm / emission 2 @620 nm) x 10000. Thus, compounds that inhibit the KRAS-G12C / SOS1 interaction cause a decrease in the HTRF signal ratio. The IC was then calculated using Graph pad Prism software. 50 The values ​​were calculated, and the results are shown in Tables 1 and 2.

[0151] Example B: Phosphorylated ERK (p-ERK) Assay This example demonstrates that representative compounds of the present invention inhibit KRas-mediated GTP nucleotide exchange mediated by SOS1, thereby inhibiting KRas activity and thereby inhibiting the generation of the downstream effector pERK.

[0152] Hela cells (23,000 / w) were seeded in black clear flat-bottom 96-well cell culture plates (Coming, #3904) and cultured overnight at 37°C. On day 2, cells were dosed with compounds of formula (I) at a starting concentration of 10 μM and serially diluted 3-fold for a total of 9 concentrations. Cells were incubated with compounds dissolved in DMSO for 1 h at 37°C. Cells were immediately fixed by adding 100 μL of 8% formaldehyde to all wells in a fume hood and plates were incubated for 1 h at room temperature. Formaldehyde was removed from the plates and the cells were washed 5 times with 200 μL of Triton Washing Solution (0.1% Triton in PBS) for 5 min each time to permeabilize them. Cells were then blocked with 150 μL of Odyssey Blocking Buffer (LI-COR Biosciences #927-50010) at room temperature on a shaker. The blocking buffer was discarded and 50 μL of primary antibodies pERK (cell signaling Technology #4370; rabbit, 1:500) and β-actin (AF5001; mouse, 1:2000) diluted in Odyssey blocking buffer was added. The plate was incubated overnight at 4 °C on a shaker.

[0153] On day 3, the primary antibody solution was removed. Each plate was washed 5 times with 200 μL of 1xPBST (PBS + 0.1% Tween 20) and incubated with 50 μL of secondary antibody. Anti-rabbit (LI-COR Biosciences #926-32211) and anti-mouse (LI-COR Biosciences #68070) were diluted 1:1000 in Odyssey blocking buffer and agitated on a shaker at room temperature for 1 hour (protected from light). The secondary antibody solution was removed and each plate was washed 5 times with PBST. Any remaining liquid was discarded and the plates were photographed using a Licor Odyssey machine with the focal length set to 3.5 mm and both 800 nm and 700 nm filters, according to the manufacturer's instructions. The β-actin normalized scan value for each well was divided by the average of the vehicle wells to calculate the % of p-ERK inhibition. IC was then calculated using Graph pad Prism software. 50 The p-ERK IC values ​​were calculated. The results are shown in Tables 1 and 2. In general, the p-ERK IC 50 Data is PPI IC 50 Matches the data. JPEG2025504495000083.jpg228170JPEG2025504495000084.jpg234170JPEG2025504495000085.jpg234170JPEG2025504495000086.jpg199170 JPEG2025504495000087.jpg172170

[0154] Finally, it should be noted that the above embodiments are only used to describe the technical solutions of the present invention, and are not intended to limit the protection scope of the present invention. Those skilled in the art can make other different forms of conversion or modification based on the above description and ideas. All embodiments need not be and cannot be exhaustive here. All modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A fused heterocyclic compound of formula (I), 【Chemistry 1】 [In the formula, X １ is N or CR １１ and X ２ and X ３ are each independently N, CR １１ or O, but not both at the same time; X ２ and X ３ If one of the groups is O, then X ２ and X ３ is linked by a single bond; R １１ is H, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, amine, cyano, alkynyl, or alkenyl; X ４ is N or CR １２ and R １２ is H, halo, haloalkyl or alkyl; R １ is H, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, amine, cyano, alkynyl, or alkenyl; R ２ and R ３ are each independently H, halo, alkyl, haloalkyl, alkoxyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, acyl, alkoxycarbonyl, or amine; A is a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or an 8-13 membered fused bicyclic ring, wherein A is optionally substituted with one or more substituents which are each independently halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, acyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, cyano, amine, alkylamino, or dialkylamino; said 8-13 membered fused bicyclic ring contains at least one aromatic ring; M is an amine, alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, aminocarbonyl, carboxyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or bridged cycloalkyl or heterocycloalkyl; M is 1 to 5 R １０ groups; each R １０ The groups are independently oxo, acyl, hydroxylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, -C(O)-(CH ２ )n-OR, -S(O) ２ -R,alk-S(O) ２ -R, alk-C(O)-R, alk-C(O)-NRR', CD ３ -O-, cyano, alkoxyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, alkyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; optionally, two R １０ the groups, together with the atom to which they are both attached, form a cycloalkyl or heterocycloalkyl; Optionally, M may be —CH ２ -, -(CH ２ ) ｎ -O-(CH ２ ) ｎ -, -(CH ２ ) ｎ -NR-(CH ２ ) ｎ -, -(CH ２ ) ｎ -C(O)-O-(CH ２ ) ｎ -, -(CH ２ ) ｎ -O-C(O)-(CH ２ ) ｎ -, -(CH ２ ) ｎ -C(O)-(CH ２ ) ｎ is attached via a linker which is -, -NR-C(O)-, or -C(O)-NR-; Each R is independently H or alkyl; Each R' is independently H or alkyl; n is 0, 1, 2, or 3; ring-forming carbon atoms or heteroatoms in cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are optionally substituted with one or two oxo groups; Any hydrogen (H) can be optionally replaced with deuterium (D). or a tautomer, stereoisomer, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein A is aryl, heteroaryl, or an 8-13 membered fused bicyclic ring, optionally substituted with one or more substituents that are each independently halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, acyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, cyano, amine, alkylamino, or dialkylamino.

