RAS inhibitors and methods of use thereof

Abstract

This disclosure provides compounds, such as compounds of formula I, and their use in treating medical diseases or conditions such as cancer. This disclosure provides pharmaceutical compositions and methods for manufacturing various indene compounds. The compounds are considered to be modulators of Ras (e.g., K-Ras).

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 588,031, filed October 5, 2023; U.S. Provisional Patent Application No. 63 / 667,196, filed July 3, 2024; and U.S. Provisional Patent Application No. 63 / 696,429, filed September 19, 2024, the contents of which are hereby incorporated herein by reference in their entirety. Background Technology

[0002] RAS proteins (such as K-Ras, H-Ras, and N-Ras) play important roles in various human cancers and represent attractive targets for anticancer therapies. Abnormal regulation of Ras proteins due to activating mutations, overexpression, or upstream activation is frequently observed in human tumor cells, and activating mutations of Ras are commonly observed in human cancers. For example, an activating mutation at codon 12 in the Ras protein acts by inhibiting both GTPase activator protein (GAP)-dependent and intrinsic GTP hydrolysis rates, significantly altering the Ras mutant protein population to an "on" (GTP-binding) state (Ras(ON)), thereby leading to oncogenic MAPK signaling. Ras proteins exhibit a strong affinity for GTP, thus enabling Ras activation even in the presence of low concentrations of this nucleotide. Mutations at codon 13 (e.g., G13D) and codon 61 (e.g., Q61K) in Ras are also the cause of oncogenic activity in some cancers.

[0003] For example, oncogenic K-Ras mutations that stabilize GTP binding and induce constitutive activation of K-Ras and downstream signaling have been reported in various types of cancer. K-Ras mutations at codons 12, 13, 61 and other positions in the primary amino acid sequence of K-Ras have been observed in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer, and small cell lung adenocarcinoma.

[0004] Despite extensive research and discoveries in the pharmaceutical industry to develop Ras (e.g., K-Ras) inhibitors for cancer treatment, such inhibitors have not yet demonstrated sufficient safety and / or efficacy to gain regulatory approval. Therefore, there is an unmet need to develop novel pan-Ras inhibitors, such as inhibitors that activate Ras mutants, that demonstrate the safety and efficacy profile required for treating Ras-mediated cancers and other Ras-affected, Ras-related, or Ras-inhibiting conditions. Summary of the Invention

[0005] This disclosure relates in part to compounds that inhibit Ras, such as various mutant forms of Ras, such as K-Ras. Pharmaceutical compositions comprising at least one of the disclosed compounds and a pharmaceutically acceptable carrier are also disclosed herein. In some embodiments, this disclosure provides a method of treating a disease or condition characterized by aberrant Ras activity due to Ras mutations (e.g., aberrant K-Ras activity due to K-Ras mutations). In some embodiments, the disease or condition is cancer.

[0006] For example, this article discloses compounds represented by formula I:

[0007] Formula I;

[0008] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0009] R 1 The group consisting of halogens, C3-C4 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups may be optionally substituted with one, two or three halogens.

[0010] R 2 It is hydrogen or optionally a C1-C6 alkyl group substituted with one or more halogens or hydroxyl groups; and

[0011] Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is selected from one or more groups independently of R A Substituents of the substituents;

[0012] or:

[0013] R 1 It is hydrogen; R 2 It is a C1-C6 alkyl group optionally substituted with one or more halogens or hydroxyl groups; and ring A is selected from the group consisting of:

[0014] ;

[0015] or:

[0016] R 1 It is hydrogen; R 2 It is hydrogen; and ring A is selected from the following groups:

[0017] ;

[0018] R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR.a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0019] R A1 Choose from the following groups: hydrogen, deuterium, chlorine, -CN, -NO2, -NR a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NRa R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0020] R 1' It is hydrogen or halogen;

[0021] R 3 Choose from the following groups: -NR a R b Halogen, C1-C2 alkyl and hydrogen, wherein the alkyl group may optionally be substituted with one, two or three halogens;

[0022] R 4 The group consisting of hydrogen and C1-C2 alkyl groups is selected, wherein the alkyl group may optionally be substituted with one, two or three halogens;

[0023] R 5 It is a C1-C2 alkyl group optionally substituted with one, two, or three halogens;

[0024] R 6 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0025] R 7 The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups;

[0026] R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups;

[0027] Ring B is selected from the group consisting of 4- to 12-membered heterocyclic groups containing at least one cyclic nitrogen;

[0028] R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b =COOH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, =CHF and =CH-C1-C6 alkyl; wherein the C1-C6 alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of: hydroxyl, halogen and C1-C3 alkoxy; or

[0029] Rings B and R BThe cycloalkyl group is absent and has been replaced by substituents selected from the group consisting of -CH2OH and C3-C4 cycloalkyl groups, wherein the cycloalkyl group is selected from -CH2OH and -CH2-NR. a R b The substituents in the group are substituted, and

[0030] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0031] R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0032] m and n are each independently 0, 1, 2, 3 or 4;

[0033] p is 1, 2, or 3;

[0034] q, r, and s are each independently 0, 1, 2, or 3; and

[0035] t can be 0, 1, or 2.

[0036] This article also discloses compounds represented by Formula II:

[0037] Formula II;

[0038] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0039] Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyridyl, pyrimidinyl, and phenyl; wherein ring A is selected from one, two, or three independently from R A Substituents of the substituents;

[0040] R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b-NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0041] R 1 Select from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 11 Substituents of the substituents;

[0042] R 2 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 22 Substituents of the substituents;

[0043] R 11 and R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR.a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0044] R 3 The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups;

[0045] R 4 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0046] R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups;

[0047] Ring B is selected from the group consisting of 5- to 10-membered heterocyclic groups containing at least one cyclic nitrogen;

[0048] R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0049] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0050] R a and R bTogether with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy; and

[0051] m can be 0, 1, 2, 3, or 4;

[0052] If ring A is benzothiophene, then R 1 It is CH3 or a substituted C1-C6 alkyl group.

[0053] This article further discloses compounds represented by Formula III:

[0054] Formula III;

[0055] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0056] R A1 and R A2 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R bC1-C6 alkyl and C1-C6 alkoxy groups;

[0057] R 1' It is hydrogen and R 1 Choose from the following groups: hydrogen, -CH3, -CF3, -CH2CH2OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkenyl, ynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four independently selected from R 22 Substituents are substituted; and

[0058] R 2 Choose from the following groups: hydrogen, -CH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 cycloalkyl, C5-C6 cycloalkyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four groups, each independently selected from R 22 Substituents of the substituents;

[0059] or:

[0060] R 1 and R 1' Together with the carbon atom to which it is attached, they can bond together to form a C3-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2 C1-C6 alkyl groups substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ;or

[0061] R 1 and R 1' Together with the carbon atom to which it is attached, they can bond together to form a C4-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2C1-C6 alkyl groups optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ;

[0062] R 11 Each time it appears, it is independently selected from the following groups: halogen, deuterium, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0063] R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b-(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0064] R 3 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0065] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0066] R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0067] R c and R d Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0068] m is 0, 1, 2, 3, or 4; and

[0069] n is 0, 1, or 2;

[0070] in:

[0071] If R 1 If it is hydrogen, then R 2 Not hydrogen, -CH3, or CH2CH2OH; and

[0072] If R 1 If it is -CH3, then R 2 It is not hydrogen, -CH3, -CH2CF2, -CH2CF3 or -CH2CH(CH3)OH.

[0073] This document also discloses pharmaceutical compositions comprising at least one compound of this disclosure and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises at least one other therapeutic agent.

[0074] This article further discloses a method for treating a patient with symptoms, diseases, or conditions affected by Ras (e.g., K-Ras), related to Ras, or who would benefit from Ras inhibition, comprising administering to said patient a therapeutically effective amount of the compound disclosed herein or a pharmaceutical composition thereof.

[0075] For example, this document discloses methods for treating Ras protein-related (e.g., K-Ras protein-related) diseases or conditions in patients in need, comprising administering to said patient a therapeutically effective amount of the compounds disclosed herein or pharmaceutical compositions thereof. For example, in some embodiments, the compounds and compositions disclosed herein can be used to treat cancers having one or more Ras mutations (e.g., K-Ras mutations). In some embodiments, the methods described herein are applicable to the treatment of cancers including (but not limited to) pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0076] This document also discloses a method for inhibiting Ras proteins (e.g., K-Ras proteins) in cells or tissues, comprising contacting said cells or tissues with a therapeutically effective amount of the compound or pharmaceutical composition thereof disclosed herein. Detailed Implementation

[0077] The features and other details of this disclosure will now be described more precisely. Before further describing this disclosure, certain terms used in this specification, examples, and appended claims are summarized herein. These definitions should be read in light of the remainder of this disclosure and understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0078] definition

[0079] The term "treatment" includes any action that causes improvement in symptoms, diseases, conditions, etc., such as reducing, decreasing, regulating, or eliminating them.

[0080] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include (but are not limited to) straight-chain or branched hydrocarbons having 1 to 6, 1 to 4, or 1 to 3 carbon atoms, referred to herein as C14, 14, 15, 16, 17, 18, 19 ... 1-6 Alkyl, C 1-4 Alkyl and C 1-3Alkyl groups. Exemplary alkyl groups include (but are not limited to) methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0081] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include (but are not limited to) straight-chain or branched groups having 2 to 6 or 3 to 4 carbon atoms, referred to herein as C1-C5 alkenyl, C2-C6 alkenyl, and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include (but are not limited to) vinyl, allyl, butenyl, pentenyl, etc.

[0082] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include (but are not limited to) straight-chain or branched groups having 2 to 6 or 3 to 6 carbon atoms, referred to herein as C14 and C24, respectively. 2-6 alkynyl group and C 3-6 Alkynyl. Exemplary alkynyl groups include (but are not limited to) ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0083] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group (alkyl-O-) bonded to an oxygen atom. Exemplary alkoxy groups include (but are not limited to) alkoxy groups having 1 to 6 or 2 to 6 carbon atoms, referred herein as C1-C5 alkoxy, C1-C6 alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include (but are not limited to) methoxy, ethoxy, isopropoxy, etc.

[0084] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array), which has 6 to 14 ring carbon atoms and zero heteroatoms ("C") provided by the aromatic ring system. 6-14 Aryl group (“C6 aryl”); in some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14"Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in these cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include (but are not limited to) groups derived from: anthracene, acenaphthene, phenanthrene, anthracene, azurite, benzene, benzoxene, fluorene, hexacene, hexaphene, hexalene, asymmetric endorsements, symmetric endorsements. Indene, indene, naphthalene, octacene, octaphene, octalene, oleophane, pentacene-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, phenanthrene, pyrene, anthracene, rubicene, benzo[a]phenanthrene, and trinaphthalene. Specifically, aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Examples of representative substituted aryl groups include the following:

[0085]

[0086] Where R 56 and R 57 One of them can be hydrogen, and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO alkyl, COO aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR 58 R 59 S-alkyl, SO-alkyl, SO2alkyl, S-aryl, SO-aryl, SO2aryl; or R 56 and R 57 They can be bonded to form cyclic rings (saturated or unsaturated) of 5 to 8 atoms, which optionally contain one or more heteroatoms selected from the group consisting of N, O, or S. R 60 and R 61Each is independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclic groups, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0087] As used in this article, the term "carbonyl" refers to the group -C(O)-.

[0088] As used in this article, the term "cyano" refers to the group -CN.

[0089] As used herein, the terms “cycloalkyl” or “carbocyclic” refer to saturated or partially unsaturated hydrocarbon groups having, for example, 3 to 6 or 4 to 6 carbons, referred to herein as C3-C, respectively. 10 cycloalkyl, C 3-6 cycloalkyl or C 4-6 Cycloalkyl groups. Exemplary cycloalkyl groups include (but are not limited to) cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0090] As used in this article, the terms "halogen" or "halogen" refer to F, Cl, Br, or I.

[0091] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Typical haloalkyl groups include (but are not limited to) trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and other similar groups. Exemplary haloalkyl groups include (but are not limited to) straight-chain or branched hydrocarbons having 1 to 6, 1 to 4, or 1 to 3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), referred to herein as C1, C2, C3, C4, C5, C6, C7, C8, C9 ... 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups and C 1-3 Halogenated alkyl groups.

[0092] When used to describe a compound or a group on a compound, the term "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any of the hydrocarbon groups described above, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheterenyl), and other groups having 1 to 5, and especially 1 to 3, heteroatoms.

[0093] As used herein, the term "heteroaryl" or "heteroaromatic group" refers to an aromatic 5- to 10-membered ring system containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur). The term may also refer to 5- to 7-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl. Where possible, the heteroaryl ring may be linked to an adjacent group via carbon or nitrogen. Examples of heteroaryl rings include (but are not limited to) furans, thiophenes, pyrroles, pyrrolopyridines, indoles, thiazoles, oxazoles, isothiazoles, isoxazoles, imidazoles, benzimidazoles, imidazolepyridines, pyrazoles, triazoles, pyridines, or pyrimidines.

[0094] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic radical” are recognized in the art and refer to saturated or partially unsaturated 4- to 10-membered ring structures whose ring structure includes one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclic ring may be connected to an adjacent group via carbon or nitrogen. The term may also be used to refer to 4- to 10-membered saturated or partially unsaturated ring structures that are bridged, fused, or spirocyclic ring structures whose ring structure includes one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include (but are not limited to) pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxoheterocyclic butane, azaheterocyclic butane, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiroheterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7-methylbridged isoindole). A "spiroheterocyclic group" or "spirocyclic ring" refers to a polycyclic heterocyclic group having a ring connected by a common atom (called a spiro atom), wherein the ring has one or more heteroatoms selected from the group consisting of N, O, and S(O) as ring atoms. m (where m is an integer from 0 to 2).

[0095] As used in this article, the terms "hydroxyl" and "hydroxyl" refer to the -OH group.

[0096] As used in this article, the term "oxo" refers to the group =O.

[0097] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans as appropriate, will not produce adverse, allergic, or other undesirable reactions. For human use, formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0098] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0099] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0100] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds disclosed herein can be applied to mammals, such as humans, but can also be applied to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), agricultural animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). “Regulation” includes antagonistic effects (e.g., inhibition), inverse agonistic effects, agonistic effects, biased agonistic effects, biased signal transduction, functionally selective agonistic effects, partial antagonistic effects, and / or partial agonistic effects.

[0101] In this specification, the term "therapeuticly effective amount" refers to the amount of the compound of the present invention that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0102] As used herein, the term "pharmaceutically acceptable salt" refers to a salt having acidic or basic groups that may be present in the compounds used in the composition. The inherently basic compounds included in the compositions of this invention are capable of forming a variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions), including (but not limited to) malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). The inherently acidic compounds included in the compositions of the present invention are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. The compounds comprising basic or acidic moieties in the compositions of the present invention can also form pharmaceutically acceptable salts with various amino acids. The compounds of this disclosure may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0103] The compounds disclosed herein may contain one or more chiral centers and thus exist in stereoisomer form. When used herein, the term "stereoisomer" comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereoforming carbon atom, these compounds may be designated by the symbols "(+)", "(-)", "R", or "S", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. This disclosure covers various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated in nomenclature as "(±)", but those skilled in the art should recognize that the structure may implicitly represent the chiral center.

[0104] The compounds disclosed herein may contain one or more double bonds, and thus exist in geometrical isomers resulting from the arrangement of substituents around the carbon-carbon double bonds. (Symbols) This indicates a bond that can be a single, double, or triple bond as described herein. Substituents around carbon-carbon double bonds are specified as “…”. Z "or" E "Configuration, in which the term" Z "and"E "Used in accordance with IUPAC standards. Unless otherwise stated, the description of the double bond structure covers..." E "and" Z "Isomers. Substituents around the carbon-carbon double bond can be alternatively referred to as "cis" or "trans", where "cis" indicates a substituent on the same side of the double bond and "trans" indicates a substituent on the opposite side of the double bond."

[0105] The compounds disclosed herein may contain a carbocyclic or heterocyclic ring, and thus exist in geometrical isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is specified as “…” Z "or" E "Configuration, in which the term" Z "and" E "Used in accordance with IUPAC standards. Unless otherwise specified, descriptions of carbocyclic or heterocyclic structures encompass..." Z "and" E "Isomers, both. Substituents around the carbocyclic or heterocyclic ring may also be referred to as 'cis' or 'trans', where the term 'cis' indicates a substituent on the same side of the ring plane, and the term 'trans' indicates a substituent on the opposite side of the ring plane. A mixture of compounds with substituents on the same and opposite sides of the ring plane is designated as 'cis / trans'."

[0106] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) linking a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) salt formation using an optically active resolving agent; (3) direct separation of the optically enantiomer mixture on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their component enantiomers by well-known methods, such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, i.e., chemical or enzymatic reactions in which single reactants form mixtures of dissimilar stereoisomers during the formation of a new stereocenter or during the transformation of a pre-existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno. Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.

[0107] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.), and this disclosure is intended to cover both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a monocrystalline or polycrystalline compound. In another embodiment, the compound is a mixture of polycrystalline compounds. In yet another embodiment, the compound is in crystalline form.

[0108] This disclosure also covers isotopically labeled compounds of this disclosure, which are identical to the compounds listed herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, the compounds disclosed herein may have one or more deuterated H atoms.

[0109] The disclosed compounds labeled with certain isotopes (e.g., via...) 3 H and 14 C-labeled compounds are suitable for determining the tissue distribution of compounds and / or substrates. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2 Substitution of heavier isotopes of H) can yield certain therapeutic advantages resulting from greater metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirement) and is therefore preferred in some cases. Isotopically labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents by following procedures similar to those disclosed in the examples herein.

[0110] The term "prodrug" refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur through various mechanisms (e.g., via esterases, amidases, phosphatases, oxidative and / or reductive metabolism) at various locations (e.g., in the intestinal lumen or during passage through the intestine, blood, or liver). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews DrugDiscovery 2008, 7, 255). For example, if the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, then the prodrug may comprise an ester formed by substituting a hydrogen atom of an acid group with, for example, the following groups: (C 1-8 )alkyl, (C 2-12 alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthaloyl, 4-crotonic acid lactone, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 )alkyl (e.g., β-dimethylaminoethyl), carbamoyl-(C 1-2 )alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidinyl-(C 2-3 )alkyl, pyrrolidinyl-(C 2-3 )alkyl or morpholino (C 2-3 )alkyl.

[0111] Similarly, if the compounds of this disclosure contain an alcohol functional group, then the prodrug can be formed by replacing the hydrogen atom of the alcohol group with, for example, the following groups: (C 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkylcarbonyloxy)ethyl(C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinyl, (C 1-6 )alkyl carbonyl, α-amino (C 1-4Alkyl carbonyl, aryl alkyl carbonyl, and α-aminoalkyl carbonyl or α-aminoalkyl carbonyl-α-aminoalkyl carbonyl, wherein each α-aminoalkyl carbonyl is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C 1-6 Alkyl group or glycosyl group (a group produced by removing the hydroxyl group from the hemiacetal form of a carbohydrate).

[0112] If the compounds of this disclosure incorporate an amine functional group, then the prodrug can be formed, for example, by generating an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, a (oxo-m-dioxacyclopentenyl)methyl derivative, an N-Mannich base, an imine, or an enamine. Additionally, secondary amines can be metabolically cleaved to produce a biologically active primary amine, or tertiary amines can be metabolically cleaved to produce a biologically active primary or secondary amine. For example, see Simplício et al., Molecules 2008, 13 ,519 and its references.

[0113] I. Compounds

[0114] This disclosure relates in part to compounds that inhibit Ras, such as various mutant forms of Ras, such as K-Ras. In some embodiments, this disclosure provides a method for treating a disease or condition characterized by aberrant Ras activity caused by a Ras mutant (e.g., aberrant K-Ras activity caused by a K-Ras mutant). In some embodiments, the disease or condition is cancer.

[0115] For example, this article discloses compounds represented by formula I:

[0116] Formula I;

[0117] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0118] R 1 The group consisting of halogens, C3-C4 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups may be optionally substituted with one, two or three halogens.

[0119] R 2 It is hydrogen or optionally a C1-C6 alkyl group substituted with one or more halogens or hydroxyl groups; and

[0120] Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is selected from one or more groups independently of R A Substituents of the substituents;

[0121] or:

[0122] R 1 It is hydrogen; R 2 It is a C1-C6 alkyl group optionally substituted with one or more halogens or hydroxyl groups; and ring A is selected from the group consisting of:

[0123] ;

[0124] or:

[0125] R 1 It is hydrogen; R 2 It is hydrogen; and ring A is selected from the following groups:

[0126] ;

[0127] R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0128] R A1Choose from the following groups: hydrogen, deuterium, chlorine, -CN, -NO2, -NR a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0129] R 1' It is hydrogen or halogen;

[0130] R 3 Choose from the following groups: -NR a R b Halogen, C1-C2 alkyl and hydrogen, wherein the alkyl group may optionally be substituted with one, two or three halogens;

[0131] R 4 The group consisting of hydrogen and C1-C2 alkyl groups is selected, wherein the alkyl group may optionally be substituted with one, two or three halogens;

[0132] R 5 It is a C1-C2 alkyl group optionally substituted with one, two, or three halogens;

[0133] R 6 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0134] R 7The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups;

[0135] R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups;

[0136] Ring B is selected from the group consisting of 4- to 12-membered heterocyclic groups containing at least one cyclic nitrogen;

[0137] R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b =COOH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, =CHF and =CH-C1-C6 alkyl; wherein the C1-C6 alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of: hydroxyl, halogen and C1-C3 alkoxy; or

[0138] Rings B and R B The cycloalkyl group is absent and has been replaced by substituents selected from the group consisting of -CH2OH and C3-C4 cycloalkyl groups, wherein the cycloalkyl group is selected from -CH2OH and -CH2-NR. a R b The substituents in the group are substituted, and

[0139] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0140] R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0141] m and n are each independently 0, 1, 2, 3 or 4;

[0142] p is 1, 2, or 3;

[0143] q, r, and s are each independently 0, 1, 2, or 3; and

[0144] t can be 0, 1, or 2.

[0145] For example, in some embodiments, R 1 Choose from the group consisting of: fluorine, chlorine, cyclopropyl, trifluoromethyl, -CH2CH2CH3, and propenyl; and R 2 It is hydrogen or -CH3. In other embodiments, R A Each time it appears, it is independently selected from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, -C(O)NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C4 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted with one, two or three halogens or -CN.

[0146] In some embodiments or examples, ring A is selected from the group consisting of:

[0147]

[0148]

[0149] .

[0150] In other embodiments, ring A is selected from, for example, the group consisting of the following:

[0151] .

[0152] In other embodiments, such as R 1 It is hydrogen and R 2 -CH3. For example, in some embodiments, ring A is selected from the group consisting of:

[0153]

[0154] ;

[0155] Where: R A The group selected is composed of C1-C3 alkyl, C1-C3 alkoxy, and C3-C4 cycloalkyl groups; wherein the alkyl and alkoxy groups are each substituted with one, two, or three halogens; and R A1 Choose the group consisting of chlorine, -CH3, and -CF3.

[0156] In some embodiments, ring A is selected from, for example, the group consisting of:

[0157]

[0158] .

[0159] In some embodiments, R 1 It is hydrogen and R2 It is hydrogen. In other embodiments, ring A is selected from, for example, the group consisting of,

[0160] .

[0161] In other embodiments, R 3 The group consisting of, for example, -NH2, chlorine, and -CHF2 is selected. In some embodiments, R 3 For example, R is -NH2. In other embodiments, R is... 4 It is hydrogen and R 5 For -CH3. In some embodiments, R 6 It is fluorine. In other embodiments, for example, R 7 It is hydrogen or -CH3. In other embodiments, R 8 and R 9 Each can be independently selected from groups consisting of, for example, hydrogen, deuterium, and -CH3.

[0162] In some other embodiments, R B Each time it appears, it is independently selected from the group consisting of: halogen, hydroxyl, -COOH, =CHCH3, =CHF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C1-C3 alkyl groups optionally substituted with hydroxyl, halogen, or -OCH3. In some embodiments, R B Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -CH3, =CHCH3, =CHF, -COOH, -CH2OH, -CH2CH2F, CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0163] In some embodiments, ring B is selected from the group consisting of, for example, the following:

[0164]

[0165] .

[0166] In other embodiments, rings B and R B It is absent and substituted with -CH2OH or cyclopropyl groups; wherein the cyclopropyl group is substituted with -CH2OH or -CH2NR. a R b Replacement. In other embodiments, rings B and R B Substituents that do not exist and are selected from groups such as -CH2OH, .

[0167] In some embodiments, for example, the compounds of this disclosure are represented by formula IA:

[0168] Formula IA;

[0169] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0170] R 1 For halogens, R 2 It is hydrogen or -CH3, and ring A is selected from the group consisting of the following:

[0171]

[0172] ;or

[0173] R 1 For hydrogen, R 2 It is -CH3, and ring A is selected from the following groups:

[0174]

[0175] ;or

[0176] R 1 For hydrogen, R 2 It is hydrogen, and ring A is selected from the group consisting of:

[0177] ;

[0178] R 7 Choose the group consisting of hydrogen and -CH3;

[0179] R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and -CH3; and

[0180] B. Choose any of the following groups.

[0181]

[0182]

[0183] .

[0184] In other embodiments, for example, the compounds of this disclosure are selected from the group consisting of...

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] ,

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201] ;

[0202] Or its pharmaceutically acceptable salts and / or stereoisomers.

