LPA receptor antagonists and uses thereof

Abstract

The present disclosure generally relates to compounds that bind to lysophosphatidic acid receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure also relates to the use of these compounds in the preparation of medicaments for treating diseases and / or conditions by binding to LPAR1, including fibrosis and liver diseases such as non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 034,220, filed on June 3, 2020, and U.S. Provisional Application No. 63 / 130,242, filed on December 23, 2020, which are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure relates to compounds that bind to lysophosphatidic acid (LPA) receptors (such as LPAR1) and act as antagonists thereof. The present disclosure also relates to the use of compounds for treating and / or preventing diseases and / or conditions associated with one or more LPA receptors (e.g., LPAR1-associated diseases or conditions). Background Art

[0004] Lysophosphatidic acid (monoacylglycerol-3-phosphate, LPA) is a class of bioactive phospholipids that can be produced, for example, from lysophosphatidylcholine (LPC) by the enzyme autotaxin. A typical LPA has glycerol, a fatty acid ester-linked at the sn-1 position, and a phosphate head group at the sn-3 position. LPAs with various fatty acids have been identified, including palmitoyl LPA (16:0), stearoyl LPA (18:0), oleoyl LPA (18:1), linoleoyl LPA (18:2), and arachidonoyl LPA (20:4). LPA exerts a wide range of cellular responses, such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis, through the rhodopsin-like G protein-coupled receptor (GPCR) family. Six LPA receptors have been characterized and found to differ in their tissue distribution and downstream signaling pathways. These six LPA receptors are often interchangeably referred to as LPAR1-6 (genes) or LPA1-6 (proteins). LPA receptor-mediated signaling has been shown to influence many biological processes, such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

[0005] In vivo studies involving LPA receptor-deficient mice or certain tool compounds have demonstrated the potential of the LPA receptor as a possible drug target in a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. Recently, LPAR1 antagonists have been studied clinically in conjunction with fibrotic disease states such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0006] However, there remains a need for LPA antagonists with desirable selectivity, potency, metabolic stability, or reduced deleterious effects. Summary of the Invention

[0007] The present disclosure provides compounds useful as inhibitors of lysophosphatidic acid receptor 1 (LPAR1). The present disclosure also relates to the use of compounds for treating and / or preventing diseases and / or conditions by binding of the compounds to LPAR1.

[0008] In one embodiment, provided herein is a compound of formula (I),

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] in:

[0012] R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C1-6 Alkyl or C 3-6 Cycloalkyl,

[0013] Each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and

[0014] Each R 1B1 、R 1B2 and R 1B3 Alkyl and each R 1B1 、R 1B2 and R 1B3 Cycloalkyl is optionally substituted with 1 to 3 halogens; or

[0015] R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 1E Replace these R 1E may be the same or different, wherein each R 1E independently selected from halogen, cyano, hydroxy, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -OR 1F1 ,-N(R 1F1 )(R 1F2 ), -C(O)N(R 1F1 )(R 1F2 ), -NR 1F1 C(O)R 1F2 , -S(O) 0-2 R 1F1,-S(O)2N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O)2R 1F2 , where each R 1F1 and R 1F2 are independently hydrogen or C 1-6 Alkyl, where each R 1E Alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 R 1G Replace these R 1G may be the same or different, and wherein each R 1G Independently C 1-4 Alkyl, C 1-4 alkoxy, hydroxy, halogen or cyano;

[0016] R 2 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0017] R 2 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0018] Each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C optionally substituted by 1 to 3 halogens 1-3 Alkyl, these halogens may be the same or different;

[0019] n is 0, 1, 2, 3 or 4;

[0020] R 4 is C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy, -C(O)N(R4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 are independently hydrogen, C 1-6 Alkyl or C 3-10 cycloalkyl; or

[0021] R 4 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 alkoxy;

[0022] X 1 、X 2 、X 3 and X 4 Each of is independently selected from CH and N;

[0023] Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 );and

[0024] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are selected from C 1-4 Alkoxy and halogen; or

[0025] Y 1 and Z together with the carbon to which they are attached form C3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 The aryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0026] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0027] R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl,

[0028] Each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and each R 1D1 and R 1D2 are independently hydrogen or C 1-6 Alkyl; or

[0029] R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 1E Replace these R 1E may be the same or different, wherein each R 1E independently selected from halogen, cyano, hydroxy, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -OR 1F1 ,-N(R 1F1 )(R 1F2 ), -C(O)N(R 1F1 )(R 1F2 ), -NR 1F1 C(O)R1F2 , -S(O) 0-2 R 1F1 ,-S(O)2N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O)2R 1F2 , where each R 1F1 and R 1F2 are independently hydrogen or C 1-6 Alkyl, where each R 1E Alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 R 1G Replace these R 1G may be the same or different, and wherein each R 1G Independently C 1-4 Alkyl, C 1-4 alkoxy, hydroxy, halogen or cyano;

[0030] R 2 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0031] R 2 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0032] Each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C optionally substituted by 1 to 3 halogens 1-3 Alkyl, these halogens may be the same or different;

[0033] n is 0, 1, 2, 3 or 4;

[0034] R 4 is C optionally substituted by 1 to 3 substituents 1-6Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 are independently hydrogen, C 1-6 Alkyl or C 3-10 cycloalkyl; or

[0035] R 4 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 alkoxy;

[0036] X 1 、X 2 、X 3 and X 4 Each of is independently selected from CH and N;

[0037] Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 );and

[0038] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are selected from C 1-4 Alkoxy and halogen; or

[0039] Y 1 and Z together with the carbon to which they are attached form C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 The aryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0040] In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0041] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0042] In some embodiments, the present disclosure provides methods of inhibiting LPAR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0043] In some embodiments, the present disclosure provides methods of treating a patient suffering from an LPAR1-mediated disorder, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (III)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION

[0044] The present disclosure relates to LPA receptor antagonists, such as antagonists of LPAR1. The present disclosure also relates to compositions and methods related to LPAR1 antagonists, and the use of such compounds for treating and / or preventing LPAR1-mediated diseases and conditions. The present disclosure also relates to compositions and methods for treating and / or preventing liver disease, comprising LPAR1 antagonists in combination with one or more additional therapeutic agents.

[0045] It is generally believed that patients with certain LPAR1-mediated diseases, such as cancer, fibrosis, inflammation, pain, cardiovascular disease, or liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), may benefit from treatment with an LPAR1 antagonist and, optionally, one or more additional therapeutic agents.

[0046] Definition and general parameters

[0047] It should be understood that the present disclosure is to be considered as an illustration of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading.

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0049] As used in this specification, the following terms and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0050] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom. The dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through the line in the structure indicates the point of attachment of the group. Unless required by chemistry or structure, directionality is not indicated or implied by the order in which the chemical groups are written or named. A solid line extending from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. For example, R in the following structure a Can be attached to any of the five carbon ring atoms, or R a Can replace hydrogen attached to nitrogen ring atoms:

[0051]

[0052] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Likewise, the term "xy-membered" ring (where x and y are numerical ranges, such as "3- to 12-membered heterocyclyl") refers to a ring containing xy atoms (e.g., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0053] Furthermore, certain commonly used alternative chemical names may or may not be used. For example, a divalent group (such as a divalent "alkyl" group, a divalent "aryl" group, etc.) may also be referred to as an "alkylene" group ("alkylenyl" group or alkylyl group), an "arylene" group ("arylenyl" group or arylyl group), respectively.

[0054] "Compounds disclosed herein" or "compounds of the present disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi). Also included are specific compounds 1 to 338 provided herein (e.g., Examples 1 to 92).

[0055] The "about" value or parameter mentioned herein includes (and describes) embodiments related to the value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. Moreover, the term "about X" includes a description of "X". Moreover, unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" include plural references. Thus, for example, reference to a "compound" includes a plurality of such compounds, and reference to "assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0056] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), 1 to 4 carbon atoms (i.e., C 1-4 Alkyl) or 1 to 3 carbon atoms (ie C 1-3 Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms are encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0057] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (ie, C 2-8 alkenyl), 2 to 6 carbon atoms (ie, C 2-6 alkenyl) or 2 to 4 carbon atoms (ie C 2-4 Examples of the alkenyl group include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0058] "Alkynyl" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (ie C2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0059] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0060] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0061] "Amino" refers to the group -NR y R z , where R y and R z independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which can be optionally substituted.

[0062] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) that are fused together. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 Aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) or 6 to 10 carbon ring atoms (i.e. C 6-10 Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl.

[0063] "Cyano" or "carbonitrile" refers to the group -CN.

[0064] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (ie C 3-6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0065] "Fused" means that one ring is bound to an adjacent ring. In some embodiments, the fused ring system is a heterocyclyl. In some embodiments, the fused ring system is an oxabicyclohexyl. In some embodiments, the fused ring system is

[0066] "Bridged" refers to ring fusions in which non-adjacent atoms on the ring are connected by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is a biscyclopentyl (biscyclo[1.1.1]pentyl]) or a biscyclooctyl (biscyclo[2.2.2]octyl). In some embodiments, the bridged ring is

[0067] "Spiro" refers to a ring substituent connected by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentyl (spiro[ab]pentyl), spirohexyl, spiroheptyl, or spirodecanyl. In some embodiments, the spiro substituent is

[0068] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0069] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 1 to 20 carbon ring atoms (i.e., C 1-20 Heteroaryl), 3 to 12 carbon ring atoms (ie, C 3-12 heteroaryl) or 3 to 8 carbon ring atoms (ie, C 3-8 and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0070] "Heterocyclyl" or "heterocycle" refers to a non-aromatic cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated ring, for example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a partially saturated ring in the specified case. The term "heterocyclyl" or "heterocycle" includes heterocycloalkenyl groups (i.e., heterocyclyl groups with at least one double bond). A heterocyclyl group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spiro. As used herein, a heterocyclyl group has 2 to 20 carbon ring atoms (i.e., C 2-20 Heterocyclyl), 2 to 12 carbon ring atoms (ie, C 2-12 Heterocyclyl), 2 to 10 carbon ring atoms (ie, C 2-10 Heterocyclyl), 2 to 8 carbon ring atoms (ie, C 2-8 Heterocyclyl), 3 to 12 carbon ring atoms (ie, C 3-12 Heterocyclyl), 3 to 8 carbon ring atoms (ie, C 3-8 heterocyclic) or 3 to 6 carbon ring atoms (ie, C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the terms "heterocycle," "heterocyclyl," and "heterocycle" are used interchangeably.

[0071] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0072] "Oxo" refers to the group (=O) or (O).

[0073] "Sulfonyl" refers to the group -S(O)2R c , where R c is an alkyl group, a heterocyclic group, a cycloalkyl group, a heteroaryl group or an aryl group. Examples of the sulfonyl group are a methylsulfonyl group, an ethylsulfonyl group, a phenylsulfonyl group and a toluenesulfonyl group.

[0074] Unless otherwise indicated, whenever a graphic representation of a group terminates in a singly bonded nitrogen atom, the group represents an -NH2 group. Similarly, unless otherwise indicated, hydrogen atoms are implied and assumed to be present where necessary to complete valence or provide stability, according to the knowledge of those skilled in the art.