3. 3. The compound of claim 1 or 2, wherein A is phenyl or fused phenyl, and A is optionally substituted with 1 to 5 substituents selected from halo, haloalkyl, alkyl, and amine.

4. The compound of any one of claims 1 to 3, wherein halo is F.

5. A is, 【Chemistry 2】 The compound according to any one of claims 1 to 4,

6. X １ The compound according to any one of claims 1 to 5, wherein is N.

7. X ４ The compound according to any one of claims 1 to 6, wherein is N.

8. X ２ and X ３ The compound according to any one of claims 1 to 7, wherein each is independently N or CH.

9. M is an alkoxycarbonyl, an alkoxyalkylcarbonyl, an aminocarbonyl, an alkylaminocarbonyl, a dialkylaminocarbonyl, an acyl, 【Chemistry 3】 【Chemistry 4】 and R １３ is H, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, acyl, -C(O)-NR １７ R １８ , -S(O) ２ -R, -alk-S(O) ２ -R, hydroxycarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, oxo, alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkyl or heterocycloalkyl; R １３ is optionally further substituted with one or more halo, alkyl, hydroxyl, haloalkyl, or alkoxy; R １４ , R １５ , and R １６ are each independently H, halo, hydroxyl, hydroxyalkyl, haloalkyl, alkyl, amine, alkoxy, or alkoxyalkyl, and optionally, R １４ and R １５ together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; or optionally, R １５ and R １６ together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R １７ and R １８ are each independently H, cycloalkyl, heterocycloalkyl, or alkyl; optionally, R １７ and R １８ together with the nitrogen atom (N) to which they are both attached form a heterocycloalkyl; R １９ and R' １９ are each independently H, alkyl, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, halo, haloalkyl, oxo, acyl, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, cyano, -S(O) ２ -R,alk-S(O) ２ -R, -C(O)-NR １７ R １８ , cycloalkenyl, heterocycloalkenyl, cycloalkyl, or heterocycloalkyl; optionally, R １９ and R' １９ together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R ２０ is H, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, acyl, oxo, -S(O) ２ -R, -alk-S(O) ２ -R, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, -C(O)-NR １７ R １８ -, cycloalkenyl, heterocycloalkenyl, cycloalkyl, heterocycloalkyl, or 【Chemistry 5】 and R ２１ is H, alkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, halo, haloalkyl, haloalkyloxy, CD ３ -O-, -NR-C(O)-R, or -(CH ２ ) ｎ -C(O)-NRR'; R ２２ , R' ２２ , R ２３ and R' ２３ are each independently H, alkyl, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, halo, haloalkyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, amine, oxo, -S(O) ２ -R,alk-S(O) ２ -R, -NR-C(O)-R, -C(O)-NR １７ R １８ , or -(CH ２ ) ｎ -C(O)-NRR'; optionally, R ２２ and R' ２２ together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; or optionally, R ２３ and R' ２３ together with the atom to which they are both attached form a cycloalkyl or heterocycloalkyl; R ２４ is H, alkyl, haloalkyl, haloalkyloxy, hydroxy, hydroxyalkyl, alkoxyl, alkoxyalkyl, or cyano; R ２５ and R ２６ are each independently H, alkyl, halo, haloalkyl, alkoxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, or heterocycloalkyl; optionally, R ２５ and R ２６ together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl; Each R is independently H or alkyl; Each R' is independently H or alkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, 5, or 6; 9. The compound according to any one of claims 1 to 8, wherein optionally M is attached to the fused triheterocyclic moiety of formula (I) via the linker -C(O)-.

10. M is, 【Chemistry 6】 【Chemistry 7】 and M is optionally connected to said fused triheterocyclic moiety of formula (I) via said linker -C(O)-.

11. R ３ The compound according to any one of claims 1 to 10, wherein is H.

12. R ２ The compound according to any one of claims 1 to 11, wherein is alkyl.

13. R １ The compound according to any one of claims 1 to 12, wherein is H or alkyl.

14. The compound according to any one of claims 1 to 13, wherein the compound is selected from the following:

15. The compound is 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 2. The compound of claim 1 ,

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharma- ceutically acceptable carrier or excipient.

17. A method of treating a disorder associated with RAS dysfunction in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16.

18. 18. The method of claim 17, wherein the disorder is cancer.

19. 20. The method of claim 18, wherein the cancer occurs in the breast, prostate, skin, lung, pancreas, stomach, brain, kidney, uterus, ovary, testis, endothelium, colon, bladder, bone or blood.

20. 20. The method of claim 19, wherein the cancer is lung cancer, colon cancer, or pancreatic cancer.

21. A compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16 for use in the manufacture of a medicament for the treatment of a disorder associated with RAS dysfunction.

22. 22. The use according to claim 21 , wherein the disorder is cancer.

Images