[0203] This article also discloses compounds represented by Formula II:

[0204] Formula II;

[0205] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0206] Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyridyl, pyrimidinyl, and phenyl; wherein ring A is selected from one, two, or three independently from R A Substituents of the substituents;

[0207] R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NRa (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0208] R 1 Select from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 11 Substituents of the substituents;

[0209] R 2 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 22 Substituents of the substituents;

[0210] R 11 and R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR.a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0211] R 3 The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups;

[0212] R 4 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0213] R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups;

[0214] Ring B is selected from the group consisting of 5- to 10-membered heterocyclic groups containing at least one cyclic nitrogen;

[0215] R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0216] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0217] R a and R bTogether with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy; and

[0218] m can be 0, 1, 2, 3, or 4;

[0219] If ring A is benzothiophene, then R 1 It is CH3 or a substituted C1-C6 alkyl group.

[0220] For example, in some embodiments, R 3 It is hydrogen or CH3. In other embodiments, R 4 It is fluorine. In other embodiments, R... 5 and R 6 Each is hydrogen. In some embodiments, for example, the compounds of this disclosure are represented by formula IIA:

[0221] Formula IIA.

[0222] In some embodiments, ring A is selected from, for example, the group consisting of: indazole, quinolinyl, quinolinone, benzothiazolyl, pyridyl, pyrimidinyl, and phenyl; wherein ring A is selected from one, two, or three independently selected from R A Substituents are substituted. In other embodiments, R A Each time it appears, it is independently selected from, for example, the group consisting of: halogen, hydroxyl, -NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C4 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted with one, two or three halogens.

[0223] For example, in some embodiments, ring A is selected from the group consisting of:

[0224]

[0225]

[0226] .

[0227] In other embodiments, ring A is selected from, for example, the group consisting of the following:

[0228]

[0229] .

[0230] In some embodiments, R1 The groups selected are from the group consisting of, for example, C1-C6 alkyl, C3-C4 cycloalkyl, -CH(CH3)-(C3-C4 cycloalkyl) and -CH2-(C3-C4 cycloalkyl), wherein the alkyl and cycloalkyl groups may optionally be substituted by one, two, three or four groups independently selected from the group consisting of: halogen, hydroxyl, cyano and -C(=O)NR. a R b In other embodiments, R 1 Choose from the following groups: -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH. .

[0231] In other embodiments, R 1 The group consisting of, for example, 5-membered heteroaryl, -CH2-(5-membered heteroaryl), and -CH(CH3)-(5-membered heteroaryl), wherein the heteroaryl group may optionally be derived from one or two independently selected -NR groups. a R b The alkyl group is substituted with a substituent of the group consisting of C1-C3 alkyl groups, wherein the alkyl group may optionally be substituted with one, two, or three halogens. For example, in some embodiments, R 1 Choose from the following groups

[0232]

[0233] .

[0234] In some embodiments, ring A is a benzothiophene group substituted with one, two, or three substituents each independently selected from the group consisting of: halogen, cyano, -NH2, and -C(O)NH2. For example, in some embodiments, ring A is selected from... A group that is formed.

[0235] In other embodiments, R 1 The group consisting of, for example, -CH3, -CH2CHF2, and -CH2CH2OH is selected. In other embodiments, R 2 The group is selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted by one, two, or three substituents, each independently selected from the group consisting of halogens and hydroxyl groups. In some embodiments, R 2 The group consisting of hydrogen, -CH3, and -CH2CH2OH is selected. In other embodiments, R... BThe group selected is, for example, composed of halogens, hydroxyl groups, and C1-C3 alkyl groups. In other embodiments, R B Choose the group consisting of halogens, hydroxyl groups, and -CH3.

[0236] In some embodiments, ring B is selected from the group consisting of, for example, the following:

[0237] In some embodiments, ring B is .

[0238] In some embodiments, the compounds disclosed herein are represented by formula IIB:

[0239] Formula IIB;

[0240] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0241] Ring A can be freely composed of the following groups

[0242]

[0243] ;

[0244] R 1 Choose from the following groups: -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH, -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH. ;

[0245] R 2 Choose the group consisting of free hydrogen, -CH3, and -CH2CH2OH; and

[0246] R 3 It is hydrogen or CH3.

[0247] In other embodiments, for example, the compounds of this disclosure are selected from the group consisting of...

[0248]

[0249]

[0250]

[0251]

[0252]

[0253] ;

[0254] Or its pharmaceutically acceptable salts and / or stereoisomers.

[0255] Compounds represented by Formula III are also disclosed:

[0256] Formula III;

[0257] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0258] R A1 and R A2 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0259] R 1' It is hydrogen and R 1Choose from the following groups: hydrogen, -CH3, -CF3, -CH2CH2OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkenyl, ynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four independently selected from R 22 Substituents are substituted; and

[0260] R 2 Choose from the following groups: hydrogen, -CH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 cycloalkyl, C5-C6 cycloalkyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four groups, each independently selected from R 22 Substituents of the substituents;

[0261] or:

[0262] R 1 and R 1' Together with the carbon atom to which it is attached, they can bond together to form a C3-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2 C1-C6 alkyl groups substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ;or

[0263] R 1 and R 1' Together with the carbon atom to which it is attached, they can bond together to form a C4-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2 C1-C6 alkyl groups optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ;

[0264] R 11 Each time it appears, it is independently selected from the following groups: halogen, deuterium, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0265] R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl;

[0266] R 3 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups;

[0267] R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or

[0268] R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups;

[0269] R c and R d Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0270] m is 0, 1, 2, 3, or 4; and

[0271] n is 0, 1, or 2;

[0272] in:

[0273] If R 1 If it is hydrogen, then R 2 Not hydrogen, -CH3, or CH2CH2OH; and

[0274] If R 1 If it is -CH3, then R 2 It is not hydrogen, -CH3, -CH2CF2, -CH2CF3 or -CH2CH(CH3)OH.

[0275] For example, in some embodiments, R A1 and R A2 Each occurrence is independently selected from, for example, the group consisting of: halogen, hydroxyl, cyano, -NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C4 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted with one, two or three halogens. In other embodiments, m is 1 or 2 and R A1 Each occurrence is independently selected from the group consisting of: halogens, C1-C4 alkyl groups, C2-C4 alkynyl groups, and C3-C4 cycloalkyl groups. In other embodiments, n is 1 and R A2It is a hydroxyl group or -NH2.

[0276] In some embodiments, Choose from the following groups

[0277] .

[0278] In other embodiments, Choose from the following groups

[0279] .

[0280] In some embodiments, R 1 ' is hydrogen. In other embodiments, R 1 It is hydrogen. In other embodiments, R is... 2 The following groups are selected: -CH2CN, -CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3. In some embodiments, R 1 It is -CH3. In other embodiments, R 2 Choose from groups consisting of, for example, the following: -CH2CH2OH, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3. .

[0281] In some embodiments, R 1 Choose from the following groups: -CF3, -CH2CF3, -CH2CH2OH, -CH2C(CH3)2OH. .

[0282] In other embodiments, R 2 Choose from the following groups: hydrogen, -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2 and -CH2CH2C(O)NHCH3.

[0283] In some embodiments, R 1' and R 1 It bonds together with the carbon atom to which it is attached to form an optional hydroxyl-substituted C3-cycloalkyl group; and R 2 It is -CH2CH2OH. For example, in some embodiments, R 1' and R 1It bonds together with the carbon atom to which it is attached to form an optionally hydroxylated C4-cycloalkyl group; and R 2 It is -CH3. In other embodiments, R 3 It is hydrogen.

[0284] In some embodiments, the compounds disclosed herein are represented by formula IIIB:

[0285] Formula IIIB;

[0286] Or its pharmaceutically acceptable salts and / or stereoisomers, wherein:

[0287] Choose from the following groups: ;and

[0288] R 1 It is hydrogen; and R 2 Choose from the following groups: -CH2CN, -CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3; or

[0289] R 1 It is -CH3; and R 2 Choose from the following groups: -CH2CH2OH, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3. ;or

[0290] R 1 Choose from the following groups: -CF3, -CH2CF3, -CH2CH2OH, -CH2C(CH3)2OH; and R 2 Choose from the following groups: hydrogen, -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2 and -CH2CH2C(O)NHCH3.

[0291] In other embodiments, the compounds of this disclosure are selected from, for example, the group consisting of:

[0292]

[0293]

[0294]

[0295] ;

[0296] Or its pharmaceutically acceptable salts and / or stereoisomers.

[0297] In other embodiments, the compounds of this disclosure are selected from, for example, the group consisting of:

[0298]

[0299]

[0300] ;

[0301] Or its pharmaceutically acceptable salts and / or stereoisomers.

[0302] In some embodiments, the compound is one of the compounds identified in Table 1 below or a pharmaceutically acceptable salt thereof.

[0303] Table 1. Exemplary compounds.

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] The following examples provide procedures for preparing the compounds described herein. In the reactions described below, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino, thio, or carboxyl groups) to prevent their undesirable participation in the reaction. The methods required for incorporating such groups, and for introducing and removing them, are known to those skilled in the art (e.g., see Greene, Wuts, ...). Protective Groups in Organic Synthesis. 2nd Edition (1999)). The deprotection step may be the final step in the synthesis, resulting in the removal of the protecting group to obtain the compound as disclosed herein. The starting materials used in the following procedures are commercially available or prepared by methods described in the chemical literature or modifications thereof, using methods known to those skilled in the art. The order of the steps may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0336] Any of the compounds disclosed herein or any of the intermediates described in the above procedures can be further derived using one or more standard synthetic methods known to those skilled in the art. Such methods may involve substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify the disclosed compounds or any of the aforementioned intermediates by modifying, introducing, or removing suitable functional groups.

[0337] When a specific enantiomer of the disclosed compound is required, this can be produced from a corresponding mixture of enantiomers using any suitable conventional procedure known to those skilled in the art for resolving enantiomers. For example, diastereomeric derivatives (e.g., salts) can be prepared by reacting a mixture of enantiomers of the disclosed compound (e.g., racemic mixtures) with a suitable chiral compound (e.g., a chiral base). The diastereomeric derivatives can then be separated by any conventional means, such as crystallization or chromatography, and the desired enantiomer can be recovered (e.g., by acid treatment in the case of a salt). Alternatively, racemic mixtures of esters can be resolved by kinetic hydrolysis using various biocatalysts (e.g., see Patel). Stereoselective Biocatalysts , Marcel Decker; New York 2000).

[0338] In another resolution method, the racemic mixtures of the disclosed compounds can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained using a suitable chiral intermediate in one of the methods described above. In cases where a specific geometrical isomer of this disclosure is required, chromatography, recrystallization, and other conventional separation procedures can also be used for the intermediates or final products.

[0339] In an alternative embodiment, the disclosed compound may further comprise one or more isotopic substitutions. For example, hydrogen may be... 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example... 13 C or 14 C; oxygen can be, for example... 18 O; nitrogen can be, for example, 15 N, etc. In other embodiments, specific isotopes (e.g., N, etc.) 3 H, 13 C 14 C 18 O or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a specific site in the compound.

[0340] II. Methods

[0341] This document further discloses methods for treating patients with symptoms, diseases, or conditions affected by Ras (e.g., K-Ras), related to Ras, or that would benefit from Ras inhibition, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition thereof disclosed herein. For example, this document discloses methods for treating Ras protein-related (e.g., K-Ras protein-related) diseases or conditions in patients of need, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition thereof disclosed herein.

[0342] In some embodiments, this disclosure provides a method for treating a disease or condition characterized by abnormal Ras activity caused by a Ras mutant (e.g., abnormal K-Ras activity caused by a K-Ras mutation). In some embodiments, for example, the compounds and compositions disclosed herein can be used to treat cancers having one or more Ras mutations (e.g., K-Ras mutations).

[0343] For example, the methods described herein can be applied to the treatment of cancers, including (but not limited to) lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. For example, in some embodiments, cancers that can be treated by the compounds, compositions, and methods disclosed herein are (but not limited to) tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcomas.

[0344] In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cardiovascular-related cancers, including tumors. Non-limiting examples covered herein include, for example, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma.

[0345] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat lung cancers, including tumors. Non-limiting examples covered herein include, for example, bronchial carcinomas (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (e.g., bronchiolar) carcinomas, bronchial adenomas, sarcomas, lymphomas, chondromatous hamartomas, and mesotheliomas.

[0346] In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the gastrointestinal system, including tumors. Non-limiting examples covered herein include, for example, esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (e.g., carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and colorectal cancer (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma).

[0347] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the genitourinary tract, including tumors. Non-limiting examples covered herein include, for example, kidney cancer (e.g., adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (e.g., adenocarcinoma, sarcoma), and testicular cancer (e.g., seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0348] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the liver, including tumors. Non-limiting examples covered herein include, for example, liver tumors (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0349] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the biliary tract, including tumors. Non-limiting examples covered herein include, for example, gallbladder cancer, ampullary cancer, and bile duct cancer.

[0350] In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the bone, including tumors. Non-limiting examples covered herein include, for example, osteosarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (e.g., osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor.

[0351] In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the nervous system, including tumors. Non-limiting examples covered herein include, for example, cancers and / or tumors of the skull (e.g., osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), cancers and / or tumors of the meninges (e.g., meningioma, meningosarcoma, gliomatosis), brain cancers (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, pineal tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers and / or tumors of the spinal cord (e.g., neurofibroma, meningioma, glioma, sarcoma).

[0352] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the gynecological system, including tumors. Non-limiting examples covered herein include, for example, cancers and / or tumors of the uterus (e.g., endometrial cancer), cancers and / or tumors of the cervix (e.g., cervical cancer, pretumoral cervical dysplasia), cancers and / or tumors of the ovary (e.g., ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancers and / or tumors of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), cancers and / or tumors of the vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), and cancers and / or tumors (carcinoma) of the fallopian tubes.

[0353] In other embodiments, the compounds, compositions, and methods disclosed herein can be used to treat blood cancers, including tumors. Non-limiting examples covered herein include, for example, blood cancers and / or tumors (e.g., myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, and non-Hodgkin's lymphoma (malignant lymphoma).

[0354] In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the skin, including tumors. Non-limiting examples covered herein include, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis. In some embodiments, the compounds, compositions, and methods disclosed herein can be used to treat cancers of the adrenal glands, including tumors such as neuroblastoma.

[0355] In some embodiments, the methods described herein may be applicable to the treatment of cancers, including (but not limited to) pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0356] Specifically, in some embodiments, this disclosure provides a method of treating a medical indication covered herein, comprising administering a therapeutically effective amount of the compound described herein to a patient in need.

[0357] In some embodiments, the Ras protein is wild-type (Ras wt Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras wt (e.g. K-Ras) wt H-Ras wt or N-Ras wt In methods for treating cancer patients. In some embodiments, the Ras protein is Ras amplified (e.g., K-Ras). amp Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras amp (K-Ras amp H-Ras amp or N-Ras amp (This refers to a method for treating cancer patients.)

[0358] In some embodiments, the cancer comprises a Ras mutation, such as the Ras mutation described herein. In some embodiments, the mutation is selected from: K-Ras mutations (e.g., G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V and combinations thereof); H-Ras mutations (e.g., Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12...). V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R and combinations thereof; and N-Ras mutations (e.g. Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T and combinations thereof); or any combination thereof.

[0359] In some embodiments, the cancer includes K-Ras mutations selected from, for example, the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In other embodiments, the cancer includes N-Ras mutations selected from, for example, the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In other embodiments, the cancer includes H-Ras mutations selected from, for example, the group consisting of Q61H and Q61L. In other embodiments, the cancer includes Ras mutations selected from, for example, the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer contains at least two Ras mutations selected from, for example, the following groups: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.

[0360] In some embodiments, the compounds disclosed herein can inhibit more than one Ras mutant. For example, in some embodiments, the disclosed compounds can inhibit both K-Ras G12C and K-Ras G13C. In other embodiments, the disclosed compounds can inhibit both N-Ras G12C and K-Ras G12C. In other embodiments, the disclosed compounds can inhibit both N-Ras G12C and K-Ras G12C. In other embodiments, the disclosed compounds can inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the disclosed compounds can inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the disclosed compounds can inhibit both K-Ras G12V and K-Ras G12S.

[0361] In some embodiments, the compounds disclosed herein, in addition to one or more other Ras mutations, also inhibit Ras. wt (e.g., K, H, or NRas) wt And K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K, H or N-Ras wt And H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or N-Ras wt And N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0362] In some embodiments, the compounds disclosed herein, in addition to one or more other Ras mutations, also inhibit Ras. amp (e.g., K-, H-, or N-Ras) ampAnd K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H- or N-Ras amp And H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K-, H- or N-Ras amp And N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0363] In some embodiments, the cancer includes Ras mutations and STK11. LOF KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation. In other embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation and STK11. LOF Mutation. In other embodiments, the cancer is non-small cell lung cancer and contains the K-Ras G12C mutation and STK11. LOF Mutations. In other embodiments, the cancer includes K-Ras G13C Ras mutations and STK11 mutations. LOFKEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12V mutation. In other embodiments, the cancer is colorectal cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12D mutation. In other embodiments, the cancer is pancreatic cancer and contains a K-Ras G12V mutation. In other embodiments, the cancer is endometrial cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer and contains a K-Ras G12D mutation. In other embodiments, the cancer is lung cancer or pancreatic cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is lung cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is colorectal cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is gastric cancer and contains a K-Ras G12C mutation. Additionally, the disclosed compound can inhibit Ras... wt (e.g., K-, H-, or N-Ras) wt ) or Ras amp (e.g., K-, H-, or N-Ras) amp ).

[0364] This document also discloses a method for inhibiting RAS proteins (e.g., K-Ras proteins) in cells or tissues, comprising contacting said cells or tissues with a therapeutically effective amount of the compound disclosed herein or a pharmaceutical composition thereof. In some embodiments, the Ras protein is a mutant Ras protein. This document further discloses a method for inhibiting Ras proteins (e.g., K-Ras proteins) in a patient, comprising administering to said patient a therapeutically effective amount of the compound disclosed herein or a pharmaceutical composition thereof.

[0365] The compounds described herein can be administered in combination with one or more other therapeutic agents to treat the conditions described herein. For clarity, this document encompasses fixed compositions comprising the disclosed compounds and, for example, another therapeutic agent disclosed herein, as well as methods of administering the disclosed compounds and the disclosed therapeutic agents individually. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein, one or more other therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, the disclosed compound and one other therapeutic agent are administered. In some embodiments, the disclosed compound and two other therapeutic agents as defined herein are administered. In some embodiments, the disclosed compound and three other therapeutic agents as defined herein are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is separately formulated and administered. For example, the disclosed compounds and other therapeutic agents can be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in the form of a single formulation, such as a pharmaceutical composition comprising, for example, the disclosed compound as a therapeutic agent and one or more other therapeutic agents. For example, the disclosed compounds and other therapeutic agents can be administered in the form of a single formulation. Combination therapy also encompasses other combinations. While two or more agents in a combination therapy can be administered simultaneously, this is not always the case. For example, the first agent (or combination of agents) may be administered minutes, hours, days, or weeks before the second agent (or combination of agents). Therefore, two or more agents may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 9 weeks. In some cases, even longer time intervals are possible. Although it is generally expected that two or more agents used in combination therapy will be present in the patient's body simultaneously, this is not always the case.

[0366] Combination therapy may also include two or more administrations of one or more of the drugs used in a combination of component drugs in different sequences. For example, if drug X and drug Y are used in combination, they may be administered once or more in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0367] In some embodiments, other therapies include the administration of side effect limiters (e.g., agents designed to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with therapeutic agents for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0368] In some embodiments, one or more other therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, one or more other therapies include therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more other therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, one or more other therapies include two therapeutic agents. In still other embodiments, one or more other therapies include three therapeutic agents. In some embodiments, one or more other therapies include four or more therapeutic agents.

[0369] Examples of non-pharmacological treatments include (but are not limited to) radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present invention can be used as neoadjuvant therapy before surgery.

[0370] Therapeutic agents can be compounds used to treat cancer or cancer-related symptoms. For example, therapeutic agents can be steroids. Non-limiting examples covered herein include (but are not limited to) 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, and cortisone. Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Fiucloronide, Flumethasone, Flunisolide, Fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednoletabonate), mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 2,5-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0371] In other embodiments, the therapeutic agents covered herein may be biologics (e.g., cytokines such as interferon or interleukins, such as IL-2) used to treat cancer or related symptoms. In some embodiments, the biologics are immunoglobulin-based biologics that activate targets to stimulate an anticancer response or antagonize antigens important to cancer, such as monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fe fusion proteins, or functional fragments thereof). Antibody-drug conjugates are also covered herein.

[0372] In other embodiments, the therapeutic agents covered herein may be T-cell checkpoint inhibitors. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fe-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L2 (e.g., a PD-L2 / Ig fusion protein) (e.g., an inhibitory antibody or a Fe fusion or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, ipilimumab, tremelimumab, or lirilumab. In other embodiments, the therapeutic agent may be an anti-TIGIT antibody, such as etigilimab.

[0373] In some embodiments, the therapeutic agents covered herein may be anticancer agents. Non-limiting examples covered herein include (but are not limited to) mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more other therapies include, for example, two or more anticancer agents to be administered in combination or separately.

[0374] Other non-limiting examples of anticancer agents include, for example, imatinib mesylate, carfilzornib, bortezornib, bicalutarnide, and gefitinib; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, and meturedopa; uredopaethylenimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylolmelamine; and acetogenin. (e.g., bullatacin and bullatacinone); camptothecin and synthetic analogues (e.g., topotecan); bryostatin; callystatin; adozelesin; carzelesin; bizelesin; cryptophycin (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin and synthetic analogues; eleutherobin; pancratistatin; sarcodictin A A); spongistatin; nitrogen mustard, such as chlorambucil, chlornaphazine, chophosphatamide, estramustine, ifosfamide, mechlorethamine, oxydichloromethyldiethylamine hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard;Nitrosoureas, such as carmustine, chlorozotocin, formofustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, such as calicheamicin γ-II and calicheamicin ω-II); dynemicins, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophores and related chromogens; enediyne antibiotic chromophores; aclacinomysin; actinomycin; and autramycin. Diazoserine, bleomycin, actinomycin C, chazim, carabicin, caminomycin, carminomycin, carzinophilin, chromomycinis, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (e.g., mitomycin C), mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs, such as denostatin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, and fluorouridine; and androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, and testosterone; anti-adrenergics such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acetylglucuronolactone; aldehyde phosphoramide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine-like substances, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; diaminonitroacin (n itracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophylloic acid; 2-ethylhydrazine; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid;Triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene, such as T-2 toxin, verracurin A, roridin A. A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactal; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; toxoids (e.g., paclitaxel and docetaxel); chlorambucil; tamoxifen; raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; onapristone; torernifene; flutamide, nilutarnide, bicarbohydrate Amines (bicalutarnide), leuprnlide, goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vincristine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; vinorelbine Elbine; Novantrone; Teniposide; Edatraxate; Daunomycin; Aminopterin; Ibandronate; Irinotecan; Topoisomerase inhibitors; Difluoromethylornithine; Retinoids, such as retinoic acid; Esperamycin; Capecitabine; and pharmaceutically acceptable salts of any of the foregoing formulations.

[0375] Other non-limiting examples of anticancer agents include trastuzumab, bevacizumab, cetuximab, rituximab, avicine, abagovomab, acridine formamide, adecatumumab, 17-N-allylamino-17-demethoxygerdomylmycin, alpharadin, avocidib, 3-aminopyridine-2-carboxaldehyde thiourea, amonafide, anthrone, antiCD22 immunotoxin, and antitumor agents. Oncology drugs (such as cell cycle nonspecific antitumor agents and other antitumor drugs described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecone, bendamustine, biricodar, brostallicin, bryophyll, sulfonamide, calyculin, dichloroacetic acid, discormolide, elsamitrucin, enoxabin, eribulin Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, Imexon, Imiquimod, Indomethacin, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolom IDE), naphthol, nedaplatin, olaparib, ortataxel, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, halosporin A, sapacitabine, swainsonine, talaporfin, tariquidar, uridine-uracil, temodarTesetaxel, triplatinum tetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, and zosuquidar.

[0376] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine); epipodophyllotoxins (e.g., etoposide and teniposide); antibiotics (e.g., styromycin (actinomycin D), donomycin, and idarubicin); anthracyclines; mitoxantrone; bleomycin; plicamycin (mithramycin); mitomycin; antiplatelet agents; antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., dichloromethyldiethylamine, cyclophosphamide and analogues, melphalan, and chlorambucil); ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa); CDK inhibitors (e.g., abemaciclib, ribociclib, palbociclib). Seliciclib and dinasiclib; alkyl sulfonates (e.g., busulfan); nitrosoureas (e.g., carmustine and analogues, and streptozotocin); triazine-dacarbazine; antiproliferative / antimitotic antimetabolites, such as folic acid analogues; pyrimidine analogues (e.g., fluorouracil, fluorouracil, and cytarabine); purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine); aromatases Inhibitors (e.g., anastrozole, exemestane, and letrozole); platinum coordination complexes (e.g., cisplatin and carboplatin); procarbazine; hydroxyurea; mitotane; aminoglutethimide; histone deacetylase (HDAC) inhibitors (e.g., trichostocin, sodium butyrate, apicidan, succinyl aniline hydroxamic acid, vorinostat, romidepsin, and panobinostat); mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus); KSP (Eg5) inhibitors; DNA binding agents; Pl3K δ and γ inhibitors; copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., sorafenib); hormones (e.g., estrogens); goserelin; leuprorelin; triptorelin; IKK inhibitors; p38MAPK inhibitors; anti-IL-6; telomerase inhibitors; aurora kinase inhibitors; cell surface monoclonal antibodies; elotuzumab; HSP90 inhibitors;P13K / Akt inhibitors; Akt inhibitors; PKC inhibitors (e.g., enzastaurin); Torcl / 2 specific kinase inhibitors; ER / UPR targets; cFMS inhibitors; JAK1 / 2 inhibitors; PARP inhibitors (e.g., olaparib and veliparib); and BCL-2 antagonists. In some embodiments, the covered anticancer agents are selected from, for example, dichloromethyldiethylamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, sorafenib, or any analogues or derivative variants thereof.