[0075] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0076] Term " substituted " means that any one or more hydrogen atoms on designated atom or group are replaced by one or more substituents other than hydrogen, with condition being no more than the normal valence of designated atom.The one or more substituents include but are not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amido, amide, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano group, guanidine radicals, halogen, haloalkyl, assorted alkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkyl sulfinyl, sulfonic acid, alkyl sulfonyl, thiocyanate, mercaptan, thioketone or their combination.The polymer obtained by definition with the substituent of unlimited additional further substituent or similar indefinite structure (for example, the aryl of the substituted alkyl, the alkyl itself substituted aryl group replaces, the aryl group substituted assorted alkyl group further replaces etc.) is not intended to be included in this article.Unless otherwise indicated, the maximum number of continuous substitutions in compounds described herein is three. For example, the continuous substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to the skilled person. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise stated, where a group is described as optionally substituted, any substituent of these groups is itself unsubstituted.

[0077] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, the one or more substituents including hydroxy, halogen, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents, the one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halogen, oxo, and hydroxy; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents, the one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted aryl" refers to an aryl group having one or more substituents. "Substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halogen, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano, and "substituted sulfonyl" refers to the group -S(O)R, wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0078] In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl and / or substituted heteroaryl include cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups having substituents on ring atoms that are attached to the remainder of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group:

[0079]

[0080] The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like should be understood broadly and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not limitation, and it is not intended that such terms and expressions be used to exclude any equivalents of the features shown and described, or portions thereof, but it should be recognized that various modifications are possible within the scope of the disclosure as claimed.

[0081] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic base or inorganic acid and an organic base or organic acid). The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic base or inorganic acid and an organic base or organic acid). In the case where the compounds of the present disclosure contain one or more acidic or basic groups, the disclosure also includes its corresponding pharmaceutically or toxicologically acceptable salt, particularly its pharmaceutically available salt. Therefore, the compounds of the present disclosure containing an acidic group may be present on these groups and may be used as, for example, alkali metal salts, alkaline earth metal salts or ammonium salts according to the disclosure. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine), amino acids or other bases known to those skilled in the art. The compounds of the present disclosure containing one or more basic groups (i.e., protonable groups) can exist in the form of addition salts thereof with inorganic or organic acids and can be used in accordance with the present disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0082] If the compounds of the present disclosure contain both acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0083] The present disclosure also includes all salts of the compounds of the present disclosure, which are not directly suitable for use in medicines due to low physiological compatibility, but which can be used, for example, as intermediates in chemical reactions or for preparing pharmaceutically acceptable salts. Acids and bases that can be used to react with the following compounds to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the following compounds (after disclosure) are known to those skilled in the art and are disclosed in, for example, Berge et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0084] In addition, the compounds disclosed herein may undergo tautomerism. Where tautomerism (e.g., keto-enol tautomerism) of a compound or its prodrugs may occur, individual forms (e.g., keto and enol forms) and mixtures thereof in any ratio are within the scope of the present disclosure. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0085] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the entire compound. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, "Protective Groups in Organic Chemistry," Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to facilitate the efficiency of a desired chemical reaction, such as forming and breaking chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0086] The skilled artisan will understand that when a list of alternative substituents includes members that cannot be used to replace a particular group due to their valence requirements or other reasons, the list is intended to be interpreted by the skilled artisan as including only those members of the list that are suitable for replacing the particular group.

[0087] Additionally, the compounds of the present disclosure may exist in the form of solvates, such as those that include water as a solvate, or pharmaceutically acceptable solvates, such as alcohols, particularly ethanol."Solvates"are formed by the interaction of a solvent and a compound.

[0088] In certain embodiments, there is provided an optical isomer, racemate or other mixture of a compound described herein or a pharmaceutically acceptable salt thereof or a mixture thereof. If desired, isomers can be separated by methods well known in the art, for example, by liquid chromatography. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by splitting. For example, splitting can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or using, for example, a chiral high pressure liquid chromatography (HPLC) column chromatography.

[0089] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0090] In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or (D)- or (L)- for amino acids based on absolute stereochemistry. Some embodiments include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolving racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers.

[0091] The compositions provided herein that include the compounds described herein, or their pharmaceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0092] Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. An isotopically labeled compound has a structure depicted by a formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, for example, wherein a radioactive isotope such as 3 H. 13 C and 14C is incorporated. Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or in radiotherapy of patients. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or examples and formulations described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0093] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and, therefore, may be used to extend the half-life of any compound of Formula (I) when administered to a mammal (e.g., a human). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0094] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have beneficial DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies.

[0095] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be a hydrogen with its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0096] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0097] "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients constituting a carrier, as well as any product obtained directly or indirectly from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present disclosure can encompass any composition made by mixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

[0098] As used herein, "pharmaceutically acceptable carriers" include excipients or agents that are not harmful to the disclosed compounds or their uses, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, for example, "Remington's Pharmaceutical Sciences", Mace Publishing Co., Philadelphia, PA, 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (G.S. Banker and C.T. Rhodes, eds.).

[0099] “IC 50 ” or “EC 50 ” refers to the inhibitory concentration required to achieve 50% of the maximal desired effect. In many cases, the maximal desired effect herein is the inhibition of LPA-induced LPAR1 activation. This term is obtained using in vitro assays that assess concentration-dependent inhibition of LPA-induced LPAR1 activity, such as a calcium mobilization assay.

[0100] "Treatment" or "treating" is a method for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis of the disease or condition); and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing quality of life, and / or prolonging survival). In some embodiments, the term "treating" means administering a compound or pharmaceutically acceptable salt of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (III) for the purpose of: (i) delaying the onset of disease, i.e., preventing or delaying the development of clinical symptoms of disease; (ii) inhibiting disease, i.e., preventing the development of clinical symptoms; and / or (iii) ameliorating disease, i.e., causing regression of clinical symptoms or their severity.

[0101] "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compound can be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0102] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0103] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, refers to an amount sufficient to achieve treatment when administered to a subject, to provide a therapeutic benefit, such as improving symptoms or slowing disease progression. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition that is responsive to an LPAR1 antagonist. A therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by one skilled in the art.

[0104] List of abbreviations and acronyms

[0105] Abbreviation meaning

[0106] ACN or MeCN Acetonitrile

[0107] aq. aqueous solution

[0108] Bn benzyl

[0109] COPD Chronic Obstructive Pulmonary Disease

[0110] DCM dichloromethane

[0111] DIEA N,N-diisopropylethylamine

[0112] DMF N,N-dimethylformamide

[0113] DMSO dimethyl sulfoxide

[0114] DPPA diphenylphosphoryl azide

[0115] EA Ethyl acetate

[0116] EDTA Ethylenediaminetetraacetic acid

[0117] ESI electrospray ionization

[0118] Et ethyl

[0119] Et2O ether

[0120] EtOAc

[0121] h or hr hours

[0122] HBSS Hank's Balanced Salt Solution

[0123] HCC Hepatocellular carcinoma

[0124] HPLC high-performance liquid chromatography

[0125] LCMS or LC / MS liquid chromatography mass spectrometry

[0126] LPA Lysophosphatidic acid

[0127] LPC Lysophosphatidylcholine

[0128] Me methyl

[0129] MeOH methanol

[0130] MS

[0131] m / z mass-to-charge ratio

[0132] NADPH dihydronicotinamide-adenine dinucleotide phosphate

[0133] NAFLD Non-alcoholic fatty liver disease

[0134] NASH Nonalcoholic steatohepatitis

[0135] NMR nuclear magnetic resonance spectroscopy

[0136] PBC Primary Biliary Cirrhosis

[0137] PE petroleum ether

[0138] PSC Primary sclerosing cholangitis

[0139] rpm revolutions per minute

[0140] RT or rt room temperature

[0141] sat. saturated

[0142] TEMPO 2,2,6,6-tetramethylpiperidinyl 1-oxyl

[0143] TFA trifluoroacetic acid

[0144] THF Tetrahydrofuran

[0145] T3P Propanephosphonic Anhydride

[0146] As used herein, "LPAR1 antagonist" refers to any agent capable of binding to and inhibiting LPAR1. LPAR1, also known as LPA1, is a GPCR that binds to the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences for LPAR1 include NCBI reference sequences NP_001392 (human protein), NP_001277415 (mouse protein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1 antagonists can act as competitive inhibitors of full or partial LPAR1 agonists, or as inverse agonists. The activity of LPAR antagonists can be measured by methods known in the art, such as those described and referenced in Castelino et al., 2010, Arthritis Rheum., May 2011, Vol. 63, No. 5: pp. 1405-1415 or Swaney et al., J Pharmacol Exp Ther., March 2011, Vol. 336, No. 3: pp. 693-700.

[0147] As used herein, "ACC inhibitor" refers to any agent capable of binding to and inhibiting acetyl-CoA carboxylase (ACC). An ACC inhibitor can act as an inhibitor or partial inhibitor of ACC. The agent can be a chemical compound or a biomolecule (e.g., a protein or an antibody). The activity of an ACC inhibitor can be measured by methods known in the art (such as those described and cited in U.S. Patent No. 8,969,557 and / or U.S. Patent No. 10,208,063, both of which are incorporated herein by reference in their entirety).

[0148] As referred to herein, an "ASK1 inhibitor" can be any agent that can inactivate the apoptosis signal-regulating kinase 1 (ASK1) protein. The agent can be a chemical compound or a biomolecule (e.g., a protein or an antibody). ASK1 protein activity can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, for example, US2007 / 0276050). Exemplary ASK1 substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragments thereof. ASK1 protein activity can also be measured by the phosphorylation level of the ASK1 protein (e.g., the phosphorylation level of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein). For example, if the ASK1 protein comprises the full-length human ASK1 protein sequence, an ASK1 inhibitor can reduce phosphorylation at T838 within the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect phosphorylation levels.

[0149] As used herein, "FXR agonist" refers to any agent that can bind to and activate the farnesoid X receptor (FXR), which may also be referred to as the bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) receptor. FXR agonists can act as agonists or partial agonists of FXR. The agent can be a chemical compound or a biomolecule (e.g., a protein or antibody). The activity of an FXR agonist can be measured by several different methods, for example, in an in vitro assay using a fluorescence resonance energy transfer (FRET) cell-free assay as described in Pellicciari et al., Journal of Medicinal Chemistry, 2002, Vol. 15, No. 45: pp. 3569-3572.

[0150] Compound

[0151] In one embodiment, provided herein is a compound of formula (I),

[0152]

[0153] or a pharmaceutically acceptable salt thereof,

[0154] in:

[0155] R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl,

[0156] Each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1Cmay be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and

[0157] Each R 1B1 、R 1B2 and R 1B3 Alkyl and each R 1B1 、R 1B2 and R 1B3 The cycloalkyl group is optionally substituted with 1 to 3 halogens, or

[0158] R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 1E Replace these R 1E may be the same or different, wherein each R 1E independently selected from halogen, cyano, hydroxy, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -OR 1F1 ,-N(R 1F1 )(R 1F2 ), -C(O)N(R 1F1 )(R 1F2 ), -NR 1F1 C(O)R 1F2 , -S(O) 0-2 R 1F1 ,-S(O)2N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O)2R 1F2 , where each R 1F1 and R 1F2 are independently hydrogen or C 1-6 Alkyl, where each R1E Alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 R 1G Replace these R 1G may be the same or different, and wherein each R 1G Independently C 1-4 Alkyl, C 1-4 alkoxy, hydroxy, halogen or cyano;

[0159] R 2 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0160] R 2 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0161] Each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C optionally substituted by 1 to 3 halogens 1-3 Alkyl, these halogens may be the same or different;

[0162] n is 0, 1, 2, 3 or 4;

[0163] R 4 is C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 are independently hydrogen, C 1-6 Alkyl or C 3-10 cycloalkyl; or

[0164] R 4 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 alkoxy;

[0165] X 1 、X 2 、X 3 and X 4 Each of is independently selected from CH and N;

[0166] Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 );and

[0167] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are selected from C 1-4 Alkoxy and halogen; or

[0168] Y 1 and Z together with the carbon to which they are attached form C 3-6 Cycloalkyl, C 6-12aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 The aryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0169] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0170] R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl,

[0171] Each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and each R 1D1 and R 1D2 are independently hydrogen or C 1-6 Alkyl; or

[0172] R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 1E Replace these R 1E may be the same or different, wherein each R 1E independently selected from halogen, cyano, hydroxy, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -OR 1F1 ,-N(R 1F1 )(R 1F2 ), -C(O)N(R 1F1 )(R 1F2 ), -NR 1F1 C(O)R 1F2 , -S(O) 0-2 R1F1 ,-S(O)2N(R 1F1 )(R 1F2 ) and NR 1F1 S(O)2R 1F2 , where each R 1F1 and R 1F2 are independently hydrogen or C 1-6 Alkyl, where each R 1E Alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 R 1G Replace these R 1G may be the same or different, and wherein each R 1G Independently C 1-4 Alkyl, C 1-4 alkoxy, hydroxy, halogen or cyano;

[0173] R 2 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0174] R 2 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0175] Each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C optionally substituted by 1 to 3 halogens 1-3 Alkyl, these halogens may be the same or different;

[0176] n is 0, 1, 2, 3 or 4;

[0177] R 4 is C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4Alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 are independently hydrogen, C 1-6 Alkyl or C 3-10 cycloalkyl; or

[0178] R 4 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 alkoxy;

[0179] X 1 、X 2 、X 3 and X 4 Each of is independently selected from CH and N;

[0180] Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 );and

[0181] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are selected from C 1-4 Alkoxy and halogen; or

[0182] Y 1and Z together with the carbon to which they are attached form C 3-6 Cycloalkyl, C 6-12 aryl, a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 The aryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0183] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia):

[0184]

[0185] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 2 For hydrogen.

[0187] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 4 is C optionally substituted by 1 to 3 substituents 1-3 Alkyl, these substituents may be the same or different and are independently selected from cyano and F. In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, R 4 is -CH3.

[0188] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 CH, X 2 CH, X 3 is CH, and X 4 For CH.

[0189] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X1 C(R 3 ), X 2 CH, X 3 is CH, and X 4 For CH.

[0190] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 C(R 3 ), X 2 CH, X 3 C(R 3 ), and X 4 For CH.

[0191] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 N, X 2 CH, X 3 is CH, and X 4 C(R 3 ).

[0192] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 CH, X 2 N, X 3 is CH, and X 4 C(R 3 ).

[0193] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 C(R 3 ), X 2 N, X 3 is CH, and X 4 For CH.

[0194] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 C(R 3 ), X 2 N, X 3 is CH, and X 4 C(R 3 ).

[0195] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 C(R 3 ), X 2 CH, X 3 C(R 3 ), and X4 For CH.

[0196] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 N, X 2 CH, X 3 is N, and X 4 C(R 3 ).

[0197] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 C(R 3 ), X 2 N, X 3 is N, and X 4 For CH.

[0198] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 CH, X 2 N, X 3 is N, and X 4 For CH.

[0199] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 N, X 2 CH, X 3 is CH, and X 4 For CH.

[0200] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 N, X 2 CH, X 3 is N, and X 4 For CH.

[0201] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 CH, X 2 N, X 3 C(R 3 ), and X 4 For CH.

[0202] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 CH, X 2 N, X 3 is CH, and X 4 For CH.

[0203] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 2 For hydrogen.

[0204] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIa):

[0205]

[0206] or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIb):

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein each R 3 Can be the same or different.

[0210] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIc):

[0211]

[0212] or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IId):

[0214]

[0215] or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIe):

[0217]

[0218] or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIf):

[0220]

[0221] or a pharmaceutically acceptable salt thereof, wherein each R 3 Can be the same or different.

[0222] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIg):

[0223]

[0224] or a pharmaceutically acceptable salt thereof, wherein each R 3 Can be the same or different.

[0225] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIh):

[0226]

[0227] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIi):

[0229]

[0230] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIj):

[0232]

[0233] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIk):

[0235]

[0236] or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (III):

[0238]

[0239] or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIm):

[0241]

[0242]

[0243] or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIn):

[0245]

[0246] or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIo):

[0248]

[0249] or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 For hydrogen.

[0251] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 、R 1B2 and R 1B3 Alkyl and each R 1B1 、R 1B2 and R 1B3 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and each R 1D1 and R 1D2 are independently hydrogen or C 1-6 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A Independently selected from halogen, cyano, hydroxyl, C 1-4 Alkoxy and C 3-6 In some embodiments, R 1A or R 1CIn some embodiments, each halogen in is -F. 1A In some embodiments, R 1A or R 1C In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A is independently selected from -F, -CN, -OH, -OCH3 or cyclopropyl. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn) or (IIo), or a pharmaceutically acceptable salt thereof, R 1 -CH3, -CHF2, -CF3,

[0252] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 1E Replace these R 1E may be the same or different, wherein each R 1E independently selected from halogen, cyano, hydroxy, oxo, C 1-4 Alkyl, C 3-10cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -OR 1F1 ,-N(R 1F1 )(R 1F2 ), -C(O)N(R 1F1 )(R 1F2 ), -NR 1F1 C(O)R 1F2 , -S(O) 0-2 R 1F1 ,-S(O)2N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O)2R 1F2 , where each R 1F1 and R 1F2 are independently hydrogen or C 1-6 Alkyl, where each R 1E Alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 R 1G Replace these R 1G may be the same or different, and wherein each R 1G Independently C 1-4 Alkyl, C 1-4 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 -R 1E Replace these -R 1E may be the same or different, wherein each R 1E independently selected from halogen and -C(O)N(R 1F1 )(R 1F1 ), where each -R 1F1 and -R 1F1 are independently hydrogen or C 1-4In some embodiments, each -R 1E Halogen is -F. In some embodiments, each -R 1G Halogen is -F. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 is independently -H, -CH3, -C2H5 or -C(CH3)3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn) or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0253] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2, -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or -C 3-6 Cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 Alkyl and each R 1B1 and R 1B2 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and each R 1D1 and R 1D2 are independently hydrogen or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 alkyl, a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen, -OR 1B1 and -C(O)N(R 1B1 )(R 1B2 ), where each R 1B1 and R 1B2 are independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, and wherein each R1A C 1-4 The alkyl group is optionally substituted with 1 to 3 halogens, and R 1A Each heteroaryl in is optionally substituted by 1 to 3 C 1-4 alkyl substituted, and wherein each R 1B1 and R 1B2 Alkyl and each R 1B1 and R 1B2 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 alkyl, a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen, -OR 1B1 and -C(O)N(R 1B1 )(R 1B2 ), where each R 1B1 and R 1B2 are independently hydrogen or C 1-4 alkyl, and wherein each R 1A C 1-4 The alkyl group is optionally substituted with 1 to 3 halogens, and R 1A Each heteroaryl in is optionally substituted by 1 to 3 C 1-4 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is cyclopropyl or cyclobutyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different and are independently selected from -F, -Cl, -CN, =O, -OH, -CH3, -CH2F, -CHF2, -CF3, -CH2-OH, -CH2-NH2, -OCH3, -NH2, -NH-CH2-CF3, -NO2, cyclopropyl, isoxazolyl, phenyl, pyridinyl, and -C(O)NH2, wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH3. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 is cyclopropyl or cyclobutyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A and -F, -Cl, -CN, =O, -OH, -CH, -CHF, -CHF, -CF, -CH-OH, -CH-NH, -OCH, -NH, cyclopropyl, isoxazolyl, phenyl, pyridinyl, and -C(O)NH, wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), or pharmaceutically acceptable salts thereof, R 1 is cyclopropyl or cyclobutyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A and -C(O)NH2, wherein each isoxazolyl or pyridyl is optionally substituted with 1 to 2 -CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0254]

[0255]

[0256] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0257]

[0258] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0259] In some embodiments, C 3-10 Cycloalkyl is C 5-10 In some embodiments, C 5-10 Bicyclic cycloalkyl is C 5-8 In some embodiments, the C 5-8 The bridged bicyclic cycloalkyl is a bicyclopentyl or bicyclooctyl group, each optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, -O-CH3, -NH-CO-CH3, -SO2-CH3 and oxetanyl. In some embodiments, the C 5-8 The bridged bicyclic cycloalkyl is bicyclopentyl or bicyclooctyl, each optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, -O-CH3, and oxetanyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 for In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), (IIj), (IIk), (III), (IIm), (IIn), (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments, C 5-10 Bicyclic cycloalkyl is C 5-10 In some embodiments, the C 5-10 The spirobicyclic cycloalkyl group is spiropentyl, spirohexyl, spiroheptyl or spirodecanyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A and -F, -Cl, -OH, -CH, -CH2F, -CHF2, -CF3, -CN, and -O-CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0260] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclic group being optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 Alkyl and each R 1B1 and R 1B2 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclic group being optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1is a 3- to 8-membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclic group being optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different and are independently selected from halogen, cyano, oxo or C 1-4 Alkyl, where each R 1A C 1-4 The alkyl group is optionally substituted with 1 to 3 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl or morpholinyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A and -F, -Cl, -OH, -CN, -CH, -CH2F, -CHF2, -CF3, -C2H5, -CH2-CF3, and -O-CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl or morpholinyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A and -F, -Cl, -OH, -CN, -CH, -CH2F, -CHF2, -CF3, and -O-CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0261] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 In some embodiments, the bicyclic heterocyclic group is a bridged bicyclic heterocyclic group. In some embodiments, the bridged bicyclic heterocyclic group is optionally substituted with 1 to 4 R 1A Substituted oxabicyclohexyl, these R 1A may be the same or different, wherein each R 1A is independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments, the bicyclic heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl is optionally substituted with 1 to 4 R 1A Substituted oxabicyclohexyl, these R 1A may be the same or different, wherein each R 1A is independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3. In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for In some embodiments, the bicyclic heterocyclic radical is a spiro bicyclic heterocyclic radical. In some embodiments, the spiro bicyclic heterocyclic radical is an oxaspiroheptane optionally substituted with 1 to 4 substituents, which substituents may be the same or different and are each independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 for

[0262] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted 6- to 10-membered aryl groups, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 Alkyl and each R 1B1 and R 1B2 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1 is optionally replaced by 1 to 4 R 1A Substituted 6- to 10-membered aryl groups, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2, -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently selected from hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 In some embodiments, R 1 is optionally replaced by 1 to 4 R 1A Substituted phenyl groups, these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, C 1-3 Alkyl or C 1-4 In some embodiments, R 1 is optionally replaced by 1 to 3 R 1A Substituted phenyl groups, these R 1A may be the same or different, wherein each R 1A Independently selected from -F, -Cl, -CN or -CH3.