[0377] In some embodiments, the anticancer agent is a HER2 inhibitor, such as a monoclonal antibody, such as trastuzumab and pertuzumab; or a small molecule tyrosine kinase inhibitor, such as gefitinib, erlotinib, pilitinib, canertinib, or lapatinib. In other embodiments, the covered anticancer agent is an ALK inhibitor, such as ceritinib, crizotinib, alectinib, brigatinib, entrectinib, ensartinib, or lorlatinib. In other embodiments, the covered anticancer agent is an SHP2 inhibitor, SOS1 inhibitor, Raf inhibitor, MEK inhibitor, ERK inhibitor, P13K inhibitor, PTEN inhibitor, AKT inhibitor, or mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor).

[0378] In some embodiments, the covered anticancer agents are other Ras inhibitors or Ras vaccines, or other therapeutic agents designed to directly or indirectly reduce the carcinogenic activity of Ras. For example, in some embodiments, the covered anticancer agents are other Ras inhibitors. In some embodiments, the Ras inhibitor targets Ras in an active or GTP-bound state (Ras(ON)). In some embodiments, the Ras inhibitor targets Ras in an inactive or GDP-bound state. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is a K-Ras G12V inhibitor.

[0379] In some embodiments, the methods described herein further include administering one or more other therapeutic agents to a patient for the treatment of diseases or conditions affected by Ras proteins (e.g., K-Ras), associated with Ras proteins, or that would benefit from Ras protein inhibition.

[0380] The methods described herein include administering to a patient a therapeutically effective amount of at least one compound as described herein, optionally formulated in a pharmaceutical composition. In various embodiments, the at least one compound described herein present in a therapeutically effective amount in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In some embodiments, the methods further include administering to the patient other therapeutic agents that treat cancer or diseases or conditions affected by Ras (e.g., K-Ras), related to Ras, or that would benefit from Ras inhibition.

[0381] In some embodiments, administering the compounds described herein to a patient allows for the administration of lower doses of other therapeutic agents compared to the doses required to achieve similar results in treating, improving, and / or preventing a patient's cancer or in treating, improving, and / or preventing a patient's Ras-affected, Ras-related, or Ras-inhibiting diseases or conditions. For example, in some embodiments, the compounds described herein enhance the activity of other therapeutic compounds, thereby enabling lower doses of other therapeutic compounds to provide the same effect.

[0382] Specifically, in some embodiments, this disclosure provides a method for treating the above medical indications, comprising administering a therapeutically effective amount of the compound described herein to a subject in need.

[0383] III. Pharmaceutical Compositions and Kits

[0384] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with a pharmaceutically acceptable carrier. Specifically, this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but in any of the given cases, the most suitable form of administration will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the disclosed compositions may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0385] The exemplary pharmaceutical compositions of this disclosure may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the disclosed compounds as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral administration. The active ingredient may be compounded with, for example, commonly used, non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of a disease.

[0386] For the preparation of solid compositions, such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, such as a conventional tablet-forming ingredient (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum), and other pharmaceutical diluents, such as water, to form a solid preformed composition containing a homogeneous mixture of the compounds of this disclosure or their non-toxic, pharmaceutically acceptable salts. When these preformed compositions are referred to as homogeneous compositions, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily further divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0387] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or calcium hydrogen phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) moisturizers. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants. In the case of capsules, tablets and pills, the composition may also contain a buffer. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0388] Tablets can be manufactured by compression or molding, optionally together with one or more adjunct ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or powders. Molded tablets can be prepared by molding a mixture of the compositions of the invention, wetted with an inert liquid diluent, in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation techniques.

[0389] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions of the present invention, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0390] In addition to the compositions of the present invention, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, and mixtures thereof.

[0391] Formulations for rectal or vaginal application may be presented in suppository form, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and which are solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active agent.

[0392] Dosage forms for transdermal application of the compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0393] In addition to the compositions of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0394] In addition to the compositions of this invention, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Aerosols may further contain conventional propellants such as chlorofluorocarbons and unsubstituted volatile hydrocarbons such as butane and propane.

[0395] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic sprayers can be used because they minimize the shear forces on the agent, which could cause degradation of the compounds contained in the compositions of the invention. Typically, aqueous aerosols are manufactured by formulating an aqueous solution or suspension of the compositions of the invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific requirements of the compositions of the invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); harmless proteins such as serum albumin; sorbitol esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0396] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise the compositions of the invention and one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, and may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0397] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate and cyclodextrin). Appropriate flowability can be maintained, for example, by using a coating material such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0398] In another aspect, this disclosure provides enteric pharmaceutical formulations comprising the disclosed compounds and enteric-coated materials; and pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials are polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Therefore, enteric materials are soluble only at the following pH values, such as about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric-coated materials include cellulose acetate phthalate (CAP); hydroxypropyl methyl cellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methyl cellulose acetate succinate (HPMCAS); cellulose trimellitate; hydroxypropyl methyl cellulose succinate; cellulose acetate succinate; cellulose hexahydrophthalate; cellulose propionate; cellulose maleate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methyl methacrylate and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate, and methacrylate; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); copolymers of ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate; natural resins such as corn gluten, shellac, and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit...). FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro. The foregoing is a list of possible materials, but those skilled in the art to which this disclosure pertains will recognize that it is not exhaustive and that other enteric-coated materials exist that meet the objectives of this disclosure.

[0399] This disclosure also provides kits for use by consumers, for example, who require treatment for the diseases or conditions described herein. Such kits include suitable dosage forms, such as those described above; and instructions describing methods of using such dosage forms to mediate, reduce, or prevent inflammation. The instructions will guide the consumer or medical professional to administer the dosage form according to administration methods known to those skilled in the art. Such kits can advantageously be packaged and sold as single or multiple kit units. An example of such kits is so-called blister packaging. Blister packaging is well-known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packaging generally consists of a sheet of relatively rigid material covered with a foil, preferably of a transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the sheet of relatively rigid material is sealed on the side of the foil opposite to the direction in which the groove is formed, relative to the plastic foil. Thus, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough that an opening can be formed at the groove location in the sheet by manually applying pressure to it, thereby allowing the tablet or capsule to be removed from the blister pack. The tablet or capsule can then be removed through said opening.

[0400] The kit may need to provide memory aids, such as numbers next to the tablets or capsules, where the numbers correspond to the number of days during the course of treatment when the specified tablets or capsules should be taken. Another example of such memory aids is a calendar printed on a card, such as "Week 1, Monday, Tuesday... etc... Week 2, Monday, Tuesday... etc." Other variations of memory aids are obvious. A "daily dose" can be a single tablet or capsule to be taken on a specified day, or several tablets or capsules. Furthermore, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0401] Example

[0402] The compounds described herein can be prepared in various ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that, unless otherwise indicated, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and post-treatment procedures) are optional as standard conditions for the reactions. Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art, and therefore, alternative methods are indicated. The starting materials of the examples are commercially available or readily prepared from known substances by standard methods.

[0403] HPLC conditions: Method AA: Column: XBridge preparative OBD C18 column, 30 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 60 mL / min; Method B: Column: Xselect CSH C18 OBD column 30 150 mm 5 µm; Mobile phase A: Water (0.05% TFA), Mobile phase B: MeCN; Flow rate: 60 mL / min; Method C: Column: Xselect CSH C18 OBD column 19 250 mm 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MeCN; Flow rate: 30 mL / min; Method PL: Phenomenex Luna C18 150 25 mm 10 μm; mobile phase: (water (0.225% FA)-MeCN).

[0404] Synthetic intermediates:

[0405] Synthesis of 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1)

[0406]

[0407] Step 1: Synthesis of (2,4,6-trichloronicotinyl)aminothiomethyliminocyanide methyl ester

[0408] A mixture of aminothiomethyliminocyanide (33.4 g, 179.2 mmol) and NaHCO3 (37.8 g, 448 mmol) in THF / H2O (90 mL, 1:2) was stirred at room temperature for 10 min. Then, 50 mL of THF containing 2,4,6-trichloronicotinyl chloride (11 g, 44 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with H2O (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound (10.1 g, 75.3%) as a yellow oil. LCMS m / z = 300 [M+H]+

[0409] Step 2: Synthesis of 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0410] DIPEA (10.93 g, 84.6 mmol) was added to a solution of (2,4,6-trichloronicotinyl)aminothiomethyliminocyanide (10.1 g, 33.8 mmol) in dioxane (100 mL), and the reaction mixture was stirred at 100 °C under N2 for 16 h. The cooled mixture was concentrated under vacuum, the residue was diluted with water, and acidified to pH 4 with 2 N HCl (aqueous solution). The precipitated solid was collected by filtration, washed with water (3 × 50 mL), and dried to give the title compound (6.1 g, 68.8%) as a yellow solid. LCMS m / z = 262 [M+H]+

[0411] Synthesis of (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate tert-butyl ester (intermediate 2)

[0412]

[0413] Imidazole (1.99 g, 29.2 mmol) and tert-butyl(chloro)diphenylsilane (4.42 g, 16.08 mmol) were added to a solution of N,N-bis(2-hydroxyethyl)carbamate tert-butyl ester (3 g, 14.62 mmol) in anhydrous DMF (10 mL), and the reaction mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in a 10-minute gradient from 10% to 50%, to give the title compound (2 g, 30.8%) as a colorless oil. LCMS m / z = 444 [M+H] +

[0414] Synthesis of (S)-(2-((tert-butyldiphenylsilyl)oxy)ethyl)(1-hydroxypropyl-2-yl)carbamate tert-butyl ester (intermediate 3)

[0415]

[0416] Step 1: Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)prop-1-ol

[0417] (2-Bromoethoxy)(tert-butyl)diphenylsilane (5.8 g, 15.96 mmol) was added to a solution of (2S)-2-aminoprop-1-ol (1.80 g, 23.94 mmol) in MeCN (20 mL), and the reaction mixture was stirred at 80 °C under N2 for 3 hours. The resulting mixture was cooled to room temperature and evaporated under reduced pressure to give the title compound (2.34 g, crude substance) as a white solid. LCMS m / z = 358 [M+H]+

[0418] Step 2: Synthesis of (S)-(2-((tert-butyldiphenylsilyl)oxy)ethyl)(1-hydroxypropyl-2-yl)aminomethyl tert-butyl ester

[0419] (Boc)₂O (1.71 g, 7.85 mmol) was added fractionally to a solution of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)prop-1-ol (2.34 g, 6.54 mmol) and TEA (1.36 mL, 9.82 mmol) in DCM (15 mL), and the reaction mixture was stirred at room temperature under N₂ for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (10 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1), to give the title compound (1.7 g, 39.7%) as a colorless oil. LCMS m / z = 458 [M+H]⁺

[0420] Synthesis of (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2-hydroxyethyl)carbamate tert-butyl ester (intermediate 4)

[0421]

[0422] Step 1: Synthesis of (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate tert-butyl ester

[0423] At 0 °C, TBDPS-Cl (17.25 g, 62.78 mmol) was added to a solution of (R)-(2-hydroxypropyl)carbamate tert-butyl ester (10 g, 57.07 mmol) and imidazole (7.77 g, 114.1 mmol) in DMF (100 mL), and the reaction mixture was stirred overnight at room temperature under N2. The reaction mixture was quenched with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc (5:1)) to give the title compound (23 g, 97.4%) as a colorless oil. LCMS m / z = 414 [M+H]+

[0424] Step 2: Synthesis of (R)-(2-(benzyloxy)ethyl)(2-((tert-butyldiphenylsilyl)oxy)propyl)amino tert-butyl carbamate

[0425] A solution of (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate (10 g, 24.18 mmol) in anhydrous DMF (100 mL) was treated with NaH (2.90 g, 72.5 mmol, 60%) at 0 °C under N2, and the mixture was stirred at 0 °C for 10 min. ((2-bromoethoxy)methyl)benzene (7.80 g, 36.26 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (100 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase column chromatography on a C18 gel, eluting with MeCN / water (0.1% FA) in a 10% to 50% gradient over 10 minutes, to give the title compound (4.5 g, 34.0%) as a white oil. LCMS m / z = 548 [M+H]+

[0426] Step 3: Synthesis of (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2-hydroxyethyl)carbamate tert-butyl Butyl acetate

[0427] Pd / C (4.71 g, 12.53 mmol) was carefully added to a solution of (R)-(2-(benzyloxy)ethyl)(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate tert-butyl ester (4.5 g, 8.58 mmol) in MeOH (50 mL), and the reaction mixture was stirred at 20 °C under H2 for 16 h. The mixture was filtered and the filter cake was washed with MeOH (3 × 40 mL). The filtrate was concentrated under reduced pressure and purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in an 80% to 90% gradient over 10 min to give the title compound (2.6 g, 66.2%) as a colorless oil. LCMS m / z = 458 [M+H]+

[0428] Synthesis of (S)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2-hydroxyethyl)carbamate tert-butyl ester (intermediate 5)

[0429]

[0430] The title compound, present as a colorless oil, was obtained from (S)-(2-hydroxypropyl)carbamate via a three-step procedure described in Intermediate 4. LCMS m / z = 458 [M+H]+

[0431] Synthesis of (R)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)(methyl)carbamate tert-butyl ester (intermediate 6)

[0432]

[0433] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-D-homoserine

[0434] Imidazole (24.84 g, 364.9 mmol) was added fractionally to a solution of (tert-butoxycarbonyl)-D-homoserine (10 g, 45.6 mmol) in DCM (500 mL). Subsequently, TBDPSCl (18.81 g, 68.42 mmol) was added fractionally, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the crude title compound as a colorless oil. LCMS m / z = 480 [M+H]+

[0435] Step 2: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-N-methyl-D-homoserine methyl ester

[0436] CH3I (178.7 g, 1.26 mol) was added dropwise to a solution of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-D-homoserine (28.8 g, 62.93 mmol) and Ag2O (72.92 g, 314.7 mmol) in DMF (500 mL) at 0 °C under N2. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction mixture was filtered, washed with EtOAc, and the filtrate was washed with saturated brine. The brine was extracted with another EtOAc (3 × 250 mL). The combined organic layers were washed with fresh brine (3 × 200 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc:PE, 1:5) to give the title compound (25.8 g, 84.4%) as a colorless oil. LCMSm / z = 486 [M+H]+

[0437] Step 3: Synthesis of (R)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)(methyl)amino tert-butyl formate

[0438] At 0 °C and under N2, NaBH4 (30.14 g, 797 mmol) was added fractionally to a solution of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-N-methyl-D-homoserine methyl ester (10 g, 20.5 mmol) in MeOH (150 mL) and THF (150 mL). The reaction mixture was slowly heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL), the combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE (1:2), to give the title compound (7 g, 74.3%) as a colorless oil. LCMS m / z = 458 [M+H]+

[0439] Synthesis of (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)(methyl)carbamate tert-butyl ester (intermediate 7)

[0440]

[0441] Following the same three-step procedure described in Intermediate 6, the title compound, which is a colorless oil, was obtained from (tert-butoxycarbonyl)-L-homoserine.

[0442] Synthesis of (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)carbamate tert-butyl ester (intermediate 8)

[0443]

[0444] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine

[0445] Following a procedure similar to that described in step 1 of intermediate 6, the title compound, 12.5 g, 60%, was obtained from (tert-butoxycarbonyl)-L-homoserine as a colorless oil. LCMS m / z = 458 [M+H]+

[0446] Step 2: Synthesis of (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)carbamate tert-butyl Butyl acetate

[0447] LiAlH4 (1.85 g, 48.8 mmol) was added dropwise to an ice-cold solution of the compound from step 1 (7.44 g, 16.3 mmol) in THF (80 mL), and the reaction mixture was stirred at room temperature under N2 for 1 hour. The reaction mixture was quenched with water at 0 °C and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE (1:3), to give the title compound (3.5 g, 48.5%) as a colorless oil. LCMS m / z = 444 [M+H]+

[0448] Synthesis of (1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)cyclopropyl)methanol (intermediate 9)

[0449]

[0450] DMSO (1.5 mL) containing tert-butyl(2-iodoethoxy)diphenylsilane (4.38 g, 10.7 mmol) was added dropwise to a solution of (1-aminocyclopropyl)methanol (1.5 g, 10.7 mmol) in DMSO (1.5 mL) and DIPEA (5.58 mL, 32.0 mmol), and the reaction mixture was stirred overnight at 60 °C. The mixture was extracted with EtOAc (2 × 250 mL), the combined organic layers were washed with brine (3 × 500 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to give the title compound (880 mg, 22.3%) as a yellow oil. LCMS m / z = 370 [M+H]+

[0451] Synthesis of (R)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)prop-1-ol (Intermediate 10)

[0452]

[0453] A mixture of (R)-(-)-2-amino-1-propanol (6.20 g, 82.6 mmol) and (2-bromoethoxy)(tert-butyl)diphenylsilane (20 g, 55.0 mmol) in MeCN (200 mL) was stirred at 80 °C for 3 h. The cooled reaction mixture was quenched with water at room temperature, the layers were separated, and the aqueous phase was extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN / water (0.1% NH4HCO3) in a 15% to 35% gradient over 10 min, to give the title compound (7.1 g, 36.1%) as a white solid. LCMS m / z = 358 [M+H]+

[0454] Synthesis of 2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)ethanol-1-ol (Intermediate 11)

[0455]

[0456] Following a procedure similar to that described in intermediate 10, the title compound, 2.63 g, 55.5%, was obtained from ethanolamine and (3-bromopropoxy)(tert-butyl)diphenylsilane as a yellow solid. LCMS m / z = 358 [M+H] +

[0457] Synthesis of (S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)prop-1-ol trifluoroacetate (intermediate 12)

[0458]

[0459] (2S)-2-aminoprop-1-ol (1.49 g, 19.9 mmol) was added to a solution of (3-bromopropoxy)(tert-butyl)diphenylsilane (5 g, 13.2 mmol) in MeCN (100 mL), and the resulting mixture was stirred overnight at 80 °C. The mixture was concentrated under reduced pressure and purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN / water (0.1% TFA) in a 10% to 100% gradient over 20 minutes, to give the title compound (2 g, 40.6%) as a yellow oil. LCMS m / z = 372 [M+H]+

[0460] Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-2-cyclopropylethanol-1-ol (Intermediate 13)

[0461]

[0462] (2-Bromoethoxy(tert-butyl)diphenylsilane (4.67 g, 12.9 mmol) was added fractionally to a stirred solution of (S)-2-amino-2-cyclopropyl ethanol-1-ol hydrochloride (1 g, 9.9 mmol), KI (0.82 g, 4.94 mmol), and Cs₂CO₃ (9.66 g, 29.7 mmol) in DMF (10 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC by elution with EtOAc to give the title compound (570 mg, 15%) as a yellow solid. LCMS m / z = 384 [M + H + Na] +

[0463] Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-(ethylamino)but-1-ol (Intermediate 14)

[0464]

[0465] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine

[0466] Following a procedure similar to that described in step 1 of intermediate 6, the title compound, 12.5 g, 60%, was obtained from (tert-butoxycarbonyl)-L-homoserine as a colorless oil. LCMS m / z = 458 [M+H]+

[0467] Step 2: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine methyl ester

[0468] CH3I (4.65 g, 32.8 mmol) was added to a stirred solution of the compound from step 1 (12.5 g, 27.3 mmol) and Ag2O (19.0 g, 81.9 mmol) in DMF (300 mL), and the reaction mixture was stirred at room temperature under N2 for 16 hours. The resulting mixture was filtered, the filter cake was washed with EtOAc, and the filtrate was diluted with saturated brine. The aqueous layer was separated and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE (1:10), to give the title compound (11.5 g, 89.3%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.61(m, 4H), 7.47 - 7.32 (m, 6H), 4.46 (td, 1H), 3.71 (d, 5H), 2.18 - 1.85 (m,2H), 1.45 (s, 9H), 1.07 (s, 9H).

[0469] Step 3: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine methyl ester

[0470] Following a procedure similar to that described in step 2 of Example 2, 3.12 g of the title compound, a yellow oil, was obtained from the compound from step 2. LCMS m / z = 372 [M+H]+

[0471] Step 4: Synthesis of O-(tert-butyldiphenylsilyl)-N-ethyl-L-homoserine methyl ester

[0472] TEA (2.01 g, 19.86 mmol) was added to a stirred solution of the compound from step 3 (2.46 g, 6.6 mmol) and acetaldehyde (0.88 g, 7.9 mmol, 40%) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature under N2 for 1.5 h. NaBH(OAc)3 (2.81 g, 13.2 mmol) was added, and the reaction mixture was stirred at room temperature for another 1.5 h. The mixture was cooled to 0 °C, diluted with brine (10 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (10 mmol NH4CO3) in an 80% to 90% gradient over 10 minutes, to give the title compound (1.55 g, 58.6%) as a colorless oil. LCMS m / z = 400 [M+H]+

[0473] Step 5: synthesis (S)-4-((tert-butyldiphenylsilyl)oxy)-2-(ethylamino)but-1-ol

[0474] Following a procedure similar to that described in step 2 of intermediate 8, the title compound, 0.55 g, 39.4%, in a yellow oil form, was obtained from the compound from step 4. LCMS m / z = 372 [M+H]+

[0475] Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-1-(methylamino)cyclobutyl)methanol (intermediate 15)

[0476]

[0477] Step 1: Synthesis of 1-((tert-butoxycarbonyl)amino)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane- 1-Formic acid

[0478] TBDPSCl (8.9 g, 32.4 mmol) was added to a solution of 1-((tert-butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylic acid (5 g, 21.6 mmol) in DMF (50 mL) at 0 °C under N2. Imidazole (4.4 g, 64.9 mmol) and DMAP (0.5 g, 4.32 mmol) were added sequentially at 0 °C, and the reaction mixture was stirred overnight at 50 °C under N2. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water (10 mmol NH4CO3) in a 10-minute gradient from 10% to 40%. The combined column eluates were extracted with EtOAc (3 × 10 mL), the combined organic layers were washed with citric acid (3 × 10 mL), dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (6.5 g, 64.0%) as a colorless oil. LCMS m / z = 471 [M+H]⁺

[0479] Step 2: Synthesis of 1-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldiphenylsilyl)oxy)cyclo Methyl butane-1-carboxylate

[0480] MeI (5.4 g, 38.3 mmol) was added dropwise to a stirred mixture of the compound from step 2 (6 g, 12.78 mmol) and NaH (919 mg, 38.3 mmol) in DMF (60 mL) at 0 °C under N2, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and Na2S2O3 (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (6 g, 94.4%) as a yellow oil. LCMS m / z = 498 [M+H]+

[0481] Step 3: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-1-(hydroxymethyl)cyclobutyl)(methyl)aminomethyl tert-butyl ester

[0482] BF3·Et2O (427.7 mg, 3.0 mmol) was added dropwise to a solution of the compound from step 2 (1.0 g, 2.0 mmol) in Et2O (20 mL) at 0 °C, followed by fractional addition of NH3·BH3 (155 mg, 5.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with HCl (1 M, 10 mL) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in a 10-minute gradient from 10% to 85%, to give the title compound (0.8 g, 84.8%) as a colorless oil. LCMS m / z = 470 [M+H]+

[0483] Step 4: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-1-(methylamino)cyclobutyl)methanol

[0484] A solution of the compound from step 3 (2.5 g, 5.32 mmol) and ZnBr2 (11.99 g, 53.2 mmol) in DCM (20 mL) was stirred at room temperature under N2 for 1 hour. The resulting mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was evaporated under reduced pressure to give the title compound (740 mg, 37.6%) as a colorless oil. LCMS m / z = 370 [M+H]+

[0485] Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-4,4,4-trifluorobut-1-ol (Intermediate 16)

[0486]

[0487] Step 1: Synthesis of (S)-(4,4,4-trifluoro-1-hydroxybut-2-yl)carbamate tert-butyl ester

[0488] A solution of (S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyric acid (1.0 g, 3.9 mmol) in THF (1.5 mL) was treated with a borane THF complex (19.44 mL, 1 M, 19.44 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with MeOH (10 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure to give the title compound (530 mg, 56.1%) as a yellow oil. LCMS m / z = 244 [M+H]+

[0489] Step 2: Synthesis of (2S)-2-amino-4,4,4-trifluorobut-1-ol hydrochloride

[0490] The compound from step 1 (1.03 g, 4.2 mmol) and a solution of dioxane containing HCl (2 mL, 4 M, 8 mmol) in dioxane (2 mL) were stirred at room temperature for 2 hours. The resulting mixture was evaporated under reduced pressure to give the title compound (600 mg, crude substance) as a yellow oil. LCMS m / z = 144 [M+H]+

[0491] Step 3: Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-4,4,4-trifluoro Butanol

[0492] Following a procedure similar to that described in intermediate 9, the title compound, 375 mg, 25%, in a yellow oil form, was obtained from the compound from step 2. LCMS m / z = 426 [M+H]+

[0493] Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino)but-1-ol (Intermediate 17)

[0494]

[0495] Step 1: Synthesis of O-(tert-butyldiphenylsilyl)-L-homoserine methyl ester

[0496] TFA (5 mL) was added to a solution of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine methyl ester (5 g, 10.6 mmol) in DCM (10 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was washed with water (5 × 5 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (3.5 g, 88.9%) as a yellow oil. LCMS m / z = 372 [M+H]+

[0497] Step 2: Synthesis of O-(tert-butyldiphenylsilyl)-N-(2,2-difluoroethyl)-L-homoserine methyl ester

[0498] A solution of 2,2-difluoroethyl trifluoromethanesulfonate (5.19 g, 24.2 mmol) in MeCN (5 mL) was added to a solution of the compound from step 1 (3 g, 8.1 mmol) in MeCN (5 mL). DIPEA (28.13 mL, 161.5 mmol) was then added dropwise, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1), to give the title compound (1.98 g, 56.3%) as a colorless oil. LCMS m / z = 436 [M+H]+

[0499] Step 3: Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino)but- 1-Alcohol

[0500] Following a procedure similar to that described in step 3 of intermediate 15, the title compound, 1.33 g, 90.3%, was obtained from the compound from step 2 as a colorless oil. LCMS m / z = 408 [M+H]+

[0501] Synthesis of (2-bromo-3,3,3-trifluoropropoxy)(tert-butyl)diphenylsilane (Intermediate 18)

[0502]

[0503] Following a procedure similar to that described in step 1 of intermediate 6, the title compound, 2.05 g (36%), was obtained from 2-bromo-1,1,1-trifluorobutane and TBDPSCl as a white oil. ¹H NMR (400 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.95 (s, 1H), 4.05 (s, 1H), 5.02–5.15 (m, 1H), 7.42–7.55 (m, 6H), 7.65 (m, 4H).