[0263] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, R 1 is a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heteroaryl group being optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1Aindependently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 Alkyl and each R 1B1 and R 1B2 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, R 1is a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heteroaryl group being optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 1B1 )(R 1B2 ), -OR 1B1 , -SR 1B1 ,-C(O)N(R 1B1 )(R 1B2 ), -NR 1B1 C(O)R 1B2 , -NR 1B1 C(O)N(R 1B2 )(R 1B3 ), -S(O) 0-2 R 1B1 ,-S(O)2N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 、R 1B2 and R 1B3 are independently hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1Aindependently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl, a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen and oxygen, -N(R 1B1 )(R 1B2 ), -OR 1B1 and -S(O) 0-2 R 1B1 , where each R 1B1 and R 1B2 are independently hydrogen or C 1-6 Alkyl, where each R 1A Alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C Independently C 1-4 In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted by 1 to 4 R 1A Replace these R 1A may be the same or different, wherein each R 1A are independently selected from halogen, cyano, oxo, methyl, cyclopropyl, morpholinyl, -N(R 1B1 )(R 1B2 ),-OR 1B1 and -S(O) 0-2 R 1B1 , where each R 1B1 and R 1B2 are independently hydrogen or methyl, wherein each R 1A Methyl, cyclopropyl and morpholinyl are optionally substituted with 1 to 4 R 1C Replace these R 1C may be the same or different, and wherein each R 1C is independently methyl, halogen or cyano. In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted with 1 to 4 substituents, which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl or C 1-4 In some embodiments, R 1is imidazolyl, pyrazolyl or pyridinyl, each optionally substituted by 1 to 4 substituents, which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl or C 1-4 In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted with 1 to 3 substituents, which substituents may be the same or different and are each independently selected from -F, -Cl, -CN, -CH3, -CHF2, -CF3, -OCH3, -NH2, -N(CH3)2, -SO2, -CH3, In some embodiments, R 1 is imidazolyl, pyrazolyl or pyridinyl, each optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F, -Cl, -CN or -CH3. In some embodiments, R 1 for In some embodiments, R 1 for

[0264] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C optionally substituted by 1 to 3 halogens 1-4 In some embodiments, each R 3 independently selected from C optionally substituted by 1 to 3 substituents 1-6Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, R 3 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, R 3 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, R 3 In some embodiments of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), or (IIn), or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0265] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, Y 1 is hydrogen, deuterium or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, independently selected from halogen, cyano, C 2-3 Alkynyl, C 1-4Alkoxy and -C(O)NH-(C 1-4 H 3-9 In some embodiments, Y1 is C optionally substituted with 1 to 3 substituents. 1-4 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 In some embodiments, Y is methyl, optionally substituted with 1 to 3 substituents, which may be the same or different and each independently selected from -F, -Cl, -CN, and -O-CH. In some embodiments, Y is -CH or -CHF.

[0266] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, Z is C optionally substituted with 1 to 3 substituents. 6-12 Aryl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from C 1-4 In some embodiments, Z is phenyl optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from halogen and C 1-4 In some embodiments, Z is phenyl optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F and -Cl. In some embodiments, Z is In some embodiments, Z is a 5-membered or 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from halogen and C 1-4 In some embodiments, Z is pyridyl optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl, -Br and -CH3. In some embodiments, Z is

[0267] In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, Y is -CH, and Z is In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, Y is -CH, and Z is

[0268] In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289] or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), (IIo), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0309]

[0310] or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0315]

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0318]

[0319] or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0321]

[0322] or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0324]

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0330]

[0331] or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments, the compound of Formula (I), (Ia) or (IIo), or a pharmaceutically acceptable salt thereof, is:

[0333]

[0334] or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the compound of Formula (I), (Ia) or (IIe), or a pharmaceutically acceptable salt thereof, is:

[0336]

[0337] or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the compound of Formula (I), (Ia) or (IIe), or a pharmaceutically acceptable salt thereof, is:

[0339]

[0340] or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound of Formula (I), (Ia) or (IIe), or a pharmaceutically acceptable salt thereof, is:

[0342]

[0343] or a pharmaceutically acceptable salt thereof.

[0344] Pharmaceutical composition and mode of administration

[0345] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0346] The pharmaceutical compositions of the present disclosure may additionally comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0347] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ophthalmic (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most appropriate route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art.

[0348] In actual use, the compounds of the present disclosure can be closely blended and combined with pharmaceutical carriers as active ingredients according to conventional pharmaceutical compounding techniques. Depending on the form of the preparation required for administration, such as oral or parenteral (including intravenous), the carrier can take various forms. When preparing a composition for oral dosage forms, any conventional pharmaceutical medium can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc. in the case of oral liquid preparations (such as suspensions, elixirs, and solutions); or in the case of oral solid preparations (such as powders, hard and soft capsules, and tablets), carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., wherein solid oral preparations are preferred over liquid preparations.

[0349] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and formulations should contain at least 0.1% active compound. Of course, the percentage of active compound in these compositions can vary and can conveniently range from about 2% to about 60% of the unit weight. The amount of active compound in such therapeutically useful compositions is such that an effective dose will be obtained. The active compound can also be administered intranasally, for example, as liquid drops or sprays.

[0350] Tablets, pills, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as a fatty oil.

[0351] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavoring).

[0352] In some embodiments, the compounds of the present disclosure may also be used as salts with various countercations to produce orally acceptable formulations.

[0353] Compounds of the present disclosure can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with a surfactant (such as hydroxypropyl cellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Under general storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0354] The pharmaceutical form that is suitable for injectable purposes comprises sterile aqueous solution or dispersion and the sterile powder for the temporary preparation of sterile injectable solution or dispersion.In all cases, this form must be sterile, and must be the fluid that reaches the degree of easy injection.It must be stable under manufacturing and storage conditions, and must prevent the contamination of microorganisms such as bacteria and fungi.Carrier can be the solvent or dispersion medium containing for example water, ethanol, polyol (for example glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.

[0355] Any suitable route of administration can be used to provide an effective dose of the compounds of the present disclosure to mammals, especially humans. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0356] Reagent test kit

[0357] Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue, and labels and / or instructions for using the compound in treating indications (including diseases or conditions described herein).

[0358] Also provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container. The container can be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

[0359] Treatment methods and uses

[0360] The present disclosure also relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by binding to LPAR1. The present disclosure also relates to the use of the compounds for preparing medicaments for treating and / or preventing diseases and / or conditions by binding to LPAR1.

[0361] The medicaments mentioned herein can be prepared by conventional methods, comprising a combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0362] In some embodiments, provided herein is a method for treating and / or preventing an LPAR1-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IIId), (IIe), (IIf), (IIg), (IIh), (III), (IIj), (IIIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, LPARl -mediated diseases or conditions include those in which an absolute or relative excess of LPA is present and / or observed.

[0364] In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis, wound healing, cancer, pain, respiratory disease, allergic disease, neurological disease, cardiovascular disease, or inflammatory disease.

[0365] In some embodiments, the disease or illness of LPAR1 mediation are interstitial lung disease (ILD).In some embodiments, interstitial lung disease (ILD) is nonspecific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, the ILD relevant to occupational exposure, progressive fibrosis ILD, idiopathic interstitial pneumonia (IIP), the interstitial lung disease (CTD-ILD) relevant to connective tissue disease, the relevant ILD of rheumatoid arthritis, the relevant ILD of scleroderma or extrinsic alveolitis.

[0366] In some embodiments, the LPAR1-mediated disease or disorder is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is complement glomerulopathy, membranous glomerulopathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS) or Alport syndrome.

[0367] In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis. In some embodiments, the fibrosis comprises pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, or myocardial fibrosis.

[0368] In some embodiments, the disease or illness of LPAR1 mediation include pulmonary fibrosis.In some embodiments, pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF).In some embodiments, pulmonary fibrosis includes progressive fibrosing interstitial lung disease (PF-ILD).In some embodiments, pulmonary fibrosis includes pulmonary fibrosis secondary to systemic inflammatory disease, such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury and acute respiratory distress (including bacterial pneumonia induction, trauma induction, viral pneumonia induction, ventilator induction, non-pulmonary sepsis induction and inhalation).

[0369] In some embodiments, the disease or disorder mediated by LPAR1 includes renal fibrosis. In some embodiments, renal fibrosis includes chronic kidney disease (renal fibrosis) associated with injury / fibrosis, such as secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts and Alport's glomerulonephritis; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis.

[0370] In some embodiments, the LPAR1-mediated disease or condition comprises liver fibrosis. In some embodiments, liver fibrosis comprises cirrhosis, alcoholic liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis.

[0371] In some embodiments, the LPAR1 -mediated disease or condition comprises head and neck fibrosis, such as radiation-induced head and neck fibrosis.

[0372] In some embodiments, LPAR1-mediated diseases or conditions include, for example, corneal scarring caused by LASIK (laser in situ keratomileusis), keratoplasty, or trabeculectomy. In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, is used to improve decreased corneal sensation caused by corneal surgery (such as LASIK or cataract surgery), decreased corneal sensation caused by corneal degeneration, and dry eye caused thereby. In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, is used to treat or prevent ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, is used to treat or prevent Sjogren's disease or an inflammatory disease associated with dry eye.

[0373] In some embodiments, the LPAR1-mediated disease or disorder comprises another fibrotic disorder, such as hypertrophic scars and keloids, e.g., burn-induced or surgical sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

[0374] In some embodiments, the LPAR1-mediated disease or condition comprises pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the pain comprises acute pain. In some embodiments, the pain comprises chronic pain.

[0375] In some embodiments, the disease or condition mediated by LPAR1 includes cancer. In some embodiments, cancer includes ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer) and thyroid cancer. In some embodiments, cancer includes solid tumors, such as bladder tumors, intestinal tumors, brain tumors, breast tumors, endometrial tumors, heart tumors, kidney tumors, lung tumors, lymphoid tissue tumors (lymphomas), ovarian tumors, pancreatic or other endocrine organ (thyroid) tumors, prostate tumors, skin tumors (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) at any stage of the disease with or without cancer cell metastasis.In some embodiments, cancer comprises acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoma, ependymoma, esophageal cancer, Ewing's tumor Tumor family, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, skin T Cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade tumor, pancreatic cancer, papillomatous hyperplasia, parathyroid cancer, penile cancer, nasopharyngeal carcinoma, moderately differentiated pineal parenchymal tumor, pineoblastoma, and supratentorial primitive neuroblastoma Transectodermal tumors, pituitary tumors, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney cancer), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing family of sarcoma tumors, sarcoma, Kaposi's disease, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymic cancer, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstmm's macroglobulinemia, and Wilms' tumor.

[0376] In some embodiments, the disease or condition mediated by LPAR1 includes a respiratory disease or an allergic disease. In some embodiments, respiratory disease or allergic disease include asthma, peribronchial fibrosis, bronchiolitis obliterans and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchiolitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis. In some embodiments, respiratory diseases include adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood onset asthma, adult onset asthma, cough variant asthma, occupational asthma, hormone-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis and hypoxia.