[0504] Synthesis of (3-(methylamino)tetrahydrofuran-3-yl)methanol (intermediate 19)

[0505]

[0506] Step 1: Synthesis of methyl 3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate

[0507] (Boc)₂O (1 g, 4.59 mmol) and Na₂CO₃ (2.43 g, 22.9 mmol) were added to a solution of methyl 3-aminotetrahydrofuran-3-carboxylate hydrochloride (500 mg, 2.29 mmol) in dioxane (2 mL) and H₂O (2 mL), and the reaction mixture was stirred overnight at room temperature. The reactants were diluted with H₂O, extracted with EtOAc, and the combined organic extracts were dried and evaporated under reduced pressure to give the title compound (500 mg, 88.9%) as a colorless oil. LCMS m / z = 246 [M+H]⁺

[0508] Step 2: Synthesis of methyl 3-((tert-butoxycarbonyl)(methyl)amino)tetrahydrofuran-3-carboxylate

[0509] Following a procedure similar to that described in step 2 of intermediate 14, the title compound, 3 g, 63.9%, was obtained from the compound from step 1 and MeI as a colorless oil. LCMS m / z = 260 [M+H]+

[0510] Step 3: Synthesis of methyl 3-(methylamino)tetrahydrofuran-3-carboxylate

[0511] The mixture of the compound from step 2 (2.5 g, 9.64 mmol) and TFA (5.50 g, 48.2 mmol) in DCM (50 mL) was stirred at room temperature under N2. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution) and evaporated under reduced pressure to give the crude title compound as a white solid. LCMS m / z = 160 [M+H]+

[0512] Step 4: Synthesis of (3-(methylamino)tetrahydrofuran-3-yl)methanol

[0513] At 0 °C and under N2, NH3·BH3 (901.8 mg, 29.21 mmol) was added to a stirred mixture of the compound from step 3 (1.55 g, 9.74 mmol) and BF3·Et2O (2.76 g, 19.47 mmol) in Et2O (30 mL). The mixture was acidified to pH 4 with concentrated HCl. The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were evaporated under reduced pressure to give 1 g of the crude substance of the title compound as a colorless oil. LCMS m / z = 131 [M+H]+

[0514] Synthesis of 3-chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenol (Intermediate 20)

[0515]

[0516] A mixture of 3-bromo-5-chloro-4-cyclopropylphenol (630 mg, 2.55 mmol), bis(pinacol)diboron (975 mg, 3.84 mmol), Pd(dppf)Cl2.CH2Cl2 (228 mg, 0.28 mmol), and KOAc (750 mg, 7.65 mmol) in dioxane (10 mL) was stirred at 100 °C under N2 for 2 h. The reaction mixture was quenched with water at room temperature, and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to give the title compound (330 mg, 41.8%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 6.97 - 6.86(m, 2H), 3.50 (s, 3H), 1.95 (m, 1H), 1.37 (s, 12H), 1.31 (s, 1H), 1.26 (s,5H), 1.08 - 0.85 (m, 3H), 0.59 - 0.42 (m, 2H).

[0517] Synthesis of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (Intermediate 21)

[0518]

[0519] Step 1: Synthesis of 1-bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene

[0520] A solution of 1-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (2.20 g, 5.83 mmol), K3PO4 (3.71 g, 17.49 mmol), cyclopropylboronic acid (0.74 g, 8.74 mmol), and Pd(dppf)Cl2 (0.41 g, 0.58 mmol) in dioxane (20 mL) and H2O (4 mL) was stirred at 100 °C under N2 for 8 hours. The cooled mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN₂ water in a 0% to 100% gradient over 20 minutes, yielding the title compound (220 mg, 12.9%) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (d, 1H), 7.03 (d, 1H), 5.11 (s, 2H), 3.46 (s, 3H), 1.69–1.64 (m, 1H), 1.19–1.07 (m, 2H), 0.78–0.62 (m, 2H).

[0521] Step 2: Synthesis of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborane

[0522] Following a procedure similar to that described in intermediate 20, the title compound, 120 mg, 46.9% (yellow solid), was obtained from the compound in step 1. LCMS: m / z = 339 [M+H]+

[0523] Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)pyridine-2-amine (Intermediate 22)

[0524]

[0525] Step 1: Synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine

[0526] NaH (1.60 g, 40.1 mmol) was added to a solution of 4-bromo-6-methylpyridin-2-amine (3 g, 16.0 mmol) in DMF (30 mL) at 0 °C, and the mixture was stirred at room temperature for 30 min. 1-(chloromethyl)-4-methoxybenzene (5.53 g, 35.3 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with DCM (50 mL), quenched with a saturated aqueous NH4Cl solution, and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography with elution of 0–30% EtOAc / hexane to give the title compound (6 g, 82%) as a white solid. LCMS m / z = 427 [M+H]+

[0527] Step 2: Synthesis of 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine

[0528] At 0℃ N -Iodosuccinimide (2.06 g, 9.17 mmol) was added to a solution of the compound from step 1 (4 g, 9.17 mmol) in AcOH (50 mL), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated Na₂SO₃ solution and extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated NaHCO₃ solution, washed with water, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of 0–100% EtOAc / hexane to give the title compound (5 g, 88%) as a white solid. LCMS m / z = 553 [M+H]⁺

[0529] Step 3: Synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine

[0530] Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.33 mL, 1.80 mmol), copper(I) iodide (430 mg, 2.25 mmol), and HPMA (800 mg, 4.52 mmol) were added to a solution of the compound from step 2 (500 mg, 0.90 mmol) in NMP (10 mL), and the reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of 0–100% EtOAc / hexane to give the title compound (300 mg, 51.6%) as a white solid. LCMS m / z = 497 [M+]+

[0531] Step 4: Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) (2-yl)-5-(trifluoromethyl)pyridine-2-amine

[0532] Following a procedure similar to that described in intermediate 20, the title compound, 200 mg, 29.1%, was obtained from the compound in step 3. LCMS m / z = 543 [M+H]+

[0533] Synthesis of (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (intermediate 23)

[0534]

[0535] A solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (1 g, 2.34 mmol), bis(pinacol)diboron (1.19 g, 4.68 mmol), Pd(dppf)Cl2 (0.17 g, 0.23 mmol), and KOAc (0.46 g, 1.63 mmol) in dioxane (10 mL) was stirred at 80 °C for 2 hours. The cooled mixture was filtered, and the filtrate was evaporated under reduced pressure to give the crude, yellow, oily title compound. LCMS m / z = 393 [M+H]+

[0536] Synthesis of (5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (intermediate 24)

[0537]

[0538] Step 1: Synthesis of 4-bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0539] A mixture of 4-bromo-5,6-dimethyl-1H-indazole (1 g, 4.44 mmol), DHP (0.81 mL, 8.88 mmol), and TsOH·H₂O (0.08 g, 0.44 mmol) in DCM (15 mL) was stirred at room temperature under N₂ for 3 hours. The reactants were quenched by adding saturated NaHCO₃ (aqueous solution) (25 mL) at 0 °C, and the resulting mixture was extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:2), to give the title compound (1.3 g, 94.6%) as a yellow oil. LCMS m / z = 309 [M+H]⁺

[0540] Step 2: (5,6-Dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid

[0541] A mixture of the compound from step 1 (500 mg, 1.62 mmol), bis(pinacol)diboron (1.1 g, 4.85 mmol), Pd(dppf)Cl2.CH2Cl2 (131 mg, 0.16 mmol), and KOAc (476 mg, 4.85 mmol) in dioxane (20 mL) was stirred at 100 °C under N2 for 4 hours. The reaction mixture was quenched with water (100 mL) at room temperature, and the resulting mixture was extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 2:1), and the product was further purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (10 mmol NH4CO3) in a 0% to 42% gradient over 30 minutes, to give the title compound (426 mg, 76.9%) as a white solid. LCMS m / z = 275 [M+H]+

[0542] Synthesis of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazo-4-yl)boronic acid (intermediate 25)

[0543]

[0544] Step 1: Synthesis of tert-butyl (4-bromo-7-fluorobenzo[d]thiazolyl)carbamate

[0545] A mixture of 4-bromo-7-fluoro-1,3-benzothiazol-2-amine (2.0 g, 8.09 mmol), Boc₂O (2.6 g, 12.14 mmol), TEA (2.5 g, 24.3 mmol), and DMAP (99 mg, 0.81 mmol) in DCM (30 mL) was stirred in air at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 20:1) to give the title compound (1.7 g, 57.5%) as a white solid. LCMS m / z = 347 [M+H]⁺

[0546] Step 2: Synthesis of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazolyl-4-yl)boronic acid

[0547] Following a procedure similar to that described in step 2 of intermediate 24, the title compound, 384 mg, 85%, was obtained from the compound in step 1 as a solid. LCMS m / z = 313 [M+H]+

[0548] Synthesis of (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[b]thiophene-2-yl) tert-butyl carbamate (intermediate 26)

[0549]

[0550] Step 1: Synthesis of tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate

[0551] Following a similar procedure to that described in step 1 of intermediate 25, the title compound was obtained as a solid, 2.7 g, 98.5%, from 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carboxynitrile and (Boc)₂O. LCMS m / z = 368 [M+H]⁺

[0552] Step 2: Synthesis of (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl) Benzo[b]thiophene-2-yl)tert-butyl carbamate

[0553] A mixture of the compound from step 1 (2.8 g, 7.54 mmol), bis(pinacol)diboron (15.7 g, 61.9 mmol), Pd(PPh3)4 (1.0 g, 0.90 mmol), and KOAc (2.9 g, 30.2 mmol) in dioxane (80 mL) was stirred at 95 °C under N2 for 4 h. The reaction mixture was quenched with water (100 mL) at 0 °C, and the mixture was extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water (10 mmol NH4CO3) in a 0% to 48% gradient over 30 min, to give the title compound (2.0 g, 63.3%) as a white solid. LCMS m / z = 417 [MH]-

[0554] Synthesis of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indazole (Intermediate 27)

[0555]

[0556] Step 1: Synthesis of 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene

[0557] CuI (72.0 g, 377.9 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (72.6 g, 377.9 mmol) were added to a solution of 1-bromo-5-fluoro-2-iodo-3-toluene (14 g, 44.5 mmol) in DMF (140 mL), and the reaction mixture was stirred at 70 °C under N2 for 12 h. The reaction mixture was filtered, and the filtrate was diluted with H2O (200 mL) and extracted with PE (200 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9 g, 78.8%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.33 - 7.31 (m, 1H), 6.95 (dd, 1H), 2.56 - 2.53 (m, 3H).

[0558] Step 2: Synthesis of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde

[0559] LDA (2 M in THF, 19.45 mL) was added to a solution of the compound from step 1 (5 g, 19.5 mmol) in THF (85 mL) at -65 °C under N2, and the mixture was stirred for 0.5 h. DMF (4.27 g, 58.4 mmol) was added dropwise at -65 °C, and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with NH4Cl (50 mL) at 0 °C, followed by extraction with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient of 0–50% EtOAc / PE to give the title compound (3.3 g, 59.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 10.35 (s,1H), 7.08 (d, 1H), 2.64 - 2.60 (m, 3H).

[0560] Step 3: Synthesis of 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole

[0561] NH₂NH₂·H₂O (17.56 g, 17.0 mL) was added to a solution of the compound from step 2 (5 g, 17.5 mmol) in DMSO (50 mL), and the reaction mixture was stirred at 60 °C for 2 h. The pH of the reaction mixture was adjusted to 7 using 1 M HCl, the mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (4.6 g, crude) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.99 (br s, 1H), 8.19 (s, 1H), 7.31 (s, 1H), 2.66–2.63 (m, 3H).

[0562] Step 4: Synthesis of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole

[0563] TsOH (567.7 mg, 3.30 mmol) was added to a solution of the compound from step 3 (4.6 g, 16.48 mmol) in DCM (100 mL), followed by the addition of MeCN (20 mL) containing DHP (5.55 g, 65.94 mmol), and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a 0–50% EtOAc / PE gradient at 100 mL / min to give the title compound (5 g, 83.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.43 (s, 1H), 5.69 (dd, 1H), 4.03 - 3.99 (m, 1H), 3.79 - 3.72 (m, 1H), 2.71 - 2.65 (m, 3H), 2.56 - 2.47 (m, 1H), 2.19 - 2.07 (m, 2H), 1.81 - 1.67 (m, 3H).

[0564] Step 5: Synthesis of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) Boronylcyclopentane-2-yl)-5-(trifluoromethyl)-1H-indazole

[0565] Pd(dppf)Cl2.CH2Cl2 (1.01 g, 1.24 mmol) and KOAc (4.86 g, 49.6 mmol) were added to a solution of the compound from step 4 (4.5 g, 12.4 mmol) and bis(pinacol)diboron (18.88 g, 74.3 mmol) in dioxane (45 mL), and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an elution gradient of 0 to 60% EtOAc / PE at 100 mL / min to give the title compound (1.9 g, 36.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.49 (s, 1H), 5.72 (dd, 1H), 3.98 (d, 1H), 3.77 - 3.71 (m, 1H), 2.62 (s, 3H), 2.57 - 2.48 (m, 1H), 2.18 - 2.15 (m, 1H), 2.08 - 2.04 (m, 1H), 1.80 - 1.66 (m, 3H), 1.45 (s, 12H), 1.27 (s, 1H).

[0566] Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (intermediate 28)

[0567]

[0568] Step 1: Synthesis of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0569] A solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4 g, 14.3 mmol), POCl3 (17.52 g, 114.2 mmol), and DIPEA (5.54 g, 42.8 mmol) in anhydrous MeCN (15 mL) was stirred at 80 °C under N2 for 0.5 h. The mixture was evaporated and cooled under reduced pressure to give the crude substance of the title compound as a yellow solid. LCMS m / z = 299 [M+H]+

[0570] Step 2: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro- 2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0571] DIPEA (3.90 g, 30.1 mmol) was added to a stirred solution of intermediate 14 (3.73 g, 10.0 mmol) and the compound from step 1 (3.00 g, 10.0 mmol) in THF (30 mL), and the resulting yellow suspension was stirred at 25 °C for 1 h. LiOtBu (2.2 M, 13.7 mL) was added, and the reaction mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with an elution gradient of 0–30% EtOAc / PE at 100 mL / min to give the title compound (2.50 g, 41.6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ:7.65 - 7.56 (m, 4H), 7.51 - 7.36 (m, 6H), 4.62 (dd, 1H), 4.37 (d, 1H), 4.29 -4.15 (m, 2H), 3.77 (br t, , 2H), 3.39 (qd, 1H), 2.53 (s, 3H), 1.97 - 1.83 (m,1H), 1.80 - 1.72 (m, 1H), 1.25 (t, 3H), 1.00 (s, 9H)

[0572] Step 3: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro- 2-(methanesulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthalene

[0573] m-CPBA (2.12 g, 10.4 mmol, 85% purity) was added to a solution of the compound from step 2 (2.50 g, 4.19 mmol) in THF (20 mL) and H2O (4 mL), and the reaction mixture was stirred at 30 °C for 1 hour. The reaction mixture was quenched with 10% Na2SO3 aqueous solution (100 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (100 mL × 2), washed with 10% Na2SO3 aqueous solution (100 mL × 2) and brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with an elution gradient of 0 to 40% EtOAc / PE at 80 mL / min to give the title compound (1.70 g, 64.5%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.62(ddd, 4H), 7.49 - 7.39 (m, 6H), 4.70 (dd, 1H), 4.47 (d, 1H), 4.39 - 4.31 (m,1H), 4.23 (qd, 1H), 3.83 - 3.73 (m, 2H), 3.51 (qd, 1H), 3.38 (s, 3H), 1.95(qd, 1H), 1.81 - 1.77 (m, 1H), 1.28 (t, , 3H), 1.01 (s, 9H)

[0574] Step 4: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan[de]naphthalene

[0575] LiOtBu (2.2 M, 2.46 mL, 5.4 mmol) was added to a stirred solution of the compound from step 3 (1.70 g, 2.70 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (516 mg, 3.24 mmol) in THF (20 mL) at 0 °C, and the resulting yellow suspension was stirred at 25 °C for 1 h. The reaction mixture was added to water (50 mL), the mixture was extracted with EtOAc (50 mL × 2), and the combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0–40% EtOAc / PE, to give the title compound (1.1 g, 57.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.61 (ddd, 4H), 7.52 -7.31 (m, 6H), 5.38 - 5.14 (m, 1H), 4.61 (dd, 1H), 4.34 (d, 1H), 4.21 (td,2H), 4.14 - 4.07 (m, 1H), 4.06 - 3.98 (m, 1H), 3.77 (br t, 2H), 3.44 - 3.33(m, 2H), 3.14 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1H), 2.16 - 2.02 (m, 2H), 1.99(s, 1H), 1.96 - 1.63 (m, 5H), 1.28 - 1.19 (m, 3H), 1.00 (s, 9H)

[0576] Synthesis of (S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (intermediate 29)

[0577]

[0578] Step 1: Synthesis of (S)-2-((2,4-dimethoxybenzyl)amino)prop-1-ol

[0579] To a stirred solution of (2S)-2-aminoprop-1-ol (10 g, 133.1 mmol) and 2,4-dimethoxybenzaldehyde (22.12 g, 133.1 mmol) in MeOH (500 mL), Na₂SO₄ (9.46 g, 66.6 mmol) was added, and the resulting mixture was stirred at room temperature under N₂ for 24 h. The mixture was cooled to 0 °C, and NaBH₄ (2.52 g, 66.6 mmol) was added dropwise, and the reaction mixture was stirred for 30 min. AcOH (4.00 g, 66.6 mmol) was added dropwise, and the reaction mixture was stirred for 15 min. The reactants were quenched with water at 0 °C, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (33 g, crude substance) as a white solid. LCMS m / z = 226 [M+H]+

[0580] Step 2: Synthesis of (S)-7-chloro-5-(2-((2,4-dimethoxybenzyl)amino)propoxy)-8-fluoro-2-(methyl) Thio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0581] NaH (60% in oil, 2.66 g, 66.6 mmol) was added to a solution of the compound from step 1 (5 g, 22.2 mmol, crude material) in THF (50 mL) at 0 °C, and the mixture was stirred for 10 min. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (6.22 g, 22.2 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 h. The cooled reaction mixture was quenched with water, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN₂ and water in a 30% to 40% gradient over 10 minutes, to give the title compound (10.2 g, 98.0%) as a yellow solid. LCMS m / z = 469 [M+H]⁺

[0582] Step 3: Synthesis of ((S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-9-methyl-2-(methylthio)-9, 10-Dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0583] TEA (6.60 g, 65.3 mmol) and PyBOP® (16.98 g, 32.6 mmol) were added to a stirred solution of the compound from step 2 (10.2 g, 21.8 mmol) in DCM (100 mL) at room temperature, and the reaction mixture was stirred at room temperature under N2 for 5 h. The resulting mixture was diluted with brine and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN: water in a 40% to 50% gradient over 10 min, to give the title compound (5.1 g, 52.%) as a yellow solid. LCMS m / z = 451 [M+H]+

[0584] Step 4: Synthesis of (9S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-9-methyl-2-(methylsulfinyl) 9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0585] A solution of m-CPBA (2.15 g, 12.4 mmol) in DCM was added dropwise to a solution of the compound from step 3 (5.1 g, 11.3 mmol) in DCM (50 mL) at -15 °C under N2, and the reaction mixture was stirred at -15 °C under N2 for 1 hour. The reaction mixture was quenched by adding a saturated NaHSO3 solution at -15 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5.28 g, crude substance) as a yellow solid. LCMS m / z = 467 [M+H]+

[0586] Step 5: Synthesis of (S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrafluoro) Hydrogen-1H-pyrrolazine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane and [de]naphthalene

[0587] To the stirred solution of the compound from step 4 (5.28 g, 11.3 mmol) in toluene (50 mL), 5.40 g, 33.9 mmol of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (5.40 g, 33.9 mmol) was added, and the mixture was stirred at room temperature under N2 for 30 min, followed by cooling to 0 °C. NaOtBu (2.17 g, 22.6 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. The mixture was diluted with brine, extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water in a 40% to 50% gradient over 10 min, to give the title compound (4 g, 62.9%) as a white solid. LCMS m / z = 562 [M+H]+

[0588] Step 6: Synthesis of (S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methyl )-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0589] TFA (20 mL) was added to a solution of the compound from step 5 (4 g, 7.1 mmol) in DCE (20 mL), and the reaction mixture was stirred at 80 °C under N2 for 16 h. The cooled mixture was concentrated under reduced pressure and the residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN: water in a 60% to 70% gradient over 10 min, to give the title compound (1.6 g, 54.6%) as a grayish-white solid. LCMS m / z = 412 [M+H]+

[0590] Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (intermediate 30)

[0591]

[0592] Steps 1 to 3: Synthesis of 5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(methylthio)-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0593] Following a three-step procedure similar to that described in steps 1 to 3 of intermediate 29, the title compound was obtained as a white solid from ethanolamine, 2,4-dimethoxybenzaldehyde, and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one. LCMS m / z = 437 [M+H]+

[0594] Steps 4 to 6: Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy 9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0595] Following a three-step procedure similar to that described in steps 4 to 6 of intermediate 29, the title compound was obtained as a white solid from the compound from steps 1 to 3 and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol. LCMS m / z = 398 [M+H]+

[0596] Synthesis of 5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (intermediate 31)

[0597]

[0598] TFA (5 mL) was added to intermediate 30, step 3 (500 mg, 1.24 mmol) in a solution of DCE (5 mL), and the reaction mixture was stirred at 80 °C under N2 for 16 hours. The cooled mixture was evaporated under reduced pressure to give the crude product of the title compound. LCMS m / z = 287 [M+H]+

[0599] Synthesis of (S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (intermediate 32)

[0600]

[0601] The title compound is obtained from intermediate 29 step 3 by following the procedure described in intermediate 31.

[0602] Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 33)

[0603]

[0604] Step 1: Synthesis of 3-bromo-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0605] NaH (77.3 g, 1.93 mol, 60% purity) was added fractionally to a solution of 3-bromo-5-fluoropyridin-2-amine (150 g, 0.77 mol) in DMF (2 L) at 0 °C under N2, and the mixture was stirred at 0 °C for 1 h. PMBCl (266 g, 1.70 mol) was added dropwise at 0 °C under N2, and the reaction mixture was stirred at room temperature for 18 h. The mixture was cooled and quenched dropwise with saturated NH4Cl (2 L), and extracted with EtOAc (2 L × 2). The combined organic layers were washed with brine (500 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0 to 25% EtOAc / PE, to give the title compound (240 g, 72.0%) as a yellow oil. LCMS m / z = 431 / 433[M+H]+

[0606] Step 2: Synthesis of 3-(1-ethoxyvinyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0607] Tributyl(1-ethoxyvinyl)tin (151 g, 417 mmol), TEA (84.2 g, 834 mmol), and Pd(PPh3)2Cl2 (8.7 g, 11.2 mmol) were added to a solution of the compound from step 1 (120 g, 278 mmol) in DMF (1.5 L), and the reaction mixture was stirred at 80 °C under N2 for 18 hours. The mixture was poured into water (2 L) and extracted with EtOAc (2 L × 2). The combined organic layers were washed with brine (500 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0 to 20% THF / PE, to give the title compound (151 g, 64.2%) as a yellow gel. LCMS m / z = 423 [M+H]+

[0608] Step 3: Synthesis of 1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl-1-one

[0609] HCl / dioxane (200 mL, 4 M) was added to a solution of the compound from step 2 (150 g, 355 mmol) in dioxane (1.5 L), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was diluted with saturated NaHCO3 (300 mL) and EtOAc (2 L). The EtOAc layer was washed with brine (500 mL), dried over Na2SO4, filtered, and the filtrate was evaporated to give the title compound (130 g, 92.8%) as a yellow oil. LCMS m / z = 395 [M+H]+

[0610] Step 4: Synthesis of (2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl) (amino)prop-1-ol

[0611] Ti(i-PrO)₄ (162 g, 570 mmol) and 4 Å molecular sieve (100 g, 380.3 mmol) were added to a solution of the compound from step 3 (150 g, 380.3 mmol) and (S)-2-aminoprop-1-ol (85.7 g, 1.14 mol) in dioxane (1.5 L), and the mixture was stirred at 110 °C under N₂ for 18 h. The mixture was cooled to 0 °C and NaBH₄ (28.8 g, 760 mmol) was added dropwise while maintaining an internal temperature below 20 °C. After the addition, the mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 °C, and saturated NaHCO₃ (200 mL) was added dropwise under N₂ while the mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (2 L) and filtered through a Celite® pad. The filter cake was washed with EtOAc (1 L × 2). The separated organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0–100% THF / PE, to give the title compound (130 g, 75.4%) as a yellow gel. LCMS m / z = 454 [M+H]+

[0612] Step 5: Synthesis of 5-((2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl (amino)propoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0613] At 0°C under N2, NaH (25 g, 625 mmol, 60% purity) was added fractionally to a solution of the compound from step 4 (80.9 g, 178 mmol) in THF (1.5 L). The mixture was stirred at 0°C for 30 min. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (50 g, 178.5 mmol) was added fractionally at 0°C under N2, and the reaction mixture was stirred at 60°C for 2.5 h. The mixture was cooled to 0°C and saturated NH4Cl (500 mL) was added dropwise while maintaining the internal temperature below 15°C. The mixture was extracted with EtOAc (1 L × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography with elution of 0-40% THF / PE to give the title compound (74 g, 59.4%) as a yellow solid.

[0614] Step 6: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxo Hexa-1,3,6,10-tetraazacycloheptan[de]naphth-10-yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2- amine

[0615] DIPEA (38.9 g, 301 mmol) and BOP-Cl (38.3 g, 150 mmol) were added to a solution of the compound from step 5 (70 g, 100.4 mmol) in DCE (1.5 L), and the reaction mixture was stirred at 90 °C for 18 hours. The mixture was washed with saturated NaHCO3 (1 L) and brine (500 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (ISCO®; 330 g SepaFlash® silica column, eluent gradient of 0 to 30% THF / PE, at 100 mL / min), followed by purification by preparative SFC (column: REGIS (s,s) WHELK-O1 (250 mm)). Purification was performed using a mobile phase of CO2 / EtOH (0.1% NH3H2O) (45:55) in isocratic elution mode, yielding the title compound (28 g, 41.1%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.41(d, 1H), 7.97 (dd, 1H), 6.89 - 6.98 (m, 1H), 6.70 (d, 4H), 6.54 (d, 4H),4.38 - 4.49 (m, 1H), 4.21 - 4.32 (m, 1H), 4.09 (d, 2H), 3.96 - 4.03 (m, 1H), 3.83 (d, 2H), 3.64 (s, 6H), 2.66 (s, 3H), 1.39 (br d, 3H), -0.13 (d, 3H)

[0616] Synthesis of 3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methanesulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptannaphth-10-yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine (intermediate 34)

[0617]

[0618] m-CPBA (7.69 g, 37.90 mmol, 85% purity) was added to a mixture of the compound from intermediate 33 (26 g, 34.45 mmol) in DCM (250 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and saturated Na2SO3 (50 mL), followed by extraction with DCM (200 mL × 3). The combined organic phases were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (24 g, 90.2%). LCMS m / z = 695 [M+H]+

[0619] Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 35)

[0620]

[0621] Steps 1 and 2: Synthesis of 3-bromo-5-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0622] Following a procedure similar to that described in steps 1 and 2 of intermediate 33, the title compound, present as a yellow oil, was obtained from 3-bromo-5-chloropyridin-2-amine, PMBCl, and tributyl(1-ethoxyvinyl)stanane. LCMS m / z = 439 [M+H]+

[0623] Step 3: Synthesis of 1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethyl-1-one

[0624] The solution of the compound from steps 1 and 2 (21 g, 47.8 mmol) and 1 M HCl (768.8 mL) in EtOAc (730 mL) was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (2 × 500 mL), and the combined organic layers were washed with NaHCO3 (3 × 100 mL) and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to give the title compound (17 g, 86.5%) as a yellow oil. LCMS m / z = 411 [M+H]+

[0625] Step 4: Synthesis of (2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethyl) (amino)prop-1-ol

[0626] Ti(i-PrO)₄ (47.04 g, 165.5 mmol) was added to a solution of the compound from step 3 (17 g, 41.4 mmol) and (2S)-2-aminoprop-1-ol (9.32 g, 124.1 mmol) in EtOH (300 mL), and the resulting mixture was stirred overnight at 80 °C. NaBH₄ (4.70 g, 124.1 mmol) and HOAc (3.73 g, 62.1 mmol) were added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched at 0 °C with water / ice (100 mL), the resulting mixture was filtered, and the filter cake was washed with EtOAc (4 × 500 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:8), to give the title compound (16.85 g, 86.7%) as a yellow oil. LCMS m / z = 470 [M+H]+

[0627] Step 5: Synthesis of 5-((2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethyl (amino)propoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0628] Following a procedure similar to that described in step 5 of intermediate 33, the title compound (6 g, 32.9%), a brown solid, was obtained from the compound from step 4. LCMS m / z = 713 [M+H]+

[0629] Step 6: Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine 2-Pyridine

[0630] DIPEA (3.80 g, 29.4 mmol) was added to a solution of the compound from step 5 (7 g, 9.81 mmol) and BOPCl (7.49 g, 29.4 mmol) in CHCl3 (120 mL), and the resulting mixture was stirred at 80 °C for 20 h. The reaction mixture was quenched with ice water at 0 °C, and extracted with DCM (3 × 100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1), to give the title compound (1.7 g, 22.4%) as a yellow solid. LCMSm / z = 695 [M+H]+

[0631] Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 36)

[0632]

[0633] Step 1: Synthesis of 5-chloro-3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfinyl)-8,9-di Hydrogen-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl) Pyridine-2-amine

[0634] A solution of m-CPBA (526.5 mg, 2.59 mmol, 85%) in DCM (10 mL) was added dropwise to a solution of intermediate 35 (1.64 g, 2.36 mmol) in DCM (40 mL) at -15 °C, and the reaction mixture was stirred at -15 °C for 1 hour. The reaction mixture was quenched with Na₂SO₃ (aqueous solution) at 0 °C, the aqueous layer was extracted with DCM (3 × 10 mL), the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.54 g, 91.9%) as a yellow solid. LCMS m / z = 711 [M+H] +

[0635] Step 2: Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azine-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene- 10-(4-methyl)ethyl)-N,N-bis(4-methoxyphenylmethyl)pyridine-2-amine

[0636] NaOtBu (243.1 mg, 2.53 mmol) was added to a solution of the compound from step 1 (900 mg, 1.27 mmol) and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol (604.0 mg, 3.80 mmol) in toluene (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with ice water at 0 °C. The aqueous layer was extracted with DCM (3 × 10 mL), the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1), to give the title compound (600 mg, 58.8%) as a white solid. LCMS m / z = 806 [M+H] +

[0637] Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 37)

[0638]

[0639] Step 1: Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetrazobenzene Heterocyclic heptanonaphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0640] Intermediate 27 (120.8 mg, 0.29 mmol), intermediate 33 (200 mg, 0.99 mmol), CataCXiumA Pd G3 (21.45 mg, 0.029 mmol), and K3PO4 (187.52 mg, 0.88 mmol) were stirred in dioxane (4 mL) / H2O (1 mL) at 80 °C under N2 for 1 h. The mixture was cooled to room temperature, the reactants were quenched with ice water, and the mixture was extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1:1) to give the title compound (110 mg, 40.3%) as a light brown solid. LCMS m / z = 928 [M+H]+

[0641] Step 2: Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazole-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10- Tetraazacycloheptan(de)naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0642] Following the procedure described in intermediate 34, the title compound, 100 mg, crude substance in solid form, was obtained from the compound from step 1. LCMS m / z = 944 [M+H]+

[0643] Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)pyridine-2-amine (Intermediate 38)

[0644]

[0645] Step 1: Synthesis of 3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2-) 5-(trifluoromethyl)-1H-indazole-4-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraaza Cyclohepta[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0646] Following the procedure described in step 1 of Example 101, the title compound (450 mg, 64.3%), presenting as a pale yellow foam, was obtained from the compound of step 4 of Example 93 and intermediate 27. LCMS m / z = 909 [M+H] + .

[0647] Step 2: Synthesis of 3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2-) 5-(trifluoromethyl)-1H-indazole-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetra- Aza-heptacyclic (de)naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0648] Following a procedure similar to that described in step 4 of intermediate 34, the title compound (200 mg, 91%), presenting as a pale brown foam, was obtained from the compound from step 1. LCMS m / z = 925 [M+H] + .

[0649] Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 39)

[0650]

[0651] Step 1: Synthesis of 3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfinyl)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine 2-Pyridine

[0652] Following a procedure similar to that described in step 3 of Example 1, 500 mg of the title compound, crude material, was obtained from the compound from step 4 of Example 93 as a yellow oil. LCMS m / z = 677 [M+H]+

[0653] Step 2: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl) Ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0654] Following a procedure similar to that described in step 5 of Example 40, the title compound, 455 mg, 79.7%, was obtained from the compound from step 1 and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol, as a white solid. LCMS m / z = 772 [M+H]+

[0655] Synthesis of (1-azabicyclo[3.2.0]hept-5-yl)methanol (intermediate 40)

[0656]

[0657] Step 1: (2R)-2-(2-chloroethyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

[0658] LDA (1.0 M in THF, 10.5 mL, 34.9 mmol) was added dropwise to a solution of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (4 g, 17.45 mmol) in THF (40 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 2 hours, followed by dropwise addition of 1-bromo-2-chloroethane (5.00 g, 34.9 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl (aqueous solution), the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (4 g, 78.6%) as a yellow oil. LCMS m / z = 236 [M+H]+

[0659] Step 2: (2R)-2-(2-chloroethyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

[0660] 4 M HCl / dioxane (50 mL) was added to a solution of the compound from step 1 (4 g, 13.7 mmol) in dioxane (0.5 mL), and the reaction mixture was stirred at room temperature under N2 for 1 hour. The resulting mixture was concentrated under reduced pressure to give the title compound (3 g, 91.3%) as a yellow oil. LCMS m / z = 192 [M+H]+

[0661] Step 3: (5R)-1-azabicyclo[3.2.0]heptane-5-carboxylic acid methyl ester

[0662] The mixture of the compound from step 2 (3 g, 15.66 mmol) and TEA (9.01 mL, 64.80 mmol) in MeCN (45 mL) was stirred at 80 °C under N2 for 2 h. The reaction mixture was quenched with ice water and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (1 g, 41.2%) as a brown oil. LCMS m / z = 156 [M+H]+

[0663] Step 4: 1-azabicyclo[3.2.0]hept-5-ylmethanol

[0664] LiAlH4 (20 mL, 0.042 mmol, 1.0 M THF solution) was added dropwise to a solution of the compound from step 3 (1 g, 6.44 mmol) in THF (10 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 hour. The reactants were quenched with Na2SO4·H2O, the mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was evaporated under reduced pressure to give the title compound (300 mg, 36.6%) as a yellow oil. LCMS m / z = 128 [M+H]+

[0665] Synthesis of (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (intermediate 41)

[0666]

[0667] Step 1: Synthesis of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(4,4,5,5-tetramethyl-1,3,2-) Dioxaborane-2-yl)cyclopropyl)-1H-indazole

[0668] A solution of 4-bromo-6-chloro-5-iodo-1-(oxan-2-yl)inazole (1 g, 2.27 mmol), 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane) (998.9 mg, 3.40 mmol), Cs₂CO₃ (1.48 g, 4.53 mmol), and Pd(dppf)Cl₂ (165.7 mg, 0.23 mmol) in dioxane (8 mL) and H₂O (1 mL) was stirred at 100 °C under N₂ for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 12:1) to give the title compound (524 mg, 48.0%) as a white solid. LCMS m / z = 482 [M+H]⁺

[0669] Step 2: Synthesis of 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cycloprop-1-ol

[0670] A solution of the compound from step 1 (524 mg, 1.09 mmol), H₂O₂ (74.01 mg, 2.18 mmol), and NaOH (87.03 mg, 2.18 mmol) in MeOH (10 mL) was stirred at 0 °C for 30 min. The reaction mixture was quenched with NaHCO₃ (0.5 mL) at 0 °C, and the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 30:1) to give the title compound (201 mg, 49.7%) as a white solid. LCMS m / z = 372 [M+H]⁺

[0671] Step 3: Synthesis of 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0672] DAST (95.41 mg, 0.59 mmol) was added fractionally to a stirred solution of the compound from step 2 (110 mg, 0.30 mmol) in DCM (5 mL) at -78 °C under N2, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (PE / EtOAc 5:1) to give the title compound (67 mg, 60.6%) as a yellow oil. LCMS m / z = 374 [M+H] +

[0673] Step 4: 6-Chloro-5-(1-fluorocyclopropyl)-1-(oxan-2-yl)indazole-4-ylboronic acid

[0674] A solution of the compound from step 3 (60 mg, 0.16 mmol), tetrahydroxydiborane (28.79 mg, 0.32 mmol), and TEA (65.0 mg, 0.64 mmol), along with CataCXium A Pd G3 (11.69 mg, 0.016 mmol), in MeOH (5 mL) was stirred at room temperature under N2 for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 30:1) to give the title compound (32 mg, 58.9%) as a yellow solid. LCMS m / z = 339 [M+H]+

[0675] Synthesis of 6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole (intermediate 42)

[0676]

[0677] Step 1: Synthesis of 4-bromo-6-chloro-5-cyclopropyl-1-(oxan-2-yl)indazole

[0678] 4-Bromo-6-chloro-5-iodo-1-(oxan-2-yl)indazole (2 g, 4.53 mmol), cyclopropylboronic acid (467 mg, 5.44 mmol), K3PO4 (2.88 g, 13.59 mmol), and Pd(dppf)Cl were added. 2.A mixture of CH2Cl2 (739.9 mg, 0.91 mmol) in dioxane (15 mL) and water (5 mL) was stirred at 100 °C under N2 for 2 hours. The mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:5), to give the title compound (0.52 g, 32.3%) as a white solid. LCMS m / z = 357 [M+H]+

[0679] Step 2: Synthesis of 6-chloro-5-cyclopropyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) Boronylcyclopentane-2-yl)inazole

[0680] Following the procedure described in intermediate 20, the title compound, 0.1 g, 23%, was obtained from the compound in step 1 as a colorless oil. LCMS m / z = 403 [M+H]+

[0681] Synthesis of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol (intermediate 43)

[0682]

[0683] Step 1: Synthesis of 4-bromo-6-methyl-1H-indazole-5-ol

[0684] NBS (6.61 g, 37.1 mmol) was added fractionally to a solution of 6-methyl-1H-indazole-5-ol (5.0 g, 33.7 mmol) in THF (100 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE:EtOAc = 1:0 to 1:1) to give the title compound (7.0 g, crude) as a brown solid. LCMS m / z = 227 [M+H]+

[0685] Step 2: Synthesis of 4-bromo-6-methyl-1-tetrahydropyran-2-yl-indazole-5-ol

[0686] At room temperature, a solution of DHP (5.19 g, 61.7 mmol) in DMF (5 mL) was slowly added to a solution of the compound from step 1 (7.00 g, 30.8 mmol) and TsOH (531 mg, 3.08 mmol) in DMF (50 mL). The resulting solution was stirred at room temperature for 14 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (300 mL × 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE:EtOAc = 1:0 to 3:1) and further purified by reversed-phase HPLC to give the title compound (3.60 g, 38%) as a yellow solid. LCMS m / z = 313 [M+H] +

[0687] Synthesis of (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (intermediate 44)

[0688]

[0689] Step 1: Synthesis of 4-bromo-6-(trifluoromethyl)-1H-indazole-5-amine

[0690] Following a procedure similar to that described in step 1 of intermediate 43, the title compound, 5.0 g (41%), was obtained from 6-(trifluoromethyl)-1H-indazole-5-amine as a yellow solid. LCMS m / z = 280 [M+H]+

[0691] Step 2: Synthesis of 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole

[0692] CuI (1.02 g, 5.36 mmol) and t-BuONO (570 mg, 5.53 mmol) were added to a solution of the compound from step 1 (500 mg, 1.79 mmol, 8 batches) in MeCN (10 mL), and the reaction mixture was stirred at 70 °C for 2 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, NH3•H2O (3 mL), PE:DCM / MeOH = 1 / 0 to 0 / 1, PE:EtOAc = 5:1), followed by re-purification by reversed-phase rapid column chromatography to give the title compound (1.10 g, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H).

[0693] Step 3: Synthesis of 4-bromo-5-iodo-1-tetrahydropyran-2-yl-6-(trifluoromethyl)indazole

[0694] Camphor-10-sulfonic acid (89.1 mg, 0.38 mmol) was added to a solution of the compound from step 2 (1.00 g, 2.56 mmol) and DHP (430 mg, 5.12 mmol) in THF (15 mL), and the reaction mixture was stirred at 70 °C for 12 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and then extracted with EtOAc (50 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (700 mg, 52%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33(s, 1H), 8.20 (s, 1H), 6.11 - 6.04 (m, 1H), 3.87 - 3.76 (m, 2H), 2.41 - 2.27(m, 1H), 2.01 (s, 2H), 1.82 - 1.70 (m, 1H), 1.60 - 1.53 (m, 2H).

[0695] Step 4: Synthesis of 4-bromo-5-cyclopropyl-1-tetrahydropyran-2-yl-6-(trifluoromethyl)indazole

[0696] The mixture of the compound from step 3 (100 mg, 0.21 mmol), cyclopropylboronic acid (27.1 mg, 0.32 mmol), Na₂CO₃ (33.4 mg, 0.32 mmol), and Pd(dppf)Cl₂ (15.4 mg, 21.0 μmol) in 2-MeTHF (1 mL) and H₂O (0.2 mL) was degassed and purged with N₂, and the reaction mixture was stirred at 100 °C under N₂ for 12 h. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 3). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, PE:EtOAc = 10:1) to give the title compound (30 mg, 34%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.20 (s, 1H), 6.10- 6.01 (m, 1H), 3.91 - 3.75 (m, 2H), 2.42 - 2.27 (m, 1H), 2.11 - 1.94 (m,3H), 1.83 - 1.68 (m, 1H), 1.65 - 1.51 (m, 2H), 1.19 - 1.09 (m, 2H), 0.76 (d,2H).

[0697] Step 5: Synthesis of (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl) boric acid

[0698] Following a procedure similar to that described in step 4 of intermediate 41, the title compound, 40 mg, crude substance, was obtained from the compound from step 4 and tetrahydroxydiboron as a yellow solid. LCMS m / z = 355 [M+H]+

[0699] Synthesis of (6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (intermediate 45)

[0700]

[0701] Step 1: Synthesis of 1,3-dioxoisoindoline-2-yl ester of 2-fluorocyclopropane-1-carboxylic acid

[0702] Dicyclohexylcarbodiimide (0.46 g, 2.24 mmol) and DMAP (3.76 g, 30.75 mmol) were added to a stirred mixture of 2-fluorocyclopropane-1-carboxylic acid (3.2 g, 30.75 mmol) and 2-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (5.52 g, 33.82 mmol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was extracted with DCM (10 mL). The combined organic layers were washed with NaHCO3 (3 × 10 mL) and NaHSO4 (10%), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (7.6 g) as a yellow solid. LCMS m / z = 250 [M+H]+

[0703] Step 2: Synthesis of 2-(2-fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0704] At room temperature under N2, tert-butyl pyridine-4-carboxylate (69.04 mg, 0.39 mmol) was added to a stirred solution of the compound from step 1 (7.61 g, 30.54 mmol) and bis(pinacol)diboron (8.53 g, 33.59 mmol) in EtOAc (100 mL). The resulting mixture was stirred overnight at 80 °C under N2. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20:1), to give the title compound (2.2 g, 38.7%) as a colorless oil. LCMS m / z = 205 [M+H]+

[0705] Step 3: Synthesis of 4-bromo-6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0706] Following a procedure similar to that described in step 1 of intermediate 41, the title compound, 120 mg, 23.6%, was obtained from the compound from step 2 and 4-bromo-6-chloro-5-iodo-1-(oxan-2-yl)inazole as a white solid. LCMS m / z = 373 [M+H]+

[0707] Step 4: Synthesis of (6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boron acid

[0708] CataCXium A Pd G3 (15.59 mg, 0.02 mmol) and K2CO3 (59.18 mg, 0.43 mmol) were added to a stirred solution of the compound from step 3 (80 mg, 0.214 mmol) and tetrahydroxydiborane (76.78 mg, 0.86 mmol) in MeOH (1.6 mL), and the reaction mixture was stirred at 40 °C under N2 for 1 hour. The resulting mixture was concentrated under vacuum to give the crude product of the title compound. LCMS m / z = 339 [M+H]+

[0709] Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(((R)-1-methylazacyclobutane-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine (intermediate 46)

[0710]

[0711] Step 1: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methanesulfonyl)-8,9-dihydro-10H-7- Oxa-1,3,6,10-tetraazacycloheptan[de]naphth-10-yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine- 2-amine

[0712] A solution of intermediate 33 (500 mg, 0.736 mmol) and m-CPBA (381.11 mg, 2.21 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1), to give the title compound (500 mg, 95.5%) as a yellow solid. LCMS m / z = 711 [M+H]+

[0713] Step 2: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(((R)-1-methylazacyclobutane-2- (I)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-5-fluoro- N,N-bis(4-methoxyphenylmethyl)pyridine-2-amine

[0714] LiOtBu (84.43 mg, 1.06 mmol) was added to a stirred solution of the compound from step 1 (250 mg, 0.35 mmol) and ((2R)-1-methylazacyclobutane-2-yl)methanol (42.67 mg, 0.42 mmol) in DCM (4 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (PE / EtOAc 1:1) to give the title compound (163 mg, 63.3%) as a yellow solid. LCMS m / z = 733 [M+H]+

[0715] Synthesis of 3-((R)-1-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-methyl-5-(tributyltinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (Intermediate 47)

[0716]

[0717] A mixture of intermediate 39 (260 mg, 0.12 mmol), bis(tributyltin) (587 mg, 0.39 mmol), Pd2(dba)3 (31 mg, 0.01 mmol), tricyclohexylphosphine (21 mg, 0.02 mmol), and LiCl (72 mg, 0.66 mmol) in dioxane (3 mL) was stirred at 110 °C under N2 for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc 1:2) to give the title compound (254 mg, 73.3%) as a pale yellow oil. LCMS m / z = 1028 [M+H]+

[0718] Synthesis of (R)-(1,2-dimethylpyrrolidone-2-yl)methanol (intermediate 48)

[0719]

[0720] Step 1: Synthesize (R)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-methyl ester

[0721] At 0℃, towards ( R1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) was dissolved in DMF (5 mL) and K₂CO₃ (904 mg, 6.54 mmol) was added, followed by the addition of MeI (0.18 mL, 2.84 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with ice-cold water (5 mL) and extracted with EtOAc (3 × 20 mL). The organic phase was washed with saturated NaCl (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 74.9%) as a pale yellow oil. LCMS m / z = 144 [M+H-Boc] + .

[0722] Step 2: Synthesis of (R)-(1,2-dimethylpyrrolidone-2-yl)methanol

[0723] At 0 °C, LiAlH4 (2 M in THF) (3.08 mL, 6.17 mmol) was added to a solution of the compound from step 1 (300 mg, 1.23 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 16 hours, then quenched with saturated Na2SO4 (3 mL) and diluted with DCM containing 5% MeOH (20 mL). The mixture was filtered through Celite® and washed with 5% MeOH / DCM (2 × 20 mL). The filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (155 mg, 82%) as a pale yellow oil. LCMS m / z = 130 [M+H] + .

[0724] Synthesis of 2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (intermediate 49)

[0725]

[0726] Step 1: Synthesis of ethyl 3-bromo-5-chloro-4-cyclopropylbenzoate

[0727] Following a procedure similar to that described in step 1 of intermediate 42, the title compound, 0.61 g (18.9%), was obtained from ethyl 3-bromo-5-chloro-4-iodobenzoate and cyclopropylboronic acid as a pale yellow solid. LCMS m / z = 305 [M+H] + .

[0728] Step 2: Synthesis of 3-bromo-5-chloro-4-cyclopropylbenzoic acid

[0729] LiOH·H₂O (0.96 g, 22.9 mmol) was added to a solution of the title compound (2.32 g, 7.64 mmol) in a mixture of THF (17.5 mL) and water (7.5 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (20 mL) and the pH was adjusted to 2 to 3 with HCl (1.5 N). The mixture was extracted with EtOAc (3 × 30 mL). The organic phase was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (2.1 g, 99%) as a grayish-white solid. LCMS m / z = 274 [(M+H)] +

[0730] Step 3: Synthesis of (3-bromo-5-chloro-4-cyclopropylphenyl)methanol

[0731] At 0 °C and under N2, a borane THF complex (15.2 mL, 15.2 mmol) was added to a solution of the title compound (2.1 g, 7.62 mmol) from step 2 in THF (21 mL). The reaction mixture was stirred at room temperature for 16 hours, followed by dilution with water (20 mL). The pH was adjusted to 2 to 3 with HCl (1.5 N) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.5 g, 74.8%) as a pale yellow solid. 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.52 (s, 1H), 7.37 (s, 1H), 5.38 (t, 1H), 4.45 (d, 2H), 1.99-1.73 (m, 1H), 1.18-1.12 (m, 2H), 0.65-0.55(m, 2H).