[0377] In some embodiments, LPAR1-mediated diseases or conditions include nervous system diseases. In some embodiments, nervous system diseases include Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological disorders found after blunt trauma or surgical trauma (including postoperative cognitive dysfunction and spinal cord injury or brainstem injury), and neurological aspects of the disease (such as lumbar degenerative disc disease and sciatica).

[0378] In some embodiments, LPAR1-mediated diseases or conditions include cardiovascular diseases. In some embodiments, cardiovascular diseases include arrhythmias (atrial arrhythmias or ventricular arrhythmias or both); atherosclerosis and its complications; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac aneurysms or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of a limb, organ, or tissue; reperfusion injury after ischemia of the brain, heart, or other organs or tissues; endotoxic shock, surgical shock, or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities; and cardiovascular insufficiency limited to a single organ or tissue.

[0379] In some embodiments, LPAR1-mediated diseases or conditions include pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative diseases, and inflammatory disorders.

[0380] In some embodiments, the disease or condition mediated by LPAR1 is a liver disease. In some embodiments, the liver disease is hepatitis C, liver cancer, familial mixed hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC) or (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease includes portal hypertension. In some embodiments, liver cancer includes hepatocellular carcinoma (HCC), bile duct cancer, angiosarcoma or hemangioendothelioma. In some embodiments, liver cancer includes HCC. In some embodiments, NAFLD includes fatty degeneration. In some embodiments, NAFLD includes NASH. In some embodiments, NAFLD or NASH include liver fibrosis. In some embodiments, NAFLD or NASH include liver cirrhosis. In some embodiments, NAFLD or NASH include compensated liver cirrhosis. In some embodiments, NAFLD or NASH include decompensated liver fibrosis. In some embodiments, NAFLD includes HCC. In some embodiments, the liver disease is NASH.

[0381] In some embodiments, provided herein is a method for treating and / or preventing NAFLD or NASH in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IIId), (IIe), (IIf), (IIg), (IIh), (III), (III), (IIIj), (IIIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises liver cirrhosis. In some embodiments, liver cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH comprises HCC.

[0382] In some embodiments, provided herein is a method of preventing a liver disease or condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IIId), (IIe), (IIf), (IIg), (IIh), (III), (III), (IIIj), (IIIk), (III), (IIIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or disorder is HCC.

[0383] In some embodiments, the present disclosure relates to the use of a compound according to Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing and / or treating an LPAR1-mediated disease or condition disclosed herein.

[0384] dose

[0385] The effective dosage of the active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art.

[0386] When treating or preventing LPAR1-mediated diseases or conditions for which the compounds of the present invention are applicable, satisfactory results are generally obtained when the compounds of the present invention are administered at a daily dose of about 0.1 mg to about 300 mg per kilogram of animal body weight. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses twice to six times a day or in a sustained release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose will typically be about 0.1 mg to about 200 mg. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dose is from about 1 mg to about 900 mg, from about 1 mg to about 800 mg, from about 1 mg to about 700 mg, from about 1 mg to about 600 mg, from about 1 mg to about 400 mg, from about 1 mg to about 300 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg.

[0387] The compounds of the present application or compositions thereof can be administered once, twice, three times, or four times daily using any suitable mode described above. Furthermore, administration or treatment with the compounds can continue for multiple days; for example, for one treatment cycle, treatment will typically continue for at least 7, 14, or 28 days. Treatment cycles are typically alternating with rest periods of about 1 to 28 days, typically about 7 or about 14 days, between cycles. In other embodiments, treatment cycles can also be continuous.

[0388] In some embodiments, the methods provided herein comprise administering to a subject an initial daily dose of about 1 mg to 800 mg of a compound described herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0389] combination

[0390] In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIj), (IIk), (III), (IIIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0391] In some embodiments, the pharmaceutical compositions provided herein have a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIj), (IIk), (III), (IIIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0392] In some embodiments, the one or more additional therapeutic agents are selected from angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP activated protein kinase (AMPK) activators, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein regulators, autotaxin inhibitors, Ax1 tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, cysteine ​​protease inhibitors, caspase-3 stimulators, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin-1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 inhibitors (DGAT1) inhibitors, diacylglycerol O acyltransferase 1 inhibitors (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endosialin modulators, endothelial nitric oxide synthase stimulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activation protein (FAP) inhibitors, fibroblast growth factor receptor ligands (e.g. FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 receptor agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, glutaminase inhibitor, glutathione precursor, G protein-coupled bile acid receptor 1 agonist, G protein-coupled receptor 84 antagonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha regulator (HNF4A), hepatocyte growth factor regulator, histone deacetylase inhibitor, HMGCoA reductase inhibitors, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors, hypoxia-inducible factor-2α inhibitors, IL-1β antagonists, IL-6 receptor agonists, IL-10 agonists, IL-11 antagonists, IL-17 antagonists, ileal sodium and bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, ketohexokinase (KHK) inhibitors, Klothoβ stimulators, leptin, leptin analogs, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor , LPL gene stimulators, lysophosphatidic acid-1 receptor (LPAR-1) antagonists, lysyl oxidase homolog 2 (LOXL2) inhibitors, LXR inverse agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MCH receptor-1 antagonists, MEKK-5 protein kinase inhibitors, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 regulators, MicroRNA-132 (miR-132) antagonists, MicroRNA-21 (miR-21) inhibitors, mitochondrial uncoupling agents, mixed lineage kinase-3 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin-1 stimulators, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2X7 purinergic receptor modulators, P2Y13 purinergic receptor stimulators, PDE 3 inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor β modulators, peptidyl-prolyl cis-trans isomerase A inhibitors, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPARα agonists, PPARγ agonists, PPARδ agonists, PPARγ modulators, PPARα / δ agonists, PPARα / y / δ agonists, protease-activated receptor-2 antagonists, protein kinase regulators, Rho-associated protein kinase 2 (ROCK2) inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors,

[0393] STAT-3 modulators, stearoyl-CoA desaturase-1 inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, cytokine signaling inhibitor-1 stimulators, cytokine signaling inhibitor-3 stimulators, spleen tyrosine kinase (SYK) inhibitors, transforming growth factor beta (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonists, TGF-β2 antagonists, TGF-β3 antagonists, latent TGFβ complex modulators), TGF-β receptor antagonists, transforming growth factor beta-activated kinase 1 (TAK1), thyroid hormone receptor beta agonists, Toll-like receptor (TLR)-4 antagonists, transglutaminase inhibitors, tumor necrosis factor alpha (TNFα) ligand inhibitors, tumor progression locus 2 (Tp12) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP / TAZ modulators and human zonulin inhibitors.

[0394] Non-limiting examples of the one or more additional therapeutic agents include:

[0395] ACE inhibitors, such as enalapril;

[0396] Acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, or PF-05221304;

[0397] Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341;

[0398] Aldehyde dehydrogenase inhibitors, such as ADX-629;

[0399] Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680;

[0400] Adiponectin receptor agonists, such as ADP-355 or ADP-399;

[0401] Amylin / calcitonin receptor agonists, such as KBP-042 or KBP-089;

[0402] AMP-activated protein kinase stimulators, such as PXL-770 or O-304;

[0403] AMP kinase activators / ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016);

[0404] AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0405] Androgen receptor agonists, such as LPCN-1144;

[0406] Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0407] Angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

[0408] Autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877;

[0409] Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428);

[0410] Bax protein stimulators, such as CBL-514;

[0411] Bioactive lipids, such as DS-102;

[0412] Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab, GWP-42004, REV-200, or CRB-4001;

[0413] Cysteine ​​protease inhibitors, such as emricasan;

[0414] Pan cathepsin B inhibitors, such as VBY-376;

[0415] Pan cathepsin inhibitors, such as VBY-825;

[0416] CCR2 / CCR5 chemokine antagonists, such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213;

[0417] CCR2 chemokine antagonists, such as propagermanium;

[0418] CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200 or DMX-250;

[0419] CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (Popifexor + cenivriviroc); CCR3 chemokine antagonists, such as bertilimumab;

[0420] Chloride channel stimulators, such as cobiprostone or lubiprostone;

[0421] CD3 antagonists, such as NI-0401 (foralumab);

[0422] CXCR4 chemokine antagonists, such as AD-214;

[0423] Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0424] Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610;

[0425] Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx or PF-06865571;

[0426] Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin;

[0427] Eotaxin ligand inhibitors, such as cefixime or CM-101;

[0428] Extracellular matrix protein modulators, such as CNX-024;

[0429] Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228:

[0430] Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0431] Fatty acid synthase inhibitors, such as TVB-2640;

[0432] FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0433] fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282;

[0434] Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, B-1344, or BMS-986036;

[0435] Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001;

[0436] Fish oil compositions, such as eicosapent ethyl

[0437] Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300), or GB1211 (Gal-400);

[0438] Glucagon-like peptide 1 receptor (GLP1R) agonists, such as AC-3174, liraglutide, cotadutide (MEDI-0382), exenatide, SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, or semaglutide;

[0439] Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

[0440] Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0441] G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009 or INT-777;

[0442] Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0443] HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin;

[0444] Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0445] IL-10 agonists, such as peg-ilodecakin;

[0446] ileal sodium-bile acid cotransporter inhibitors, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309);

[0447] Insulin sensitizers such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101;

[0448] Insulin ligands / dual-chain insulin receptor agonists, such as ORMD-0801;

[0449] integrin antagonists, such as IDL-2965;

[0450] IL-6 receptor agonists, such as KM-2702;

[0451] Ketohexokinase (KHK) inhibitors, such as PF-06835919;

[0452] βKlotho (KLB)-FGFlc agonists, such as MK-3655 (NGM-313);

[0453] 5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102);

[0454] Lipoprotein lipase inhibitors, such as CAT-2003;

[0455] LPL gene stimulators, such as alipogene tiparvovec;

[0456] Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238;

[0457] Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198;

[0458] Lysyl oxidase homolog 2 inhibitors, such as simtuzumab or PXS-5382A (PXS-5338);

[0459] Macrophage mannose receptor 1 modulators, such as temanose-Cy3 (technetium Tc 99m temanose);

[0460] membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201;

[0461] MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015 or GS-444217, GST-HG-151;

[0462] MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0463] Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839, or ZN-1345;

[0464] Methyl CpG binding protein 2 modulators, such as cysteamine;

[0465] Mitochondrial uncouplers, such as 2,4-dinitrophenol or HU6;

[0466] Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0467] Myelin basic protein stimulators, such as olesoxime;

[0468] NADPH oxidase 1 / 4 inhibitors, such as GKT-831 or APX-311;

[0469] Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0470] Nitazoxinide;

[0471] NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349);

[0472] Nuclear receptor modulators, such as DUR-928 (DV-928);

[0473] P2X7 purinergic receptor modulators, such as SGM-1019;

[0474] P2Y13 purinergic receptor stimulators, such as CER-209;

[0475] PDE 3 / 4 inhibitors, such as talukast (MN-001);

[0476] PDE 5 inhibitors, such as sildenafil or MSTM-102;

[0477] PDGF receptor β modulators, such as BOT-191 or BOT-509;

[0478] Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, or NV-556 (NVP-025);

[0479] Phenylalanine hydroxylase stimulators, such as HepaStem;

[0480] PPAR agonists (including PPAR alpha agonists, PPAR alpha / delta agonists, PPAR alpha / delta / gamma agonists, PPAR delta agonists) such as elafibranor (GFT-505), MBX-8025, the deuterated R-enantiomer of pioglitazone, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR alpha agonists such as aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, pemafibrate, roniflbrate, bisfibrate, omega-3 fatty acids (fish oils, e.g., eicosapent ethyl) or docosahexaenoic acid), pironic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saroglitazar;

[0481] PPARα / δ agonists, such as elabenolide;

[0482] PPARα / δ / γ agonists, such as laniflbranor;

[0483] PPARδ agonists, such as seladelpar;

[0484] Protease-activated receptor-2 antagonists, such as PZ-235;

[0485] Protein kinase modulators, such as CNX-014;

[0486] Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325) or KD-025;

[0487] Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A;

[0488] S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0489] sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, or sotagliflozin;

[0490] SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463;

[0491] Stearoyl-CoA desaturase-1 inhibitors, such as aramchol;

[0492] Thyroid hormone receptor (THR) beta agonists, such as resmetriom (MGL-3196), MGL-3745, or VK-2809;

[0493] TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0494] TLR-4 antagonists, such as JKB-121;

[0495] Tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137 (repurposed nitazoxanide);

[0496] GPCR modulators, such as CNX-023;

[0497] Nuclear hormone receptor modulators, such as Px-102;

[0498] Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0499] Human zonulin inhibitors, such as lorazotide acetate (INN-202).