[0732] Step 4: Synthesis of 3-bromo-5-chloro-4-cyclopropylbenzaldehyde

[0733] Add pyridinium chlorochromate (494 mg, 2.29 mmol) to a solution of the title compound (400 mg, 1.53 mmol) in DCM (8 mL), and stir the reaction mixture at 0 °C for 1 hour. Dilute the mixture with DCM (10 mL) and pass it via Celite. ®The mixture was filtered and washed with DCM (3 × 20 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (0–100% EtOAc / hexane) to give the title compound (300 mg, 73.3%) as a pale yellow solid. 1 H-NMR (400 MHz, CDCl3): δ 9.90 (s,1H), 7.97 (d, 1H), 7.82 (d, 1H), 1.88-1.81 (m, 1H), 1.31-1.26 (m, 2H), 0.87-0.83 (m, 2H).

[0734] Step 5: Synthesis of 1-bromo-3-chloro-2-cyclopropyl-5-(difluoromethyl)benzene

[0735] At -78°C, DAST (0.46 mL, 3.47 mmol) was added to a solution of the title compound (300 mg, 1.16 mmol) from step 4 in DCM (6 mL). The reaction mixture was stirred at room temperature for 16 hours, then diluted with 10% NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (270 mg, 83%) as a pale brown oil. 1 H-NMR (400MHz, CDCl3): δ 7.63 (d, 1H), 7.47 (d, 1H), 6.70-6.42 (m, 1H), 1.83-1.78 (m,1H), 1.30-1.21 (m, 2H), 0.86-0.78 (m, 2H).

[0736] Step 6: Synthesis of 2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dichlorophenylpropanediol Oxyborane

[0737] Following a procedure similar to that described in intermediate 20, the title compound (200 mg, 66.5%), which was a pale yellow oil, was obtained from the compound from step 5. 1 H-NMR (400 MHz, DMSO- d 6): δ 7.58-7.56 (m,2H), 6.59 (t, 1H), 2.12-2.07 (m, 1H), 1.43 (s, 12H), 1.12-1.05 (m, 2H), 0.62-0.57 (m, 2H).

[0738] Example 1: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 101)

[0739]

[0740] Step 1: Synthesis of (S)-7-chloro-5-(3-methyl-2-(methylamino)butoxy)-2-(methylthio)pyrido[4,3- d]Pyrimidine-4(3H)-one

[0741] (2S)-3-methyl-2-(methylamino)but-1-ol (536.5 mg, 4.58 mmol) was added to a suspension of NaH (534.1 mg, 13.35 mmol, 60%) in THF (10 mL) at 0 °C under N2, and the mixture was stirred at 0 °C for 10 min. A solution of 5,7-dichloro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one (1 g, 3.82 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled and quenched with ice water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL), the combined organic layers were washed with brine (7 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in a 10% to 70% gradient over 10 minutes, yielding the title compound (650 mg, 50%) as a brown solid. LCMS m / z = 343 [M+H]+

[0742] Step 2: Synthesis of (S)-5-chloro-9-isopropyl-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1, 3,6,10-Tetraazacycloheptan[de]naphthalene

[0743] PyBOP (1.14 g, 2.19 mmol) and TEA (1.18 g, 11.7 mmol) were added to a solution of (S)-7-chloro-5-(3-methyl-2-(methylamino)butoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (500 mg, 1.46 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc 1:1) to give the title compound (400 mg, 84.4%) as a white solid. LCMS m / z = 325 [M+H]+

[0744] Step 3: Synthesis of (9S)-5-chloro-9-isopropyl-10-methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxo Hexa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0745] m-CPBA (106.3 mg, 0.62 mmol) was added to a solution of (S)-5-chloro-9-isopropyl-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (200 mg, 0.62 mmol) in DCM (6 mL) at -15 °C under N2, and the reaction mixture was stirred at -15 °C for 1 hour. The reaction mixture was quenched at 0 °C with saturated NaHSO3 (10 mL), and the mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound (200 mg, crude). LCMS m / z = 341 [M+H]+

[0746] Step 4: Synthesis of (S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)- 9-Isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0747] NaH (88.4 mg, 2.21 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (117.3 mg, 0.74 mmol) in anhydrous THF (2 mL) at 0 °C under N2, and the mixture was stirred at 0 °C for 10 min. A solution of (9S)-5-chloro-9-isopropyl-10-methyl-2-(methanesulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (200 mg crude) in THF (5 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase column chromatography (C18 silica gel, eluted with MeCN / water (10 mmol / L NH₄HCO₃) in a 10% to 70% gradient over 10 minutes) to give the title compound (70 mg, 21.2%) as a white solid. LCMS m / z = 436 [M+H] +

[0748] Step 5: Synthesis of (S)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene- 1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9, 10-Dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0749] (S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (70 mg, 0.16 mmol), cataCXium-A-Pd-G3 (23.4 mg, 0.032 mmol), K3PO4 (102.3 mg, 0.48 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (164.6 mg, 0.32 mmol) in dioxane / H2O (6 The mixture in mL (v / v = 5:1) was stirred at 60 °C under N2 for 2 hours. The cooled mixture was diluted with water (3 mL), extracted with DCM (10 × 5 mL), and the combined organic layers were washed with brine (10 × 3 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give the title compound (130 mg, 96.9%) as a yellow solid. LCMS m / z = 786 [M+H]+

[0750] Step 6: Synthesis of 6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy (-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)-5- ((triisopropylsilyl)ethynyl)naphth-2-phenol

[0751] A solution of (S)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (70 mg, 0.089 mmol) in dioxane (2 mL) containing 4 N HCl was stirred at room temperature under N2 for 3 hours. The resulting mixture was evaporated under reduced pressure to give the title compound (60 mg, crude). LCMS m / z = 742 [M+H]+

[0752] Step 7: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane [de]naphthyl-5-yl)naphthyl-2-phenol

[0753] CsF (194.5 mg, 1.28 mmol) was added to a solution of 6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-phenol (95 mg, 0.128 mmol) in anhydrous DMF (2 mL), and the reaction mixture was stirred at room temperature under N2 for 2 hours. The reaction mixture was concentrated under vacuum and purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (0.1% FA) in a 10- to 50% gradient over 10 minutes, to give the title compound (28.4 mg, 37.5%) as a grayish-white solid. LCMS m / z = 586 [M+H]+ 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.33 (s, 1H), 10.22 (d, 1H), 7.94 (dd, 1H), 7.45(t, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 4.81 (ddd, 1H), 4.63 (dq,2H), 4.43 (dd, 1H), 3.81 (dt, 5H), 3.45 (s, 3H), 2.64 - 2.52 (m, 1H), 2.48(s, 1H), 2.31 (dd, 1H), 2.26 - 2.00 (m, 4H), 1.01 (td, 6H).

[0754] Example 2: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 103)

[0755]

[0756] Step 1: Synthesis of (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-((7-chloro-2-(methylthio)-4-oxy) 3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)but-2-yl)methyl)tert-butyl carbamate

[0757] Following the procedure described in step 1 of Example 1, the title compound, 209 mg, 7.7%, was obtained from 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (intermediate 1) and (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)(methyl)carbamate tert-butyl ester (intermediate 7) as a white solid.

[0758] Step 2: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7-chloro- 2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0759] TFA (5 mL) was added to a stirred solution of (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-((7-chloro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)but-2-yl)(methyl)carbamate (300 mg, 0.44 mmol) in DCM (20 mL), and the reaction mixture was stirred at room temperature under N2 for 1 hour. The resulting mixture was evaporated under reduced pressure to give the title compound (400 mg crude) as a yellow oil. LCMS m / z = 583 [M+H]+

[0760] Steps 3 to 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan[de]naphthalene

[0761] The title compound was obtained from (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7-chloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol, following the same three-step procedure described in steps 2 to 4 of Example 1. LCMS m / z = 676 [M+H]+

[0762] Step 6: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-3-(methoxy) methoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0763] Following a procedure similar to that described in step 5 of Example 1, the title compound, 30 mg, 98.8%, was obtained from (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane as a yellow oil. [M+H]+

[0764] Step 7: Synthesis of 2-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan(de)naphth-9-yl)ethyl-1-ol

[0765] Following a procedure similar to that described in step 7 of Example 1, the title compound was obtained as a white solid from (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene, 15 mg, 81.3%. LCMS m / z = 632 [M+H]+

[0766] Step 8: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane [de]naphthyl-5-yl)naphthyl-2-phenol

[0767] To a solution of 2-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphth-9-yl)ethanol-1-ol (15 mg, 0.024 mmol) in DCM (2 mL), dioxane (5 mL) containing 4N HCl was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum at room temperature, and the crude product was purified by preparative HPLC (Method A, 23% to 48% B within 8 minutes) to give the title compound (3.6 mg, 25.5%) as a white solid. LCMS m / z = 588 [M+H] + . 1H NMR (400 MHz, DMSO- d 6) δ 10.06(s, 2H), 7.92 (dd, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 7.21 - 7.04 (m, 1H), 7.02(s, 1H), 5.28 (d, 2H), 4.74 (t, 1H), 4.72 - 4.53 (m, 1H), 4.43 (d, 1H), 4.20 - 3.88 (m, 4H), 3.56 (d, 2H), 3.17 - 3.05 (m, 2H), 3.02 (s, 1H), 2.83 (q,1H), 2.12 (d, 1H), 2.02 (d, 2H), 1.92 - 1.64 (m, 5H).

[0768] Example 3: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphth-9-yl)propionitrile (Compound 105)

[0769]

[0770] Step 1: Synthesis of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy 10-Methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)ethyl-1-ol

[0771] CsF (336.9 mg, 2.22 mmol) was added to a solution of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (Example 2, step 5) (150 mg, 0.22 mmol) in anhydrous DMF (7.50 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was purified by C18 silica gel reversed-phase column chromatography, eluting with MeCN:water (10 mmol / NH4HCO3) in a 10-minute gradient from 10% to 50%, to give the title compound (80 mg, 82.4%) as a white solid. LCMS m / z = 438 [M+H]+

[0772] Step 2: Synthesis of methanesulfonic acid 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- (methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)ethyl ester

[0773] Methanesulfonic anhydride (23.87 mg, 0.137 mmol) was added dropwise to a solution of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)ethanol-1-ol (40 mg, 0.09 mmol) and TEA (37.0 mg, 0.36 mmol) in DCM (4 mL) at 0 °C under N2, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (2 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give the title compound, 46 mg, crude substance. LCMS m / z = 516 [M+H]⁺

[0774] Step 3: Synthesis of 3-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy 10-Methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)propionitrile

[0775] KCN (42.3 mg, 0.65 mmol) was added to a solution of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)ethyl ester (46 mg, 0.09 mmol) and KI (119.6 mg, 0.72 mmol) in DMSO (4 mL), and the reaction mixture was stirred at 100 °C for 2 h. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated FeSO4 to remove excess KCN, followed by washing with brine (3 × 10 mL), drying with Na2SO4, and concentrating under vacuum. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (10 mmol / L NH4CO3) in a 10-minute gradient from 10% to 50%, yielding the title compound (23 mg, 57.7%) as a white solid. LCMS m / z = 447 [M+H]+

[0776] Step 4: Synthesis of 3-((S)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphth-9-yl)propionitrile

[0777] Following a procedure similar to that described in step 5 of Example 1, the title compound, a brown solid, was obtained from 3-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane[de]naphthyl-9-yl)propionitrile and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)naphthyl)ethynyl)triisopropylsilane, 30 mg, 84.1%. LCMS m / z = 797 [M+H]+

[0778] Step 5: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan[de]naphthyl-9-yl)propionitrile

[0779] Following the procedure described in step 1, the title compound was obtained as a white solid from 3-((S)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphth-9-yl)propionitrile. LCMS m / z = 641 [M+H]+

[0780] Step 6: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-2-(((2R,7aS)-2-fluorotetrafluoro Hydrogen-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclo Heptanonaphthyl-9-yl)propionitrile

[0781] TFA (1 mL) was added dropwise to a solution of 3-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphth-9-yl)propionitrile (18 mg, 0.028 mmol) in DCM (5 mL), and the reaction mixture was stirred at 0 °C for 1.5 h. The mixture was concentrated under vacuum and the crude product was purified by preparative HPLC (Method C, gradient: 15% to 30% B over 8 minutes) to give the title compound (4.5 mg, 26.3%) as a white solid. LCMS m / z = 596 [M+H]+. 1 H NMR (400 MHz, DMSO- d6) δ 10.77 (s,1H), 10.13 (d, 1H), 7.94 (dd, 1H), 7.45 (t, 1H), 7.33 (d, 1H), 7.13 (d, 2H),5.58 (d, 1H), 4.86 - 4.65 (m, 1H), 4.58 (q, 2H), 4.45 (dd, 1H), 4.15 - 4.04(m, 1H), 4.06 - 3.88 (m, 2H), 3.81 (d, 3H), 2.74 (dd, 2H), 2.29 (s, 1H), 2.27- 2.10 (m, 2H), 2.02 (q, 3H).

[0782] Example 4: Synthesis of 5-ethyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 104)

[0783]

[0784] Step 1: Synthesis of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan(de)naphth-9-yl)ethyl-1-ol

[0785] 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-9-yl)ethanol-1-ol (Example 3, Step 1) (20 mg, 0.046 mmol), cataCXium A Pd G3 (6.65 mg, 0.009 mmol), K3PO4 (38.78 mg, 0.184 mmol), and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (24.7 mg, 0.069 mmol) were placed in dioxane (3 mL) and H2O (0.3 mL). The mixture in mL was stirred at 100 °C under N2 for 1 hour. The cooled mixture was concentrated under vacuum and the residue was purified by reversed-phase column chromatography (C18 silica gel, eluted with MeCN / water (10 mmol / L NH4HCO3) in 10-minute gradients from 10% to 50%) to give the title compound (23 mg, 79.2%) as a white solid. LCMS m / z = 636 [M+H]+

[0786] Step 2: Synthesis of 5-ethyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- (2-hydroxyethyl)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de] (Naphthalene-5-yl)naphthyl-2-phenol

[0787] TFA (0.2 mL) was added dropwise to a solution of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphth-9-yl)ethanol-1-ol (30 mg, 0.047 mmol) in DCM (1 mL), and the reaction mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Method A, gradient: 27% to 52% B over 7 minutes) to give the title compound (6.5 mg, 22.7%) as a white solid. LCMS m / z = 592 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 9.88 (s, 1H),7.80 - 7.56 (m, 1H), 7.39 - 7.13 (m, 2H), 7.19 - 6.79 (m, 2H), 5.45 - 5.11(m, 1H), 4.88 - 4.56 (m, 2H), 4.48 (d, 1H), 4.22 - 4.06 (m, 2H), 3.99 (d,1H), 3.55 (s, 2H), 3.16 - 2.94 (m, 3H), 2.90 - 2.72 (m, 1H), 2.46 - 2.25 (m,1H), 2.14 (ddd, 2H), 2.09 - 1.93 (m, 2H), 1.95 - 1.36 (m, 5H).

[0788] Example 5: Synthesis of 2-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphth-10-yl)ethanol (Compound 106)

[0789]

[0790] Steps 1 and 2: Synthesis of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7- Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0791] Following the same two-step procedure described in steps 1 and 2 of Example 2, the title compound was obtained from tert-butyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate (intermediate 2) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one. LCMS m / z = 587 [M+H]+

[0792] Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 9,10-Dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0793] TEA (499.8 mg, 4.94 mmol) and PyBOP® (771.1 mg, 1.48 mmol) were added to a solution of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (580 mg, 0.99 mmol) in DCM (10 mL), and the reaction mixture was stirred overnight at room temperature under N2. The reaction mixture was concentrated under vacuum and the residue was purified by preparative TLC (DCM / MeOH 20:1) to give the title compound (230 mg, 40.9%) as a brown solid. LCMS m / z = 569 [M+H] +

[0794] Steps 4 to 6: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-3-(methyl) (2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0795] The title compound was obtained from 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane. LCMS m / z = 1030 [M+H]+

[0796] Steps 7 and 8: Synthesis of 2-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10- Tetraazacycloheptan(de)naphth-10-yl)ethanol

[0797] Following a two-step procedure similar to that described in steps 5 and 6 of Example 3, the title compound was obtained as a white solid from 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene. LCMS m / z = 592 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 10.18 (s, 1H), 7.97 (dd, 1H), 7.46 (t, 1H), 7.38(d, 1H), 7.15 (d, 1H), 5.55 (d, 1H), 4.90 (t, 1H), 4.57 (s, 3H), 4.15 - 3.98(m, 4H), 3.88 - 3.66 (m, 5H), 2.30 (s, 2H), 2.09 (d, 4H), 1.35 - 1.12 (m,1H).

[0798] Example 6: Synthesis of 5-ethyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 113)

[0799]

[0800] Steps 1 and 2: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7- Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate

[0801] The title compound was obtained from 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one and (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybut-2-yl)(methyl)carbamate tert-butyl ester (intermediate 7) following the same two-step procedure as described in steps 1 and 2 of Example 2. LCMS m / z = 601 [M+H]+

[0802] Step 3: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl- 2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0803] PyBOP (233.7 mg, 0.45 mmol) was added to a solution of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate (180 mg, 0.30 mmol) and TEA (151.5 mg, 1.5 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature under N2 for 5 hours. The reaction mixture was quenched with water and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by elution with PE / EtOAc (5:1) on a silica gel column to give the title compound (100 mg, 57.3%) as a white solid. LCMS m / z = 583 [M+H]+

[0804] Step 4: Synthesis of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl 2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0805] Following the procedure described in step 3 of Example 1, the title compound was obtained from (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene. LCMS m / z = 599 [M+H] +

[0806] Step 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan[de]naphthalene

[0807] A solution of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl-2-(methanesulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (50 mg, 0.083 mmol) and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol (39.9 mg, 0.25 mmol) in toluene (1 mL) was stirred at room temperature under N2 for 30 min, followed by cooling in an ice bath. Sodium tert-butoxide (16.04 mg, 0.166 mmol) was added, and the reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with ice water (5 mL) at 0 °C, and the mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1), to give the title compound (30 mg, 51.8%) as a white solid. LCMS m / z = 694 [M+H]+

[0808] Step 6: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthyl-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy 10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane[de]naphthalene

[0809] (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (25 mg, 0.036 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane (25.94 mg, 0.072 mmol), K3PO4 (22.93 mg, 0.108 mmol), and cataCXium-A-Pd-G3 (2.10 mg, 0.003 mmol) were prepared in dioxane / H2O. The mixture in (6 mL, v / v = 5:1) was stirred at 100 °C under N2 for 1 hour. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (15:1), to give the title compound (20 mg, 62.3%) as a white solid. LCMS m / z = 892 [M+H]+

[0810] Step 7: Synthesis of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-Tetraazacycloheptan(de)naphth-9-yl)ethyl-1-ol

[0811] CsF (42.57 mg, 0.28 mmol) was added to a solution of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (25 mg, 0.028 mmol) in DMF (1 mL), and the reaction mixture was stirred at 60 °C under N2 for 30 min. The cooled reaction mixture was purified directly by C18 silica reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in a 60% to 70% gradient over 10 minutes, to give the title compound (10 mg, 54.%) as a white solid. LCMS m / z = 654 [M+H]+

[0812] Step 8: Synthesis of 5-ethyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane [de]naphthyl-5-yl)naphthyl-2-phenol

[0813] TFA (0.2 mL) was added to a solution of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphth-9-yl)ethanol-1-ol (10 mg, 0.015 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature under N2 for 30 min. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC (Method B, gradient: 20% B to 35% B over 7 minutes) to give the title compound (1.0 mg, 9.0%) as a yellow solid. LCMS m / z = 610 [M+H]+. 1 H NMR (400 MHz, DMSO- d 6) δ 10.02 - 9.93(m, 1H), 7.75 (dd, 1H), 7.39 - 7.29 (m, 1H), 4.75 - 4.52 (m, 2H), 4.52 - 4.43(m, 1H), 2.19 (d, 2H), 2.05 (d, 1H), 1.80 (d, 1H), 1.24 (s, 1H), 0.80 (dt, 2H).

[0814] Example 7: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 102)

[0815]

[0816] Step 1: Synthesis of (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-((7-chloro-2-(methylthio)-4-oxy) 3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)tert-butyl carbamate

[0817] (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate, intermediate 2 (2 g, 4.51 mmol), was added to a suspension of NaH (378.6 mg, 15.78 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred for 15 min. A solution of 5,7-dichloro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one, intermediate 1 (1.18 g, 4.51 mmol), in THF (2 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at 60 °C under N2 for 1 h. The cooled reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude compound was purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (0.1% TFA) in a 10% to 50% gradient over 10 minutes, yielding the title compound (800 mg, 26.5%) as a white oil. LCMS m / z = 670 [M+H]+

[0818] Step 2: Synthesis of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro- 2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate

[0819] TFA (2.67 mL, 35.9 mmol) was added to a solution of (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-((7-chloro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)carbamate (800 mg, 1.2 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature under N2 for 0.5 h. The mixture was evaporated under reduced pressure to give 600 mg of the crude title compound. LCMS m / z = 570 [M+H]+

[0820] Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylthio)-9,10- Dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0821] TEA (231.1 mg, 2.29 mmol) and PyBOP® (356.6 mg, 0.69 mmol) were added to a solution of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate (260 mg, 0.457 mmol) in DCM (5 mL), and the reaction mixture was stirred overnight at room temperature under N2. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH 20:1) to give the title compound (170 mg, 67.5%) as a brown solid. LCMS m / z = 551 [M+H]+

[0822] Step 4: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylsulfinyl)- 9,10-Dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0823] m-CPBA (13.3 mg, 0.54 mmol) was added to a solution of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (300 mg, 0.544 mmol) in DCM (10 mL) at -15 °C, and the reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with Na₂SO₃ solution and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, and evaporated under reduced pressure to give the title compound (200 mg, 64.8%) as a brown solid. LMS m / z = 267 [M+H]+

[0824] Step 5: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane [de]Naphthalene

[0825] (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (61.75 mg, 0.39 mmol) was added to a suspension of NaH (25.4 mg, 1.06 mmol) in anhydrous THF (5 mL) at 0 °C, and the mixture was stirred at 0 °C under N2 for 15 min. A solution of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methanesulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (200 mg, 0.35 mmol) in THF (2 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (5 mL) at 0 °C, followed by extraction with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH 20:1) to give the title compound (100 mg, 77.9%) as a white solid. LCMS m / z = 662 [M+H]⁺

[0826] Step 6: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-8-((triisopropyl) Silyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0827] The following were added: 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (70 mg, 0.11 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-yl)oxy)triisopropylsilane (132.1 mg, 0.212 mmol), cataCXium-A-Pd-G3 (15.40 mg, 0.021 mmol), and K3PO4 (67.31 mg, 0.318 mmol). A mixture of [M+H]+ in dioxane / H2O (5 mL, v / v = 4:1) was stirred at 80 °C under N2 for 1 h. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 20:1) to give the title compound (75 mg, 63.1%) as a brown solid. LCMS m / z = 1124 [M+H]+

[0828] Step 7: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) (methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl) Naphthalene-2-phenol

[0829] A mixture of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene (70 mg, 0.062 mmol) and CsF (94.5 mg, 0.62 mmol) in anhydrous DMF (2 mL) was stirred at 60 °C under N2 for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC (Method C, gradient: 15% to 30% B over 7 minutes) to give the title compound (12.6 mg, 24.0%) as a white solid. LCMS m / z = 574 [M+H]+. 1 H NMR (400 MHz, DMSO-) d6) δ 10.36 - 10.59 (s, 1H), 8.15 (s, 1H), 7.92 (dd, 1H), 7.43(t, 1H), 7.31 (d, 1H), 5.29 (d, 1H), 4.88 (s, 1H), 4.64 - 4.41 (m, 3H), 4.14- 3.92 (m, 8H), 3.85 - 3.65 (m, 6H), 3.17 - 3.07 (m, 4H), 3.03 (s, 3H), 2.93- 2.78 (m, 2H), 2.19 - 1.90 (m, 4H), 1.90 - 1.69 (m, 4H).

[0830] Examples 8 to 13

[0831] Following a 7-step procedure similar to that described in Example 7, the compounds in Table 2 were obtained from a suitable 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, a suitable alcohol, ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol.

[0832] Table 2.

[0833]

[0834]

[0835]

[0836] Example 14: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 114)

[0837]

[0838] Steps 1 to 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- Tetraazacycloheptan[de]naphthalene

[0839] Following a five-step procedure similar to that described in steps 1 to 5 of Example 7, the title compound was obtained in solid form from 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, i.e., intermediate 8, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol. LCMS m / z = 680 [M+H]+

[0840] Steps 6 and 7: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azine-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan [de]naphthyl-5-yl)naphthyl-2-phenol

[0841] Following a two-step procedure similar to that described in steps 6 and 7 of Example 7, the title compound, a grayish-white solid, was obtained from the compound from steps 1 to 5 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 592 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (dd, 1H), 7.95 (dd, 1H), 7.45 (t,1H), 7.36 (d, 1H), 7.16 (dd, 1H), 5.44 - 5.16 (m, 1H), 4.46 (d, 2H), 4.17 -3.86 (m, 4H), 3.61 (d, 2H), 3.13 - 2.93 (m, 3H), 2.89 - 2.63 (m, 2H), 2.13 -1.92 (m, 3H), 1.87 - 1.68 (m, 5H).