[0500] Additional non-limiting examples of the one or more additional therapeutic agents include:

[0501] ACE inhibitors, such as benazepril and imidapril;

[0502] Adenosine A3 receptor antagonists, such as FM-101;

[0503] Adropin stimulators, such as RBT-2;

[0504] Albumin modulators, such as SYNT-002;

[0505] Aldosterone / mineralocorticoid receptor antagonists, such as MT-3995;

[0506] Allogeneic bone marrow-derived mesenchymal stem cell therapy, such as ORBCEL-M;

[0507] Allogeneic expanded adipose-derived stem cell therapy, such as Elixcyte TM ;

[0508] AMP-activated protein kinase stimulators / proprotein convertase PC9 inhibitors, such as

[0509] O-304;

[0510] AMP-activated protein kinase stimulators, such as DZCY-01, MK-8722, and PXL-770;

[0511] Angiotensin II AT-1 receptor / CCR2 chemokine antagonists, such as DMX-200;

[0512] Angiotensin II AT-2 receptor agonists, such as MOR-107 and irbesartan;

[0513] Angiotensin II receptor antagonists, such as losartan;

[0514] Angiotensinogen ligand inhibitors, such as ALN-AGT;

[0515] anti-C1 antibodies, such as BIVV-009 (sutimlimab);

[0516] anti-CB1 antibodies, such as GFB-024;

[0517] Anti-CX3CR1 nanobodies, such as BI-655088;

[0518] Anti-IL-6 antibodies, such as COR-001;

[0519] Anti-VEGF-B antibodies, such as CSL-346;

[0520] APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors, such as apabetalone;

[0521] Bone morphogenetic protein-7 ligand modulators, such as BMP-7;

[0522] Calcium channel inhibitors, such as TBN (xiaotongqin);

[0523] Cannabinoid CB1 receptor antagonists, such as JNJ-2463;

[0524] CB1 inverse agonists, such as CRB-4001;

[0525] Chymase inhibitors, such as fulacimstat (BAY-1142524);

[0526] Cyclooxygenase 1 inhibitors, such as GLY-230;

[0527] Cyclooxygenase 2 / epoxide hydrolase inhibitors, such as COX-2 / soluble epoxide hydrolase;

[0528] Cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors;

[0529] Ectonucleotide pyrophosphatase PDE-2 inhibitors, such as BLD-0409;

[0530] Endothelin ET-A / endothelin ET-B receptor antagonists, such as aprocitentan;

[0531] Enteropeptidase inhibitors, such as SCO-792;

[0532] Erythropoietin receptor antagonists, such as EPO-018B;

[0533] Farnesoid X receptor agonists, such as LMB-763;

[0534] FGF / PDGF / β receptor antagonists / p38 MAP kinase inhibitors, such as pirfenidone;

[0535] GHR / IGF1 gene inhibitors, such as atesidorsen sodium;

[0536] GPR40 agonists / GPR84 antagonists, such as PBI-4050;

[0537] G protein β subunit inhibitors, such as galleon;

[0538] G protein-coupled receptor 84 modulators, such as PBI-4425;

[0539] Growth hormone ligands / growth hormone receptor agonists, such as Jintropin AQ TM ;

[0540] Growth hormone receptor agonists, such as LAT-8881;

[0541] Guanylate cyclase receptor agonists / guanylate cyclase stimulators, such as praliciguat;

[0542] Guanylate cyclase stimulators, such as MRL-001 and runcaciguat;

[0543] Heme oxygenase 1 regulators, such as RBT-1;

[0544] HIF prolyl hydroxylase inhibitors, such as TRGX-154;

[0545] Insulin sensitizers / kallikrein 1 modulators, such as DM-199;

[0546] Integrin α-V / β-3 antagonists, such as VPI-2690B;

[0547] Interleukin-33 ligand inhibitors, such as MEDI-3506;

[0548] Kelch-like ECH-related protein 1 regulator / nuclear factor erythroid 2-related factor 2 stimulator, such as SFX-01;

[0549] LDHA gene inhibitors, such as nedosiran;

[0550] 5-lipoxygenase activating protein inhibitors, such as AZD-5718;

[0551] Lysophosphatidic acid-1 receptor antagonists, such as BMS-002 and EPGN-696;

[0552] Extracellular matrix phosphorylated glycoprotein regulators / phosphoenol receptor agonists, such as TPX-200;

[0553] MEKK-5 protein kinase inhibitors, such as sildenafil;

[0554] Membrane copper amine oxidase inhibitors, such as UD-014;

[0555] Midkine ligand inhibitors, such as CAB-101;

[0556] Mineralocorticoid receptor antagonists, such as AZD-9977, ezetimibe, finerenone, and KBP-5074;

[0557] Myosin 2 inhibitors, such as DeciMab TM ;

[0558] NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors, such as setanaxib;

[0559] NADPH oxidase inhibitors, such as APX-115;

[0560] NK1 receptor antagonists / κ opioid receptor agonists / μ opioid receptor antagonists, such as AV-104;

[0561] stimulator of nuclear factor erythroid 2-related factor 2 / TGFβ ligand inhibitors, such as

[0562] CU01-1001;

[0563] Nuclear factor-κB inhibitors, such as meflunisal and bardoxolone methyl (NSC-713200);

[0564] PDE 4 inhibitors, such as ART-648 and PCS-499;

[0565] PDGF receptor β modulators, such as BOT-191;

[0566] PDGF / VEGF receptor antagonists, such as ANG-3070;

[0567] PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists and partial activators of peroxisome proliferator-activated receptors (PPARs), such as PBI-4547;

[0568] PRKAA2 gene stimulators / AMPK activators, such as PF-06679142 and PF-06685249;

[0569] Prostaglandin I2 (PGI2) agonists, such as YS-1402;

[0570] Protein C activators / glycoprotein Ib (GPIb) antagonists, such as AB-002;

[0571] Protein NOV homologous regulators, such as BLR-200;

[0572] Protein tyrosine phosphatase-1B inhibitors, such as MSI-1436;

[0573] Reactive oxygen species modifier inhibitors, such as SUL-121;

[0574] Renin inhibitors, such as imarikiren hydrochloride;

[0575] Rho-associated protein kinase 2 inhibitors, such as ANG-4201 and RXC-007;

[0576] Sodium glucose transporter-2 inhibitors, such as canagliflozin, dapagliflozin propylene glycol, and empagliflozin;

[0577] Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors, such as

[0578] SER-150;

[0579] Tissue transglutaminase inhibitors, such as ZED-1227;

[0580] TRP cation channel C5 inhibitors, such as GFB-887;

[0581] TRP cation channel C6 inhibitors, such as ALGX-2224;

[0582] cell adhesion molecule inhibitors, such as glycoside bacterial adhesion antagonists;

[0583] Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors, such as velinol (RDEA3170);

[0584] VIP 1 / VIP 2 receptor agonists, such as LBT-3627; and

[0585] Xanthine oxidase inhibitors, such as TMX-049, TMX-049DN.

[0586] In some embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aliperkin, AMX-342, AN-3015, eicosanylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cinevir, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-030, or CNX-031. 4. CNX-025, cobiprostone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elabeno (GFT-505), enlicasin, enalapril, erpagliflozin, emragliflozin, F-351, fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide, Icosabutate (PRC-4016), eicosapent ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, empagliflozin, irbesartan, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (zopifenoxol), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, Cysteamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namasizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, nordeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, pegylated iloleukin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603,PX-L493, PXS-4728A, PZ-235, RDX-009, repagliflozin etabonate, RG-125 (AZD4076), RPI-500, sarogliflozin, semaglutide, cintuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), Symbiotic, TCM-606F, TEV-45478, TQA-3526, Tylus (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, voxibater potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, and ZYSM-007.

[0587] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.

[0588] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

[0589] ASK1 inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Patent No. 2007 / 0276050, US Patent No. 2011 / 0009410, and US Patent No. 2013 / 0197037.

[0590] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.

[0591] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (fisocostat, FIR).

[0592] ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Pat. No. 9,453,026 and US Pat. No. 10,183,951.

[0593] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a PPAR agonist (e.g., a PPARα agonist, a PPARα / δ agonist, a PPARα / δ / γ agonist, a PPARδ agonist) or fish oil, a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor (such as GS-0976 (fisocostat, FIR)) and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPARα agonist. In some embodiments, the PPARα agonist is selected from clofibrate aluminum, bezafibrate), ciprofibrate, fenofibrate choline, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, pemabibrate, ronifibrate, simfibrate, pironic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, moraglitazar, and saroglitazar. In some embodiments, the PPAR agonist (e.g., a PPARα agonist) is fibrate. In some embodiments, the PPAR agonist (e.g., a PPARα agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPARα / δ agonist (e.g., elabenot). In some embodiments, the PPAR agonist is a PPARα / δ / γ agonist (e.g., lanfiberol). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., Serradepa). In some embodiments, the fish oil is an omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl ester (e.g., ).

[0594] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof.

[0595] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0596] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure:

[0597]

[0598] or a pharmaceutically acceptable salt thereof.

[0599] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0600] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a TGFβ antagonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) as provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. TGFβ-specific antibodies can be prepared and characterized using methods known to those skilled in the art (such as those described in PCT International Application Publication No. WO 2018 / 129329 and U.S. Patent No. 9,518,112). In some embodiments, the TGFβ antagonist binds to a TGFβ potential-associated peptide (LAP) (e.g., TGFβ1-LAP). TGFβ1-LAP specific antibodies can be prepared and characterized using methods known to those skilled in the art (such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in an environment-dependent manner (e.g., regardless of the expression of TGFδβ in a specific tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in an environment-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) located in the extracellular matrix (e.g., connective tissue of the liver). In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) located in the thymus, lymph nodes, or tumor microenvironment (e.g., patients with liver cancer). In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) by potential TGFβ binding protein (LTBP). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) by glycoprotein-A repeat major protein (GARP), such as described in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-latency-associated peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in the extracellular matrix (ECM) of connective tissue, such as in the liver.In some embodiments, anti-LAP antibodies specifically bind to the LAP-TGFβ complex on the surface of certain immunosuppressive cell types such as regulatory T cells (Treg), tumor-associated macrophages, or myeloid-derived suppressor cells (e.g., in a tumor microenvironment). In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in any environment. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist includes a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. For example, TGFβ antagonists comprising a TGFβ receptor that can be used in combination with the compositions and methods provided herein have been described in PCT International Publication Nos. WO 2019 / 113123 A1 and WO2019 / 113464 A1.