[0842] Example 15: Synthesis of 3-((S)-5-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphth-10-yl)propionamide (Compound 178)

[0843]

[0844] Step 1: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10- Tetraazacycloheptan[de]naphthyl-10-yl)propionitrile

[0845] To the stirred mixture of Steps 1 to 5 of Example 14 (230 mg, 0.34 mmol) and acrylonitrile (26.9 mg, 0.51 mmol) in DCM (5 mL), phenylmethyltrimethylammonium hydroxide (11.31 mg, 0.07 mmol) was added, and the reaction mixture was stirred at room temperature under N2 for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM / MeOH = 12:1) to give the title compound (150 mg, 54.5%) as a grayish-white solid. LCMS m / z = 733 [M+H]+

[0846] Step 2: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10- Tetraazacycloheptan[de]naphth-10-yl)propionamide

[0847] The mixture of the compound from step 1 (30 mg, 0.041 mmol) and Parkin's catalyst (3.50 mg, 0.008 mmol) in EtOH (1 mL) was stirred at 80 °C under N2 for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH = 10:1) to give the title compound (20 mg, 59.9%) as a brown solid. LCMS m / z = 752 [M+H]+

[0848] Step 3: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro) 3-(methoxymethoxy)naphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-10-yl)propionamide

[0849] Following a procedure similar to that described in step 6 of Example 7, the title compound, 25 mg, 41.8%, was obtained from the compound from step 2 and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane in solid form.

[0850] Step 4: Synthesis of 3-((S)-5-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluoro) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-te ... Aza-hepta-[de]naphth-10-yl)propionamide

[0851] Dioxane containing HCl (1 mL) was added to a mixture of the compound from step 3 (30 mg, 0.032 mmol) in DCM (0.2 mL), and the reaction mixture was stirred at room temperature under N2 for 1 hour. The resulting mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC (Method D, gradient: 11% B to 33% B over 7 minutes) to give the title compound (3.1 mg, 11.8%) as a grayish-white solid. LCMS m / z = 713 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, 1H), 7.45 - 7.28 (m, 2H), 7.03 (dd, 1H), 5.66 - 5.23 (m, 2H),4.69 - 4.65(m, 1H), 4.39 - 4.35 (m, 2H), 4.33 - 4.22 (m, 3H), 3.76 - 3.57 (m,3H), 3.46 - 3.17 (m, 3H), 2.98 - 2.93 (m, 1H), 2.87 - 2.71 (m, 1H), 2.63 -2.60 (m, 1H), 2.45 - 2.41 (m, 2H), 2.35 - 2.27 (m, 1H), 2.24 - 2.18 (m, 2H), 2.11 - 2.02 (m, 2H), 2.98 - 2.02 (m, 3H), 1.85 - 1.72 (m, 2H), 1.51 - 1.40 (m, 1H).

[0852] Example 16: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphth-5-yl)naphth-2-phenol carbamate (Compound 146)

[0853]

[0854] Steps 1 to 3: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2-(methylimide) (sulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthalene

[0855] Following a three-step procedure similar to that described in steps 1 to 3 of Example 1, the title compound, a white solid, was obtained from intermediate 11 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one. LCMS m / z = 599 [M+H]+

[0856] Step 4: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraaza Cyclohepta-naphthalene

[0857] A solution of the compounds from steps 1 to 3 (0.36 g, 0.60 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.29 g, 1.80 mmol) in toluene (5 mL) was stirred at room temperature under N2 for 30 min, followed by cooling to 0 °C. NaOtBu (0.12 g, 1.20 mmol) was added, and the reaction mixture was stirred again at 0 °C for 30 min. The resulting mixture was diluted with brine and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica reversed-phase column chromatography, eluting with MeCN:water (10 mmol NH4CO3) in a 60% to 70% gradient over 10 minutes, to give the title compound (0.176 g, 42.2%) as a white solid. LCMS m / z = 694 [M+H]+

[0858] Step 5: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-4-fluoro-5-(7-fluoro-8-((triisocyanate)) propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0859] To a stirred solution of the compound from step 4 (0.176 g, 0.25 mmol) and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane (237.6 mg, 0.38 mmol) in dioxane (4 mL) and H₂O (1 mL), K₃PO₄ (161.4 mg, 0.76 mmol) and cataCXium-A-Pd-G₃ (18.46 mg, 0.025 mmol) were added, and the reaction mixture was stirred at 80 °C under N₂ for 1 hour. The cooled mixture was diluted with brine and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH:DCM (1:20) to give the title compound (0.22 g, 74.7%) as a grayish-white solid. LCMS m / z = 615 [M+H]+

[0860] Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-(3-hydroxypropyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de] Naphthyl-5-yl)naphthyl-2-phenol carboxylate

[0861] At room temperature under N2, CsF (0.43 g, 2.84 mmol) was added fractionally to a stirred solution of the compound from step 5 (0.22 g, 0.19 mmol) in DMF (2 mL). The resulting mixture was stirred at 60 °C under N2 for 1 hour, then cooled to room temperature. The resulting mixture was diluted with brine and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (Method D, gradient: 15% B to 30% B over 7 minutes) to give the title compound (32.7 mg, 26.5%) as a grayish-white solid. LCMS m / z = 597 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.15 (br s, 1H), 8.15 (s, 1H), 7.96 (dd, 1H), 7.46 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.39 -5.18 (m, 1H), 4.53 (t, 2H), 4.18 - 3.74 (m, 7H), 3.51 (t, 2H), 3.17 - 2.98(m, 3H), 2.89 - 2.78 (m, 1H), 2.18 - 1.94 (m, 3H), 1.92 - 1.70 (m, 5H).

[0862] Example 17: Synthesis of 4-((S)-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptannaphth-5-yl)-5-ethynyl-6-fluoronaphth-2-phenol (Compound 138)

[0863]

[0864] Following a six-step method similar to that described in Example 16, the title compound, in the form of a white solid, was obtained from intermediate 14, 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one, ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol. LCMS m / z =620 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.95 (dd, 1H), 7.46 (d,1H), 7.36 (d, 1H), 7.19 (d, 1H), 5.39 - 5.17 (m, 1H), 4.84 - 4.57 (m, 2H), 4.38 - 4.19 (m, 2H), 4.19 - 3.92 (m, 4H), 3.55 (t, 3H), 3.16 - 2.96 (m, 3H), 2.84 (td, 1H), 2.19 - 1.93 (m, 3H), 1.91 - 1.68 (m, 5H), 1.36 - 1.19 (m, 3H).

[0865] Example 18: Synthesis of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 119)

[0866]

[0867] Steps 1 to 3: Synthesis of (9R)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-9- Methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0868] Following a three-step procedure similar to that described in steps 1 to 3 of Example 1, the title compound, a white solid, was obtained from intermediate 10 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one. LCMS m / z = 599 [M+H]+

[0869] Step 4: Synthesis of (R)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1, 3,6,10-Tetraazacycloheptan[de]naphthalene

[0870] A solution of the compounds from steps 1 to 3 (1.36 g, 2.27 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.72 g, 4.54 mmol) in toluene (20 mL) was stirred at room temperature under N2 for 30 min. NaOtBu (0.65 g, 6.81 mmol) was added at 0 °C, and the resulting mixture was stirred at 0 °C under N2 for 10 min. The reaction mixture was quenched with water. The aqueous layer was extracted with DCM (3 × 30 mL), the combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (400 mg, 25.4%) as a white solid. LCMS m / z = 694 [M+H]+

[0871] Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azine-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraaza Cyclohepta[de]naphth-5-yl)naphth-2-phenol

[0872] Following a two-step procedure similar to that described in steps 5 and 6 of Example 16, the title compound, which is a yellow solid, is obtained from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 668 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.95 (dd, 1H), 7.45 (td, 1H), 7.36 (d, 1H), 7.15 (dd, 1H), 5.21(d,1H), 4.88 (s, 1H), 4.55 (td, 1H), 4.41 (dd, 1H), 4.21 (dt, 3H), 4.12 - 3.95 (m, 4H), 3.91 - 3.73 (m, 2H), 3.13 -2.99 (m, 3H), 2.84 (q, 1H), 2.17 - 1.94 (m, 3H), 1.80 (dt, 2H), 1.28 (d, 3H).

[0873] Example 19: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 120)

[0874]

[0875] Step 1: Synthesis of (S)-5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)propoxy)-7- Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0876] NaH (2.35 g, 58.7 mmol, 60%) was slowly added to a solution of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)prop-1-ol (intermediate 3, step 1, 7 g, 19.6 mmol) in THF (100 mL) at 0 °C, and the mixture was stirred at 0 °C under N2 for 10 min. THF (20 mL) containing 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one (10.97 g, 39.2 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (column, C18 silica gel; mobile phase, MeOH / water (0.1% TFA), 95% to 100% gradient over 10 minutes) to give the title compound (4.6 g, 39.1%) as a white solid. LCMS m / z = 601 [M+H]+

[0877] Steps 2 to 4: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1, 3,6,10-Tetraazacycloheptan[de]naphthalene

[0878] Following a two-step procedure similar to that described in steps 2 through 4 of Example 18, the title compound, a white solid, was obtained from the compound from step 1 and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol. LCMS m / z = 694 [M+H]+

[0879] Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azine-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraaza Cyclohepta[de]naphth-5-yl)naphth-2-phenol

[0880] Following a two-step procedure similar to that described in steps 5 and 6 of Example 18, the title compound, a white solid, was obtained from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 606 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.95 (dd, 1H), 7.52 - 7.31 (m,2H), 7.15 (dd, 1H), 5.40 - 5.16 (m, 1H), 4.55 (td, 1H), 4.41 (dd, 1H), 4.28 -4.16 (m, 2H), 4.11 (dd, 1H), 4.07 - 3.93 (m, 2H), 3.91 - 3.74 (m, 2H), 3.68(dd, 1H), 3.58 (dt, 2H), 3.16 - 3.07 (m, 3H), 3.03 (s, 1H), 2.84 (q, 1H), 2.18 - 1.94 (m, 2H), 1.91 - 1.66 (m, 2H), 1.28 (d, 3H).

[0881] Example 20: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 145)

[0882]

[0883] Step 1: Synthesis of (S)-5-(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)propoxy)-7- Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0884] Following a procedure similar to that described in step 1 of Example 1, the title compound, 3 g, 90.6%, was obtained from intermediate 12 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one as a yellow solid. LCMS m / z = 631 [M+H]+

[0885] Step 2: Synthesis of (S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-9-methyl 2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0886] Except for purification of the residues by reversed-phase chromatography (column, C18; mobile phase, MeCN / water (0.1% TFA), 10% to 100% gradient over 30 minutes), following a procedure similar to that described in step 2 of Example 1, the title compound was obtained as a white solid, 560 mg, 57.7%. LCMS m / z = 597 [M+H]+

[0887] Step 3: Synthesis of (9S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-9-methyl 2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0888] Following the procedure described in step 4 of Example 7, the title compound, 830 mg, 89.8%, was obtained as a yellow solid from the compound from step 2. LCMS m / z = 613 [M+H]+

[0889] Step 4: Synthesis of (S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1, 3,6,10-Tetraazacycloheptan[de]naphthalene

[0890] Except for reversed-phase chromatography (column, C18; mobile phase, MeCN / water (0.1% TFA), 10% to 100% gradient over 10 minutes), a procedure similar to that described in step 4 of Example 16 was followed, yielding the title compound as a white solid, 135 mg, 14.3%, from ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol and the compound from step 3. LCMS m / z = 708 [M+H]+

[0891] Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azine-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraaza Cyclohepta[de]naphth-5-yl)naphth-2-phenol carboxylate

[0892] Following a two-step procedure similar to that described in steps 5 and 6 of Example 16, the title compound, a white solid, was obtained from the compound from step 4 and tert-butyl((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6-((triisopropylsilyl)oxy)naphth-1-yl)ethynyl)diphenylsilane. LCMS m / z = 620 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.96 (dd, 1H), 7.46 (td,1H), 7.37 (d, 1H), 7.15 (dd, 1H), 5.28 (d, 1H), 4.80 - 4.48 (m, 2H), 4.37(dd, 1H), 4.29 - 3.93 (m, 5H), 3.50 (d, 3H), 3.19 - 2.94 (m, 3H), 2.83 (t,1H), 2.19 - 1.62 (m, 8H), 1.37 - 1.09 (m, 3H).

[0893] Example 21: Synthesis of 4-((S)-9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl)-5-ethynyl-6-fluoronaphthyl-2-phenol (Compound 144)

[0894]

[0895] Step 1: Synthesis of (S)-5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-2-cyclopropyl ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0896] Following a procedure similar to that described in step 1 of Example 19, the title compound, a yellow solid, was obtained from intermediate 13 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one, at a concentration of 30.6% (100 mg). LCMS m / z = 627 [M+H] +

[0897] Step 2: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- Fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthalene

[0898] PyBOP® (311.1 mg, 0.6 mmol) was added dropwise to a stirred mixture of the compound from step 1 (250 mg, 0.4 mmol) and TEA (201.7 mg, 2.0 mmol) in DCM (3 mL) at 0 °C under N2. The reaction mixture was irradiated with microwave at 0 °C for 15 hours. The resulting mixture was extracted with EtOAc (2 × 20 mL), the combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give the title compound (210 mg) as a grayish-white solid. LCMS m / z = 609 [M+H]+

[0899] Step 3: Synthesis of (9S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- Fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthalene

[0900] Following the procedure described in step 3 of Example 1, the title compound was obtained from the compound from step 2. LCMSm / z = 625 [M+H]+

[0901] Step 4: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3, 6,10-Tetraazacycloheptan[de]naphthalene

[0902] A solution of the compound from step 3 (190 mg, 0.3 mmol) in toluene (9.50 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (193.5 mg, 1.22 mmol) was stirred at room temperature under N2 for 30 min. NaOtBu (58.4 mg, 0.61 mmol) was added fractionally at 0 °C, and the reaction mixture was irradiated with microwave at 0 °C for 10 min. The mixture was extracted with EtOAc (2 × 30 mL), the combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 3:1) to give the title compound (150 mg, 68.5%) as a white solid. LCMS m / z = 720 [M+H]+

[0903] Step 5: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-9-cyclopropyl-4-fluoro-5- (7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrafluoro) Hydrogen-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de] Naphthalene

[0904] Following a procedure similar to that described in step 5 of Example 16, the title compound, 95 mg, was obtained as a yellow solid from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 1070 [M+H]+

[0905] Step 6: Synthesis of 4-((S)-9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de] (naphthyl-5-yl)-5-ethynyl-6-fluoronaphth-2-phenol

[0906] Following a procedure similar to that described in step 7 of Example 6, the title compound, a white solid, was obtained from the compound from step 5, 63.9 mg, 87.1%. LCMS m / z = 632 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, 1H), 8.02 - 7.93 (m, 1H), 7.54 -7.43 (m, 1H), 7.41 -7.36 (m, 1H), 7.25 - 7.06 (m, 1H), 5.63-5.50 (m, 1H), 4.86 (s, 1H), 4.75 -4.63 (m, 1H), 4.63 - 4.48 (m, 2H), 4.47 - 4.36 (m, 2H), 4.05 -3.96 (m, 1H),3.90 - 3.80 (m, 3H), 3.79 - 3.66 (m, 4H), 3.32 - 3.30 (m, 3H), 2.29 - 2.18 (s, 3H), 2.02 - 1.96 (m, 1H), 1.03 - 0.96 (m, 1H), 0.66 - 0.55 (m, 3H), 0.45- 0.38 (m, 1H).

[0907] Example 22: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 169)

[0908]

[0909] Steps 1 to 5: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro- 8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluoro) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3, 6,10-Tetraazacycloheptan[de]naphthalene

[0910] Following a five-step procedure similar to that described in steps 1 to 5 of Example 21, the title compound, a yellow solid, was obtained from intermediate 16, 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol, and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 1224 [M+H]+

[0911] Step 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6, 10-Tetraazacycloheptan[de]naphth-5-yl)naphth-2-phenol

[0912] Following a procedure similar to that described in step 1 of Example 3, the title compound, 5.7 mg, 29.6%, was obtained from the products of steps 1 to 5 as a grayish-white solid. LCMS m / z = 674 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.18 (d, 1H), 7.98 (dd, 1H), 7.52 - 7.43 (m, 1H),7.39 (t, 1H), 7.21 (d, 1H), 5.63 (s, 0.5H), 5.50 (s, 0.5H), 5.01 (s, 1H), 4.78 - 4.66 (m, 1H), 4.57 (dd, 3H), 4.50 (d, 1H), 4.38 (t, 1H), 4.03 (s, 1H),3.87 (s, 1H), 3.78 (s, 5H), 2.83 (dd, 1H), 2.30 (d, 1H), 2.17 (s, 3H), 2.02 (s, 1H), 1.51 (d, 1H), 1.23 (s, 1H).

[0913] Example 23: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cycloheptan[de]naphth-9,1'-cyclopropane]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphth-2-phenol (Compound 170)

[0914]

[0915] Step 1: Synthesis of 5-((1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)cyclopropyl)methoxy )-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0916] Following a procedure similar to that described in step 4 of Example 1, the title compound, 170 mg, 38.1%, was obtained from intermediate 9 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one as a yellow solid. LCMS m / z = 613 [M+H]+

[0917] Step 2: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cycloheptan[de]naphthalene-9,1'-cyclopropyl]-1(10a),2,3a,3a1(6a), 5-Pentene

[0918] Following the procedure described in step 2 of Example 16, the title compound, 200 mg, 58.9%, was obtained as a white solid from the compound from step 1. LCMS m / z = 595 [M+H] +

[0919] Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylsulfinyl) (-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthyl-9,1'-cyclopropyl]-1(10a),2,3a,3a1) (6a),5-pentane

[0920] m-CPBA (126.1 mg, 0.73 mmol) was added to a solution of the compound from step 2 (290 mg, 0.49 mmol) in DCM (3 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 15 min. The mixture was extracted with DCM (2 × 10 mL), the combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (290 mg, crude substance) as a white solid. LCMS m / z = 985 [M+H] +

[0921] Step 4: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclic] [de]naphthalene-9,1'-cyclopropyl]-1(10a),2,3a,3a1(6a),5-pentane

[0922] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (226.6 mg, 1.42 mmol) was added to a solution of the compound from step 3 (290 mg, 0.47 mmol) in toluene (5 mL), and the mixture was stirred at room temperature for 1 hour. NaOtBu (91.20 mg, 0.95 mmol) was added fractionally, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:10), to give the title compound (220 mg, 65.7%) as a colorless oil. LCMS m / z = 706 [M+H] +

[0923] Step 5: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-8-((triisocyanate)) propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazine-7a(5H)-yl)methoxy)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclo [Propyl]-1(10a),2,3a,3a1(6a),5-pentane

[0924] ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane (351.6 mg, 0.56 mmol) and cataCXium-A-Pd-G3 (20.62 mg, 0.03 mmol) were added to a solution of the compound from step 4 (200 mg, 0.28 mmol) in dioxane (1 mL). K2CO3 (117.4 mg, 0.85 mmol) was added, followed by H2O (0.1 mL), and the reaction mixture was stirred at room temperature under N2 for 1 hour. The resulting mixture was extracted with EtOAc (3 × 10 mL), the combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1:1) elution to give the title compound (320 mg, 96.7%) as a brown solid. LCMS m / z = 1169 [M+H]+

[0925] Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-(2-hydroxyethyl)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cycloheptan[de]naphthalene-9, 1'-Cyclopropyl]-1(10a),2,3a,3a1(6a),5-pentene-5-yl)naphthyl-2-phenol

[0926] CsF (415.9 mg, 2.74 mmol) was added to a solution of the compound from step 5 (160 mg, 0.137 mmol) in DMF (2 mL), and the reaction mixture was stirred at 60 °C for 30 min. The resulting mixture was filtered, and the filter cake was washed with DMF (2 mL). The crude product was purified by preparative HPLC (Method D, gradient: 5% B to 35% B over 7 minutes) to give the title compound (44.0 mg, 51.9%) as a yellow solid. LCMS m / z = 618 [M+H]+ 1 H NMR (400MHz, DMSO-d6) δ 10.14 (s, 1H), 8.04 - 7.86 (m, 1H), 7.46 (m, 1H), 7.37 (s,1H), 7.18 (s, 1H), 5.41 - 5.18 (m, 1H), 5.09 - 4.91 (s, 1H), 4.88 - 4.61 (m,1H), 4.32 - 4.05 (m, 4H), 4.05 - 3.95 (s, 1H), 3.81 - 3.49 (s, 4H), 3.19 -2.89 (m, 2H), 2.32 - 2.01 (m, 3H), 2.01 - 1.71 (m, 3H), 1.62 - 1.40 (s, 1H), 1.34 - 1.21 (m, 2H), 1.21 - 1.13 (m, 1H), 1.13 - 0.95 (m, 1H).

[0927] Example 24: Synthesis of 5'-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cycloheptano[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-3-ol (Compound 154)

[0928]

[0929] Steps 1 and 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-10'-methyl-2'-(methyl) Thioyl)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cycloheptano[de]naphthalene]-1' (10a'),2',3a',3a1'(6a'),5'-pentane

[0930] Following a procedure similar to that described in steps 1 and 2 of Example 1, the title compound, a yellow solid, was obtained from intermediate 15 and 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one. LCMS m / z = 596 [M+H]+

[0931] Step 3: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-10'-methyl-2'-(methylthio) (-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cycloheptano[de]naphthalene]-1' (10a'),2',3a',3a1'(6a'),5'-pentane

[0932] The solution of the compounds from steps 1 and 2 (590 mg, 0.99 mmol) and m-CPBA (256.5 mg, 1.49 mmol) in DCM (10 mL) was stirred at room temperature for 0.5 h. The resulting mixture was evaporated under reduced pressure to give the title compound (600 mg, crude substance) as a white solid. LCMS m / z = 612 [M+H]+

[0933] Step 4: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-2'-(((2R,7aS)-2-fluoro) Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazine Heterospiro[cyclobutane-1,9'-cycloheptan[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentane

[0934] A solution of the compound from step 3 (570 mg, 0.93 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (222.7 mg, 1.40 mmol) in toluene (20 mL) was stirred at room temperature for 1 hour. NaOtBu (179.2 mg, 1.87 mmol) was added fractionally over 2 minutes at room temperature, and the reaction mixture was stirred for 0.5 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with elution using DCM / EtOAc (1:1) to give the title compound (310 mg, 47.1%) as a white solid. LCMS m / z = 707 [M+H]+

[0935] Steps 5 and 6: Synthesis of 5'-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4'-fluoro-2'-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetrafluoro Azaspiro[cyclobutane-1,9'-cycloheptano[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-3-olcarboxylic acid Salt.

[0936] Following a two-step procedure similar to that described in steps 5 and 6 of Example 16, the title compound, a yellow solid, was obtained from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 618 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.46 (m, 1H), 7.37 - 7.31 (m 1H), 7.15 (m, 1H), 5.35 - 5.32 (m, 1H), 4.70 (s, 1H), 4.52 - 4.37 (m, 1H), 4.12(m, 1H), 4.06 - 3.97 (m, 2H), 3.30 - 3.34(m, 3H), 3.17 - 3.00 (m, 3H), 2.99 -2.89 (m, 1H), 2.89 - 2.75 (m, 2H), 2.62 - 2.54 (m, 1H), 2.44 - 2.29 (m, 1H), 2.24 - 1.94 (m, 4H), 1.91 - 1.72 (m, 3H).

[0937] Example 25: Synthesis of 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (Compound 158)

[0938]

[0939] Step 1: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino) (butoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0940] A solution of intermediate 17 (1 g, 2.45 mmol) in THF (5 mL) was added to a solution of NaH (294.4 mg, 7.36 mmol, 60%) in THF (5 mL) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 30 min. A solution of 5,7-dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one (687.2 mg, 2.45 mmol) in THF (5 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at 80 °C for 1 day. The reaction mixture was quenched with HCl (1 M) at 0 °C, and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (C18 silica gel); mobile phase: MeCN / water (0.1% TFA), with a 0% to 45% gradient over 20 minutes, to give the title compound (523 mg, 19.6%) as a brown oil. LCMS m / z = 651 [M+H]+

[0941] Step 2: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2-difluoro) (Ethyl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0942] PyBOP® (958.9 mg, 1.84 mmol) was added fractionally to a solution of the compound from step 1 (800 mg, 1.23 mmol) and TEA (372.9 mg, 3.68 mmol) in THF (2 mL) at 0 °C, and the reaction mixture was stirred overnight at 40 °C. The mixture was extracted with EtOAc (3 × 80 mL), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to give the title compound (240 mg, 24.7%) as a white oil. LCMS m / z = 633 [M+H]+

[0943] Step 3: Synthesis of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2-difluoro) (Ethyl)-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0944] Following a procedure similar to that described in step 3 of Example 24, 460 mg of the title compound, a white solid, was obtained from the compound from step 2. LCMS m / z = 649 [M+H]+

[0945] Step 4: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2-difluoro) Ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0946] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (176.6 mg, 1.11 mmol) was added to a solution of the compound from step 3 (240 mg, 0.37 mmol) in toluene (1.5 mL), and the mixture was stirred at room temperature under N2 for 1 hour. NaOtBu (71.1 mg, 0.74 mmol) was added fractionally, and the reaction mixture was stirred at room temperature overnight. The residue was purified by preparative TLC (EtOAc) to give the title compound (200 mg, 62.5%) as a white solid. LCMS m / z = 744 [M+H]+

[0947] Step 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-10-(2,2-difluoroethyl)- 4-Fluoro-5-(7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- Tetraazacycloheptan[de]naphthalene

[0948] Following a procedure similar to that described in step 5 of Example 16, the title compound, 150 mg, 84.1%, was obtained from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane, as a yellow solid. LCMS m / z = 1206 [M+H]+

[0949] Step 6: Synthesis of 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azine-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan [de]naphthyl-5-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0950] Except for purification of the compound by preparative HPLC (Method A, 25% B to 52% B within 7 minutes), the procedure was similar to that described in step 6 of Example 23, to obtain the title compound, 35 mg, 4%, as a yellow solid from the compound from step 5. LCMS m / z = 656 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.14 (m, 1H),7.96 (m, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.28 - 7.01 (m, 1H), 6.78 - 6.17(m, 1H), 5.45 - 5.02 (m, 1H), 4.83 - 4.60 (m, 1H), 4.45 (m, 2H), 4.41 (m,1H), 4.22 (m, 1H), 4.17 - 4.10 (m, 1H), 4.08 (m, 1H), 4.02 - 3.79 (m, 1H), 3.98 (m, 1H), 3.97 - 3.69 (s, 2H), 3.19 - 2.90 (m, 3H), 2.84 (m, 1H), 2.18 -1.97 (m, 3H), 1.96 - 1.68 (m, 5H).