[0601] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an additional therapeutic agent selected from the group consisting of an ACE inhibitor, an adenosine A3 receptor antagonist, an adropin stimulator, an albumin modulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II receptor antagonist, an angiotensinogen ligand inhibitor, an APOA1 gene stimulator, apolipoprotein L1 modulator, a bone morphogenetic protein-7 ligand modulator, a bromodomain-containing protein 2 inhibitor, a bromodomain-containing protein 4 inhibitor, a calcium channel inhibitor, a cannabinoid CB1 receptor antagonist, a CB1 inverse agonist, a CCR2 chemokine antagonist, a chymase inhibitor, an inhibitor of the C1s subcomponent of complement, a CX3CR1 chemokine antagonist, a cyclooxygenase 1 inhibitor, a cyclooxygenase 2 inhibitor, a cytochrome P45011B2 inhibitors, ectonucleotide pyrophosphatase PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enteropeptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesoid X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonists, GPR40 agonists, GPR84 antagonists, G protein β subunit inhibitors, G protein-coupled receptor 120 agonists, G protein-coupled receptor 84 modulators, growth hormone ligands, growth hormone receptor agonists, guanylate Cyclase receptor agonists, guanylate cyclase stimulators, heme oxygenase 1 regulators, HIF prolyl hydroxylase inhibitors, IGF1 gene inhibitors, IgG receptor FcRn large subunit p51 regulators, IL-6 receptor antagonists, integrin α-V / β-3 antagonists, interleukin-33 ligand inhibitors, Kelch-like ECH-related protein 1 regulators, LDHA gene inhibitors, 5-lipoxygenase activating protein inhibitors, lysophosphatidic acid-1 receptor antagonists, extracellular matrix phosphorylated glycoprotein regulators, membrane copper amine oxidase inhibitors, midkine ligand inhibitors, mineralocorticoid receptor antagonists, myosin 2 inhibitors, NADPH oxidase 1 inhibitors, NADPH oxidase 4 inhibitors, NADPH oxidase inhibitors, NK1 receptor antagonists, nuclear factor erythroid 2-related factor 2 stimulators, nuclear factor κB inhibitors, K opioid receptor agonists, μ opioid receptor antagonists, p38 MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor β modulators, phosphoinositol receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, protein C activators, protein NOV homologous regulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species regulator inhibitors, renin inhibitors, Rho-associated protein kinase 2 inhibitors, SLC22A12 inhibitors, sodium glucose transporter-2 inhibitors, solute carrier family inhibitors, TGFβ ligand inhibitors, TGFβ receptor antagonists, thromboxane A2 receptor antagonists, thromboxane synthesis inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, unspecified cell adhesion molecule inhibitors, urate anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP 1 receptor agonists, VIP 2 receptor agonists and xanthine oxidase inhibitors.

[0602] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an additional therapeutic agent selected from the group consisting of a VEGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, an autotoxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin 3 antibody, an integrin α v -β6 / α v -β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymase inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene / thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors and xanthine oxidase inhibitors.

[0603] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an additional therapeutic agent selected from nintedanib, pirfenidone, panrelumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, sitanacoxib, SER150, RDEA3170, pracciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

[0604] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an additional therapeutic agent selected from A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGFβ antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, antisense oligonucleotide therapy targeting microribonucleic acid, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment TM (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, Sugarheal variant, SZ-005, TCF-12, UMC119-06, VAR-400, veverimer, VS-105, and XRx-221.

[0605] Example

[0606] The following examples are included to demonstrate the specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the technology disclosed in the subsequent examples represents technology that fully functions in the practice of the present disclosure, and therefore can be considered to constitute the specific pattern of its practice. However, according to the present disclosure, it will be appreciated by those skilled in the art that these embodiments are exemplary rather than exhaustive. Without departing from the spirit and scope of the present disclosure, many changes can be made in the disclosed specific embodiments and still similar or similar results can be obtained.

[0607] The compounds disclosed herein can be prepared using appropriate materials according to the procedures of the following schemes and examples, and are further illustrated by the following specific examples. In addition, by utilizing the procedures described herein, in combination with ordinary skills in the art, other compounds of the present disclosure claimed herein can be easily prepared. The examples further illustrate the details for preparing the compounds disclosed herein. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. For the compounds of the embodiments described in this disclosure, inspection of the structure of the compound to be synthesized will provide the identification of each of the substituent groups. In some cases, in view of the examples herein, by inspection process, the identification of the final product can cause the identification of the obvious starting material to be presented. The compound can be separated in the form of its pharmaceutically acceptable salt, such as those described above. The compounds described herein are generally stable and separable at room temperature and pressure.

[0608] The following illustrates the preparation of the compounds disclosed herein. Unless otherwise indicated, the variables have the same meanings as above. The examples presented below are intended to illustrate specific embodiments of the present disclosure. Suitable starting materials, building blocks, and reagents employed in the synthesis described below are commercially available, for example, from AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be conventionally prepared by procedures described in the literature, for example, in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," 5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application," 2nd edition, Wiley-VCH, 2003; Fieser et al., "Fiesers' Reagents for organic Synthesis," John Wiley & Sons 2000.

[0609] General approach

[0610] Plan A

[0611]

[0612] Scheme A provides the general synthesis of triazole carbamate aryl- and heteroaryl-formamide (VI). In the scheme disclosed herein, "A" can be a halogen, such as Cl, Br or I. Aryl or heteroaryl halides (I) can be easily prepared by electrophilic aromatic halogenation of the corresponding aryl or heteroarylamine. Step one describes the acylation of arylamine and heteroarylamine (I). Amine (I) can be treated with acyl chloride or formic acid under standard peptide coupling conditions (such as using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)) to obtain the corresponding amide (II). Alternatively, amine (I) can also be treated with chloroformate to obtain the corresponding carbamate (II). Alternatively, amine (I) can first be treated with phosgene to produce intermediate isocyanate, which can then be trapped by amine to obtain the corresponding urea (II).

[0613] Step 2 describes the general synthesis of aryl or heteroaryl triazole carboxylic acid (IV) via cross-coupling reaction. Aryl or heteroaryl halide (II) can first be converted into corresponding borate such as pinacol borate via Miyaura boronation, and then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid (III) to obtain desired aryl or heteroaryl triazole carboxylic acid (IV). Alternatively, bromotriazole carboxylic acid (III) can first be converted into organozinc species via lithium-halogen exchange and captured with zinc chloride. Next, root-gate cross coupling with aryl or heteroaryl halide (II) gives desired aryl or heteroaryl triazole carboxylic acid (IV).

[0614] Step 3 describes the general synthesis of triazole carbamate aryl- or heteroaryl-carboxamides (VI). Aryl or heteroaryl triazole carboxylic acids (IV) undergo Curtius rearrangement upon treatment with diphenylphosphoryl azide (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilyl azide. The intermediate isocyanate is then trapped with an alcohol (V) to yield the desired aryl or heteroaryl triazole carbamate (VI).

[0615] Plan B

[0616]

[0617] Scheme B provides an alternative synthesis of triazole carbamates aryl- and heteroaryl-formamides (VI). Step one describes the general synthesis of amino-aryl or -heteroaryl triazole carbamates (XI) carried out via cross-coupling reaction. Bromotriazole carbamates (X) can first be converted into organozinc species via lithium-halogen exchange and captured with zinc chloride. Next, cross-coupling with aryl or heteroaryl halide (I) root shore obtains desired amino-aryl or -heteroaryl triazole carbamates (XI). Alternatively, aryl or heteroaryl halide (I) can first be converted into corresponding borate such as pinacol borate via Miyaura boronation, then subjected to Suzuki reaction conditions with bromotriazole carbamates (X), obtain desired amino-aryl or -heteroaryl triazole carbamates (XI).

[0618] Step 1A to step 1B has described the alternative synthesis of amino-aryl or-heteroaryl triazole carbamate (XI).By processing corresponding aryl or heteroaryl amine with tert-Butyl dicarbonate, t-butyl carbamate (XII) can be easily prepared.Can first via Miyaura boronization aryl or heteroaryl halide (XII) be changed into corresponding boric acid ester such as pinacol borate, then make its experience and the Suzuki reaction condition of bromotriazole carbamate (X), obtain desired aryl or heteroaryl triazole carbamate (XIII).Alternatively, can first via lithium-halogen exchange and capture bromotriazole carbamate (X) be changed into organozinc material with zinc chloride.Next, with aryl or heteroaryl halide (XII) root bank cross coupling, obtain desired aryl or heteroaryl triazole carbamate (XIII). Next, the tert-butyl aryl or heteroaryl triazole carbamate (XIII) can be treated with an acid such as hydrogen chloride (HCl) to provide the amino-aryl or -heteroaryl triazole carbamate (XI) as the hydrochloride salt.

[0619] Step 2 describes the general synthesis of triazole carbamate aryl- and heteroaryl-formamides (VI). Amino-aryl or -heteroaryl triazole carbamates (XI) can be treated with acyl chloride or formic acid under standard peptide coupling conditions (such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) to obtain the corresponding amides (VI). Alternatively, amines (XI) can also be treated with chloroformate to obtain the corresponding carbamates (VI). Alternatively, amines (XI) can first be treated with phosgene to produce intermediate isocyanates, which can then be trapped by amines to obtain the corresponding ureas (VI).

[0620] Plan C

[0621]

[0622] Scheme C provides the general alternative synthesis of aryl or heteroaryl triazole carbamate (VI).Step one describes the general synthesis of aryl or heteroaryl triazole carboxylic acid (XIV) carried out via cross-coupling reaction.Can first be converted into corresponding boric acid ester such as pinacol borate by Miyaura boronization by aryl or heteroaryl halide (XII), then make it experience the Suzuki reaction conditions with bromotriazole carboxylic acid (III), obtain desired aryl or heteroaryl triazole carboxylic acid (XIV).Alternatively, can first be converted into organozinc species by bromotriazole carboxylic acid (III) via lithium-halogen exchange and with zinc chloride capture.Next, with the root shore cross coupling of aryl or heteroaryl halide (XII), obtain desired aryl or heteroaryl triazole carboxylic acid (XIV).

[0623] Step 2 describes the general synthesis of aryl or heteroaryl triazole (XIII) containing carbamate. Aryl or heteroaryl triazole carboxylic acid (XIV) undergoes Curtius rearrangement when treated with diphenylphosphoryl azide (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilyl azide. The intermediate isocyanate is then trapped with alcohol (V) to obtain the desired aryl or heteroaryl triazole carbamate (XIII). Step 3 describes the general synthesis of amino-aryl or -heteroaryl triazole carbamate (XI). Available acid such as hydrogen chloride (HCl) can be used to process aryl or heteroaryl tert-butyl carbamate (XIII) to obtain amino-aryl or -heteroaryl triazole carbamate (XI) as a hydrochloride.