[0951] Example 26: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cycloheptan[de]naphthyl-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthyl-2-phenol (Compound 165)

[0952]

[0953] Step 1: Synthesis of 7-chloro-8-fluoro-5-((3-(methylamino)tetrahydrofuran-3-yl)methoxy)-2-(methylthio)pyridine Aceto[4,3-d]pyrimidin-4(3H)-one

[0954] NaH (548.8 mg, 22.9 mmol) was added to a solution of intermediate 19 (1 g, 7.62 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred for 15 min. 5,7-Dichloro-8-fluoro-2-(methylthio)-3H-pyrido[4,3-d]pyrimidin-4-one (1.07 g, 3.81 mmol) was added, and the reaction mixture was heated and stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (3 × 40 mL). The combined organic extracts were concentrated under reduced pressure to give the title compound (1 g, crude substance) as a grayish-white solid. LCMS m / z = 375 [M+H]+

[0955] Step 2: Synthesis of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-4',5'-dihydro-2'H,8H,10H-7-oxa- 1,3,6,10-Tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentane

[0956] Following a procedure similar to that described in step 2 of Example 1, the title compound, a pale yellow solid, was obtained from the compound from step 1, 400 mg, 47.3%. LCMS m / z = 357 [M+H]+.

[0957] Steps 3 and 4: Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy )-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'- [furan]-1(10a),2,3a,3a1(6a),5-pentane

[0958] Following a two-step procedure similar to that described in steps 3 and 4 of Example 23, the title compound, a grayish-white solid, was obtained from the compound from step 2. LCMS m / z = 468 [M+H]+

[0959] Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cycloheptan] [de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentane-5-yl)naphthyl-2-phenol

[0960] Following a two-step procedure similar to that described in steps 5 and 6 of Example 16, the title compound, which is a white solid, is obtained from the compound from steps 3 and 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane. LCMS m / z = 618[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.01-7.96 (m, 1H), 7.46 (t,1H), 7.37 (d, 1H), 7.25 - 7.07 (m, 1H), 5.42 - 5.18 (m, 1H), 4.54 (s, 2H),4.24 - 4.00 (m, 5H), 3.95 - 3.72 (m, 2H), 3.26 (s, 3H), 3.15 - 3.06 (m, 2H),3.04 - 3.01 (m, 1H), 2.91 - 2.85 (m, 1H), 2.38 - 2.31 (m, 1H), 2.19 - 2.00 (m, 4H), 1.92 - 1.76 (m, 3H).

[0961] Example 27: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthyl-5-yl)naphthyl-2-phenol trifluoroacetate (Compound 157)

[0962]

[0963] Step 1: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5,7-dichloro-8-fluoro-2-(methylthio) pyrido[4,3-d]pyrimidin-4-amine

[0964] The solution of intermediate 28 (4.8 g, 16.1 mmol), (2-aminoethoxy)(tert-butyl)dimethylsilane (5.64 g, 32.2 mmol), and DIPEA (6.23 g, 48.2 mmol) in anhydrous DCM (15 mL) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (MeOH / DCM 1:10) to give the title compound (2.4 g, 34.1%) as a yellow solid. LCMS m / z = 437 [M+H]+

[0965] Step 2: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthalene

[0966] A solution of the compound from step 1 (1.87 g, 4.28 mmol), 2-bromo-3,3,3-trifluoroprop-1-ol (1.65 g, 8.55 mmol), and NaH (307.8 mg, 12.8 mmol) in anhydrous THF (10 mL) was stirred at 60 °C for 2 days. The mixture was cooled to room temperature and the reaction mixture was quenched with water (15 mL). The mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (1:10), to give the title compound (190 mg, 8.7%) as a yellow solid. LCMS m / z = 513 [M+H]+

[0967] Step 3: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylsulfinyl) 9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptan[de]naphthalene

[0968] The solution of the compound from step 2 (190 mg, 0.37 mmol) and m-CPBA (191.7 mg, 1.11 mmol) in anhydrous DCM (3 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (MeOH / DCM 1:20) to give the title compound (110 mg, 54.5%) as a yellow solid. LCMS m / z = 529 [M+H]+

[0969] Step 4: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1, 3,6,10-Tetraazacycloheptan[de]naphthalene

[0970] A mixture of the compound from step 3 (100 mg, 0.18 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.8 mg, 0.27 mmol), and LiOtBu (29.4 mg, 0.37 mmol) in anhydrous DCM (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (MeOH / DCM = 1:10) to give the title compound (40 mg, 33.9%) as a yellow solid. LCMS m / z = 624 [M+H]+

[0971] Step 5: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-8-((triisocyanate)) propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazine-7a(5H)-yl)methoxy)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptane and [de]naphthalene

[0972] The compound from step 4 (40 mg, 0.064 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)oxy)triisopropylsilane (80.1 mg, 0.13 mmol), cataCXium-A-Pd-G3 (4.67 mg, 0.006 mmol), and K3PO4 (40.81 mg, 0.19 mmol) were stirred in anhydrous dioxane (2 mL) at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (MeOH / DCM = 1:10) to give the title compound (crude substance) as a yellow solid. LCMS m / z = 1087 [M+H]+

[0973] Step 6: Synthesis of 2-(4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilane) 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-9-(trifluoromethyl) (-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloheptan-10-naphthyl)ethyl-1-ol

[0974] TFA (20.5 mg, 0.18 mmol) was added to a solution of the compound from step 5 (65 mg, 0.06 mmol) in anhydrous DCM (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (MeOH / DCM 1:10) to give the title compound (48 mg, 76.8%) as a yellow solid. LCMS m / z = 972 [M+H]+

[0975] Step 7: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraaza Heterocyclic heptanonaphth-5-yl)naphth-2-phenol trifluoroacetate

[0976] CsF (70.3 mg, 0.46 mmol) was added to a solution of the compound from step 6 (45 mg, 0.046 mmol) in DMF (1 mL), and the reaction mixture was stirred at room temperature for 3 hours. The residue was dissolved in water (5 mL), the mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude substance was purified by HPLC (Method E, gradient: 22% B to 47% B over 9 minutes) to give the title compound (2 mg, 5.6%) as a yellow solid. LCMS m / z = 660 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.19 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (d,1H), 7.17 (dd, 1H), 5.72 - 5.42 (m, 2H), 5.09 - 4.60 (m, 1H), 4.66 - 4.50 (m,2H), 4.38 (dd, 2H), 4.26 - 4.04 (m, 2H), 4.04 - 3.88 (m, 1H), 3.92 - 3.43 (m,3H), 3.31 (s, 1H), 2.51 (s, 1H), 2.50 - 2.39 (m, 2H), 2.39 - 2.21 (m, 1H), 2.16 (m, 2H), 2.03 (s, 1H).

[0977] Example 28: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloheptano[de]naphthyl-5-yl)naphthyl-2-phenol (Compound 161)

[0978]

[0979] Purification Example 27 (10 mg, 0.015 mmol) by preparative chiral HPLC: Column: (CHIRALPAK IE3; Mobile phase A: MtBE:Hex (0.2% DEA):(EtOH:DCM=1:1)=30:70, at 1 mL / min; Gradient: isocratic; Peak 1 (1 mg, 8.5%) was obtained as a white solid: LCMS m / z = 660 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, 1H), 8.05 - 7.90 (m, 1H), 7.47 (s, 1H), 7.39 (d, 1H), 7.17 (dd, 1H), 5.53 (s, 1H), 5.32 (d, 1H), 5.05 - 4.82 (m, 1H). 4.46 - 4.24 (m, 2H),4.24 - 3.84 (m, 4H), 3.77 (s, 3H), 3.12 - 3.04 (m, 2H), 3.01 - 2.55 (m, 1H),2.38 - 1.98 (m, 3H), 1.82 (s, 3H), 1.42 - 1.05 (m, 1H)...

Claims

1. A compound represented by formula I: Equation I; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: R 1 The group consisting of halogens, C3-C4 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups may be optionally substituted with one, two or three halogens. R 2 It is hydrogen or optionally a C1-C6 alkyl group substituted with one or more halogens or hydroxyl groups; and Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is selected from one or more groups independently of R A Substituents of the substituents; or: R 1 It is hydrogen; R 2 It is a C1-C6 alkyl group optionally substituted with one or more halogens or hydroxyl groups; and ring A is selected from the group consisting of: ； or: R 1 It is hydrogen; R 2 It is hydrogen; and ring A is selected from the following groups: ； R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R A1 Choose from the following groups: hydrogen, deuterium, chlorine, -CN, -NO2, -NR a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R 1' It is hydrogen or halogen; R 3 Choose from the following groups: -NR a R b Halogen, C1-C2 alkyl and hydrogen, wherein the alkyl group may optionally be substituted with one, two or three halogens; R 4 The group consisting of hydrogen and C1-C2 alkyl groups is selected, wherein the alkyl group may optionally be substituted with one, two or three halogens; R 5 It is a C1-C2 alkyl group optionally substituted with one, two, or three halogens; R 6 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups; R 7 The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups; R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups; Ring B is selected from the group consisting of 4- to 12-membered heterocyclic groups containing at least one cyclic nitrogen; R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b =COOH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, =CHF and =CH-C1-C6 alkyl; wherein the C1-C6 alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of: hydroxyl, halogen and C1-C3 alkoxy; or Rings B and R B The cycloalkyl group is absent and has been replaced by substituents selected from the group consisting of -CH2OH and C3-C4 cycloalkyl groups, wherein the cycloalkyl group is selected from -CH2OH and -CH2-NR. a R b The substituents in the group are substituted, and R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; m and n are each independently 0, 1, 2, 3 or 4; p is 1, 2, or 3; q, r, and s are each independently 0, 1, 2, or 3; and t can be 0, 1, or 2.

2. The compound according to claim 1, wherein R 1 Choose from the group consisting of: fluorine, chlorine, cyclopropyl, trifluoromethyl, -CH2CH2CH3, and propenyl; and R 2 It is hydrogen or -CH3.

3. The compound according to claim 1 or 2, wherein R A Each time it appears, it is independently selected from the group consisting of: halogen, hydroxyl, cyano, -NH2, -C(O)NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C6 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted with one, two or three halogens or -CN.

4. The compound according to any one of claims 1 to 3, wherein ring A is selected from the group consisting of: 。 5. The compound according to any one of claims 1 to 4, wherein ring A is selected from the group consisting of: 。 6. The compound according to claim 1, wherein R 1 It is hydrogen and R 2 It is -CH3.

7. The compound according to claim 1 or 6, wherein ring A is selected from the group consisting of: ； in: R A The group is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, and C3-C4 cycloalkyl; wherein the alkyl and alkoxy groups are each substituted with one, two, or three halogens; and R A1 Choose the group consisting of chlorine, -CH3, and -CF3.

8. The compound according to any one of claims 1 and 6 to 7, wherein ring A is selected from the group consisting of: 。 9. The compound according to claim 1, wherein R 1 It is hydrogen and R 2 It is hydrogen.

10. The compound according to claim 1 or 9, wherein ring A is selected from the group consisting of... 。 11. The compound according to any one of claims 1 to 10, wherein R 3 Choose the group consisting of -NH2, chlorine, and -CHF2.

12. The compound according to any one of claims 1 to 11, wherein R 3 It is -NH2.

13. The compound according to any one of claims 1 to 12, wherein R 4 It is hydrogen and R 5 It is -CH3.

14. The compound according to any one of claims 1 to 13, wherein R 6 It is fluorine.

15. The compound according to any one of claims 1 to 14, wherein R 7 It is hydrogen or -CH3.

16. The compound according to any one of claims 1 to 15, wherein R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and -CH3.

17. The compound according to any one of claims 1 to 16, wherein R B Each time it appears, it is independently selected from the group consisting of: halogen, hydroxyl, -COOH, =CHCH3, =CHF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C1-C3 alkyl groups optionally substituted with hydroxyl, halogen or -OCH3.

18. The compound according to any one of claims 1 to 17, wherein R B Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -CH3, =CHCH3, =CHF, -COOH, -CH2OH, -CH2CH2F, CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

19. The compound according to any one of claims 1 to 18, wherein ring B is selected from the group consisting of: 。 20. The compound according to any one of claims 1 to 16, wherein rings B and R B It is absent and substituted with -CH2OH or cyclopropyl groups; wherein the cyclopropyl group is substituted with -CH2OH or -CH2NR. a R b replace.

21. The compound according to any one of claims 1 to 16 and 20, wherein rings B and R B Substituents that do not exist and are selected from the following groups of groups: -CH2OH, .

22. The compound according to claim 1, wherein the compound is represented by formula IA: IA; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: R 1 For halogens, R 2 It is hydrogen or -CH3, and ring A is selected from the group consisting of the following: ;or R 1 For hydrogen, R 2 It is -CH3, and ring A is selected from the following groups: ;or R 1 For hydrogen, R 2 It is hydrogen, and ring A is selected from the group consisting of: ； R 7 Choose the group consisting of hydrogen and -CH3; R 8 and R 9 Each is independently selected from the group consisting of hydrogen, deuterium, and -CH3; and B. Choose any of the following groups. 。 23. The compound of claim 1, wherein the compound is selected from the group consisting of... 、 ； Or its pharmaceutically acceptable salts and / or stereoisomers.

24. A compound represented by formula II: Formula II; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: Ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiophene, benzothiazolyl, pyridyl, pyrimidinyl, and phenyl; wherein ring A is selected from one, two, or three independently from R A Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R 1 Select from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 11 Substituents of the substituents; R 2 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -CH(CH3)-(C3-C6 cycloalkyl), -CH2-(C3-C6 cycloalkyl), phenyl, 5-membered heteroaryl and -CR c R d -(5-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be selected independently from R by one, two, three, or four groups. 22 Substituents of the substituents; R 11 and R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl; R 3 The group consisting of hydrogen and C1-C6 alkyl groups optionally substituted with one or more halogens or hydroxyl groups; R 4 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups; R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, and C1-C3 alkyl groups; Ring B is selected from the group consisting of 5- to 10-membered heterocyclic groups containing at least one cyclic nitrogen; R B Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy; and m can be 0, 1, 2, 3, or 4; If ring A is benzothiophene, then R 1 It is CH3 or a substituted C1-C6 alkyl group.

25. The compound according to claim 24, wherein R 3 It is hydrogen or CH3.

26. The compound according to claim 24 or 25, wherein R 4 It is fluorine.

27. The compound according to any one of claims 24 to 26, wherein R 5 and R 6 Each is hydrogen.

28. The compound according to any one of claims 24 to 27, wherein the compound is represented by formula IIA: Formula IIA.

29. The compound according to any one of claims 24 to 28, wherein ring A is selected from the group consisting of: indazole, quinolinyl, quinolinone, benzothiazolyl, pyridyl, pyrimidinyl, and phenyl; wherein ring A is selected from one, two, or three independently selected from R A Substituents are substituted.

30. The compound according to any one of claims 24 to 29, wherein R A Each time it appears, it is independently selected from the group consisting of: halogen, hydroxyl, -NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C4 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted with one, two or three halogens.

31. The compound according to any one of claims 24 to 30, wherein ring A is selected from the group consisting of: 。 32. The compound according to any one of claims 24 to 31, wherein ring A is selected from the group consisting of... 。 33. The compound according to any one of claims 24 to 32, wherein R 1 The group is selected from the group consisting of: C1-C6 alkyl, C3-C4 cycloalkyl, -CH(CH3)-(C3-C4 cycloalkyl) and -CH2-(C3-C4 cycloalkyl), wherein the alkyl and cycloalkyl groups may optionally be substituted by one, two, three or four groups independently selected from the group consisting of: halogen, hydroxyl, cyano and -C(=O)NR. a R b .

34. The compound according to any one of claims 24 to 33, wherein R 1 Choose from the following groups: -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH. .

35. The compound according to any one of claims 24 to 32, wherein R 1 The group consisting of 5-membered heteroaryl, -CH2-(5-membered heteroaryl), and -CH(CH3)-(5-membered heteroaryl) is selected, wherein the heteroaryl group may optionally be derived from one or two independently selected -NR groups. a R b The alkyl group is substituted with a substituent of the group consisting of C1-C3 alkyl groups, wherein the alkyl group may optionally be substituted with one, two or three halogens.

36. The compound according to any one of claims 24 to 32 and 35, wherein R 1 Choose from the following groups 。 37. The compound according to any one of claims 24 to 28, wherein ring A is a benzothiophene group substituted with one, two or three substituents each independently selected from the group consisting of: halogen, cyano, -NH2 and -C(O)NH2.

38. The compound according to any one of claims 24 to 28 and 37, wherein ring A is selected from... A group that is formed.

39. The compound according to any one of claims 24 to 28 and 37 to 38, wherein R 1 Choose the group consisting of -CH3, -CH2CHF2 and -CH2CH2OH.

40. The compound according to any one of claims 24 to 39, wherein R 2 The group is selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted by one, two or three substituents, each independently selected from the group consisting of halogens and hydroxyl groups.

41. The compound according to any one of claims 24 to 40, wherein R 2 Choose the group consisting of free hydrogen, -CH3, and -CH2CH2OH.

42. The compound according to any one of claims 24 to 41, wherein R B Choose from the group consisting of halogens, hydroxyl groups, and C1-C3 alkyl groups.

43. The compound according to any one of claims 24 to 42, wherein R B Choose the group consisting of halogens, hydroxyl groups, and -CH3.

44. The compound according to any one of claims 24 to 43, wherein ring B is selected from the group consisting of: 。 45. The compound according to any one of claims 24 to 44, wherein ring B is 。 46. ​​The compound according to claim 24, wherein the compound is represented by formula IIB: Formula IIB; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: Ring A can be freely composed of the following groups ； R 1 Choose from the following groups: -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH, -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH. ; R 2 Choose the group consisting of free hydrogen, -CH3, and -CH2CH2OH; and R 3 It is hydrogen or CH3.

47. The compound of claim 24, wherein the compound is selected from the group consisting of... ； Or its pharmaceutically acceptable salts and / or stereoisomers.

48. A compound represented by formula III: Formula III; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: R A1 and R A2 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl group may optionally be substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, oxo, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R 1' It is hydrogen and R 1 Choose from the following groups: hydrogen, -CH3, -CF3, -CH2CH2OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkenyl, ynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four independently selected from R 22 Substituents are substituted; and R 2 Choose from the following groups: hydrogen, -CH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 cycloalkyl, C5-C6 cycloalkyl, phenyl, 5-membered heteroaryl, and -CR c R d -(5-membered heteroaryl); wherein the alkyl group is selected from one, two, three or four independently selected from R 11 Substituents; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl groups may optionally be substituted by one, two, three, or four groups, each independently selected from R 22 Substituents of the substituents; or: R 1 and R 1' Together with the carbon atom to which it is attached, it can bond together to form a C3-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2 C1-C6 alkyl groups substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ;or R 1 and R 1' Together with the carbon atom to which it is attached, it can bond together to form a C4-cycloalkyl group optionally substituted with one, two, or three halogens or hydroxyl groups; and R 2 C1-C6 alkyl groups optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, and C(=O)NR. a R b ; R 11 Each time it appears, it is independently selected from the following groups: halogen, deuterium, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl; R 22 Each time it appears, it is independently selected from the following groups: halogen, deuterium, hydroxyl, -CN, -NO2, -NR. a R b , Oxygenated, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -COOH, -C(=O)NR a R b -NR a (C=O)R b -O(C=O)NR a R b -NR a (C=O)OR b -NR a (C=O)NR a R b -(C=O)C1-C6 alkyl, -(C=O)OC1-C6 alkyl, -O(C=O)C1-C6 alkyl, -O(C=O)OC1-C6 alkyl, -SH, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR a R b and -NR a S(O)2C1-C6 alkyl; R 3 Choose from the group consisting of: halogens, hydrogen, deuterium, and C1-C3 alkyl groups; R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b Together with the nitrogen to which it is attached, it can form a 4- to 7-membered heterocyclic group, which is optionally substituted by one or more substituents, each independently selected from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; R c and R d Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2; in: If R 1 If it is hydrogen, then R 2 Not hydrogen, -CH3, or CH2CH2OH; and If R 1 If it is -CH3, then R 2 It is not hydrogen, -CH3, -CH2CF2, -CH2CF3 or -CH2CH(CH3)OH.

49. The compound according to claim 48, wherein R A1 and R A2 Each time it appears, it is independently selected from the group consisting of: halogen, hydroxyl, cyano, -NH2, C1-C4 alkyl and C2-C4 alkynyl, C1-C4 alkoxy and C3-C4 cycloalkyl, wherein the alkyl, alkynyl, alkoxy and cycloalkyl may optionally be substituted by one, two or three halogens.

50. The compound according to claim 48 or 49, wherein m is 1 or 2 and R A1 Each time it appears, it is independently selected from the group consisting of: halogen, C1-C4 alkyl, C2-C4 alkynyl and C3-C4 cycloalkyl.

51. The compound according to any one of claims 48 to 50, wherein n is 1 and R A2 It is a hydroxyl group or -NH2.

52. The compound according to any one of claims 48 to 51, wherein Choose from the following groups 。 53. The compound according to any one of claims 48 to 52, wherein Choose from the following groups 。 54. The compound according to any one of claims 48 to 53, wherein R 1 'It is hydrogen.' 55. The compound according to any one of claims 48 to 54, wherein R 1 It is hydrogen.

56. The compound according to any one of claims 48 to 55, wherein R 2 Choose from the following groups: -CH2CN, -CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2 and -CH2CH2C(O)NHCH3.

57. The compound according to any one of claims 48 to 54, wherein R 1 It is -CH3.

58. The compound according to any one of claims 48 to 54 and 57, wherein R 2 Choose from the following groups: -CH2CH2OH, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3. .

59. The compound according to any one of claims 48 to 54, wherein R 1 Choose from the following groups: -CF3, -CH2CF3, -CH2CH2OH, -CH2C(CH3)2OH. .

60. The compound according to any one of claims 48 to 54 and 59, wherein R 2 Choose from the following groups: hydrogen, -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2 and -CH2CH2C(O)NHCH3.

61. The compound according to any one of claims 48 to 53, wherein R 1' and R 1 It bonds together with the carbon atom to which it is attached to form an optional hydroxyl-substituted C3-cycloalkyl group; and R 2 It is -CH2CH2OH.

62. The compound according to any one of claims 48 to 53, wherein R 1' and R 1 It bonds together with the carbon atom to which it is attached to form an optionally hydroxylated C4-cycloalkyl group; and R 2 It is -CH3.

63. The compound according to any one of claims 48 to 54, wherein R 3 It is hydrogen.

64. The compound according to claim 48, wherein the compound is represented by formula IIIB: Formula IIIB; Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: Choose from the following groups: ;and R 1 It is hydrogen; and R 2 Choose from the following groups: -CH2CN, -CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3; or R 1 It is -CH3; and R 2 Choose from the following groups: -CH2CH2OH, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3. ;or R 1 Choose from the following groups: -CF3, -CH2CF3, -CH2CH2OH, -CH2C(CH3)2OH; and R 2 Choose from the following groups: hydrogen, -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2 and -CH2CH2C(O)NHCH3.

65. The compound of claim 49, wherein the compound is selected from the group consisting of... ； Or its pharmaceutically acceptable salts and / or stereoisomers.

66. A compound selected from the group consisting of: ； Or its pharmaceutically acceptable salts and / or stereoisomers.

67. A pharmaceutical composition comprising a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt and / or stereoisomer thereof, and a pharmaceutically acceptable excipient.

68. A method of treating a patient with Ras-related disease or condition, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 66.

69. The method of claim 68, wherein the disease or symptom is characterized by abnormal Ras activity in the patient due to a Ras mutation.

70. The method according to claim 68 or 69, wherein the Ras mutation is a K-Ras mutation, an H-Ras mutation, or an N-Ras mutation.

71. The method according to any one of claims 68 to 70, wherein the disease or condition is cancer.

72. A method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 66.

73. The method of claim 72, wherein the cancer is a Ras-mutated cancer.

74. The method according to claim 72 or 73, wherein the cancer is a K-Ras mutant cancer.

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