[0624] Step 4 describes the general synthesis of triazole carbamate aryl- and heteroaryl-formamides (VI). Available acid chlorides or formic acid can be used to treat amino-aryl or -heteroaryl triazole carbamates (XI) under standard peptide coupling conditions (such as using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)) to obtain the corresponding amides (VI). Alternatively, amines (XI) can also be used to treat chloroformates to obtain the corresponding carbamates (VI). In the case of using phenyl chloroformate, the obtained phenyl carbamate (VI) can be treated with amines to produce the corresponding urea (VI). Alternatively, amines (XI) can first be treated with phosgene to produce intermediate isocyanates, which can then be trapped by amines to obtain the corresponding urea (VI).

[0625] Plan D

[0626]

[0627] Scheme D describes an alternative synthesis of triazole carbamate aryl- and heteroaryl-carboxamides (VI). E can be a halogen, such as -Br or -I. In step one, an aryl- or heteroaryl-dihalide (XV) is Sonagashira coupled with a propargyl alcohol to produce an aryl- or heteroaryl-alkyne (XVI). The alkyne is then subjected to a thermal or catalytic cycloaddition with an azide to produce the corresponding hydroxymethyltriazole (XVII) in step two. Finally, the primary alcohol is oxidized using tetramethylpiperidinyloxy (TEMPO) and sodium chlorite to provide the triazole carboxylic acid (XVIII) in step three.

[0628] In step four, the triazole carboxylic acid (XVIII) is protected as the methyl ester (XIX), such as by treatment with thionyl chloride. In step five, the aryl- or heteroaryl-halide (XIX) is then subjected to a Buchwald-type amination with tert-butyl carbamate to produce the Boc-protected amine (XX).

[0629] In step six, the Boc-protected amine (XX) is exposed to hydrochloric acid to give the hydrochloride (XXI), which can be reacted in step seven with an acyl chloride or formic acid under standard peptide coupling conditions (such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) to give the corresponding amide (XXII). Alternatively, the amine (XXI) can be treated with chloroformate to give the corresponding carbamate (XXII). Alternatively, the amine (XXI) can be first treated with phosgene to produce an intermediate isocyanate, which can then be trapped by an amine to give the corresponding urea (XXII). In step eight, the triazole ester (XXII) can be hydrolyzed when treated with a base such as sodium hydroxide to give the triazole carboxylic acid (IV). Finally, step nine describes the Curtius rearrangement of the triazole carboxylic acid (IV) when treated with diphenylphosphoryl azide (DPPA) or alternatively with a 1-propanephosphonic anhydride (T3P) solution and trimethylsilyl azide. The intermediate isocyanate is then trapped with an alcohol (V) to provide the desired aryl- or heteroaryl-triazole carbamate (VI).

[0630] Example 1: Preparation of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1)

[0631]

[0632] Step 1: 4,5-dibromo-2H-1,2, 3 -Triazole

[0633] Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol) in water (600 mL) at 40° C. The resulting mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with water (2×300 mL) and dried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole.

[0634] Step 2: 4,5-Dibromo-1-methyl-1H-1,2,3-triazole

[0635] To a mixture of 4,5-dibromo-2H-1,2,3-triazole (704 mmol) and KCO (1.4 mol) in THF (1000 mL) was added iodomethane (1.0 mol). The mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (2 x 500 mL). The filtrate was concentrated at 40° C. to give a crude product which was purified by column chromatography to give 4,5-dibromo-1-methyl-1H-1,2,3-triazole.

[0636] Step 3: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde

[0637] To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) in THF (600 mL) was added isopropylmagnesium chloride (252.0 mmol) at -10°C. The mixture was stirred for 15 minutes and DMF (840 mmol) was added. After 1 hour, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 x 350 mL). The combined organics were washed with 250 mL of brine, dried over Na2SO4, filtered, and concentrated to afford 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde.

[0638] Step 4: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0639] Potassium persulfate (651 mmol) is added to a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde (536 mmol) in DMF (800 mL), and the resulting suspension is stirred at room temperature overnight. The mixed reaction is diluted with H O (1000 mL), adjusted to pH 3 with 1N HCl, and the aqueous phase is extracted with ethyl acetate (3×800 mL). The combined organic matter is washed with saturated Na CO (2×500 mL), and the aqueous phase is adjusted to pH 3 with 1N HCl. The precipitate is isolated by filtration and dried under reduced pressure to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1).

[0640] Example 2: Preparation of (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Formate (Intermediate 2A)

[0641]

[0642] To a suspension of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (24.3 mmol) in toluene (80 mL) was added DPPA (24.5 mmol), triethylamine (24.5 mmol) and (R)-1-(2-chlorophenyl)ethan-1-ol (36.5 mmol). The mixture was heated at 80° C. for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography to give (R)-1-(2-chlorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A).

[0643] Example 3: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl) Carbamate (Intermediate 2B)

[0644]

[0645] Under argon atmosphere, 4-bromo-1-methyl-1H-1,2,3-triazole-5-formic acid (95mmol), 50% 1-propanephosphonic anhydride solution (143mmol) in DMF and trimethylsilyl azide (143mmol) are suspended in THF (350mL). Triethylamine (143mmol) is added, and the resulting solution is stirred for 30 minutes. (R)-1-(2-chloropyridin-3-yl) second-1-alcohol (143mmol) is added, and the mixture is heated under reflux for 12 hours, wherein an auxiliary bubbler is connected to allow exhaust. The reaction mixture is cooled to room temperature, and THF is removed under vacuum. The gained crude material is dissolved in 500mL ethyl acetate, and extracted three times with 300mL water. Then the crude mixture is dried over sodium sulfate, filtered, and concentrated filtrate. The crude material was purified by silica gel column chromatography to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B).

[0646] Example 4: Preparation of (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl) Carbamate (Intermediate 2C)

[0647]

[0648] Following the procedure described in Example 3 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (143 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) was obtained.

[0649] Example 5: Preparation of (R)-1-(3-fluorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Formate (Intermediate 2D)

[0650]

[0651] Following the procedure described in Example 3 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(3-fluorophenyl)ethan-1-ol (230 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(3-fluorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D) was obtained.

[0652] Example 6: Preparation of methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (Intermediate 3A)

[0653]

[0654] Intermediate 3A was prepared generally according to Scheme D.

[0655] Step 1: 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol

[0656] Under a nitrogen atmosphere, compound prop-2-yn-1-ol (370mmol), triethylamine (1.06mol), cuprous iodide (17.6mmol) and bis(triphenylphosphine)palladium chloride (II) (10.6mmol) were added to a mixture of 5-bromo-2-iodopyridine (352.2mmol) in THF (400mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (500mL) and the solid was filtered. The filtrate was extracted with ethyl acetate (3×500mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate and ether, stirred for 2 hours and filtered. The filter cake was washed with ether to obtain 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol.

[0657] Step 2: (4-(5-Bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0658] Cuprous iodide (0.94mmol) and tetrabutylammonium iodide (0.94mmol) are mixed together and dissolved in THF (30mL), stirred for 20 minutes, to produce a solution.Then, 3-(5-bromo-2-pyridyl) prop-2-yn-1-ol (9.43mmol) is added, and the reactant is bubbled with argon for 2 minutes. Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride (II) (0.47mmol) and azidomethyltrimethylsilane (24mmol) are added, the reactant is sealed and heated to 80°C for 16 hours. The reaction mixture is concentrated in vacuo and then redissolved in THF (50mL). Tetrabutylammonium fluoride (10mL 1M THF solution) is added dropwise at room temperature and stirred for 1 hour. The mixture is quenched with saturated sodium bicarbonate solution (100mL) and extracted with DCM (3 × 100mL). The organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol.

[0659] Step 3: 4-(5-Bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0660] [5-(5-Bromo-2-pyridyl)-3-methyl-triazol-4-yl]methanol (4.83 mmol), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) (0.48 mmol), and sodium dihydrogen phosphate (12.08 mmol) were suspended in acetonitrile (50 mL) and water (40 mL). The solution was heated to 45°C. Then, 10 mL of a 1 M aqueous sodium chlorite solution and a separate sodium hypochlorite solution (10 mL of a 0.01 M aqueous solution) were added simultaneously over 1 hour. The reaction was stirred at 45°C for 16 hours. The mixture was cooled to room temperature and concentrated to remove the acetonitrile. The product was filtered, and the filter cake was washed with water (2×50 mL) and diethyl ether (50 mL) to give 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. LCMS M / Z(M+1)=283.1.

[0661] Step 4: 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[0662] 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (14.1mmol) was dissolved in 40mL methanol. The solution was cooled to 0°C with an ice bath. Trimethylsilyldiazomethane (18.4mmol) was added dropwise over 15 minutes. The ice bath was removed and the reactants were stirred for 5 hours. The reactants were quenched by adding a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester.

[0663] Step 5: 4-(5-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[0664] 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-methyl formate (11.1mmol), tert-butyl carbamate (33mmol), cesium carbonate (33mmol) and Xantphos Pd G3 precatalyst (1.1mmol) are suspended in dioxane (50mL). The suspension is bubbled with argon for 10 minutes, then heated to 95°C and kept for 4 hours. After the reaction is complete, the mixture is cooled, diluted with water (100mL) and extracted with ethyl acetate (2×100mL). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography to obtain 4-(5-((tert-butyloxycarbonyl) amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-methyl formate.

[0665] Step 6; 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester hydrochloride (intermediate Body 3A)

[0666] To methyl 4-(5-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (6 mmol) was added 4M HCl in dioxane (14 mL), and the reaction was stirred vigorously at room temperature for 3 hours. After completion of the reaction, the solution was concentrated in vacuo to afford methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A).

[0667] Step 7: Preparation of 4-(5-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate acid (Intermediate 3B)

[0668]

[0669] 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50mmol) is dissolved in 500mL tetrahydrofuran and immersed in -78 ℃ of baths, keeps 15 minutes.In 15 minutes, add dropwise the tetrahydrofuran solution (54mmol) of 1M bis(trimethylsilyl) lithium amide.In 20 minutes, add dropwise the hexane solution of 2.5M n-butyl lithium (105mmol), and it is stirred for another 1 hour.In 15 minutes, add dropwise the 2-methyltetrahydrofuran solution of 1.9M zinc chloride (105mmol).By being immersed in a water bath, make the reaction mixture warm up to ambient temperature and it is stirred 30 minutes.Gained mixture is bubbled with argon for 10 minutes, then add (6-bromopyridin-3-yl) tert-butyl carbamate (50mmol) and [1,1 '-bis(diphenylphosphino) ferrocene] dichloropalladium (II) complexed with dichloromethane (5mmol). The reaction was heated at 75 ° C for 3 hours and then cooled to ambient temperature. The reaction was diluted with 350 mL of 2M sodium hydroxide aqueous solution and 300 mL of diethyl ether. The aqueous layer was separated and the organic layer was extracted with 1M sodium hydroxide aqueous solution (100 mL). The combined aqueous layer was washed with a 1:1 mixture of ethyl acetate and diethyl ether (150 mL×2). Under vigorous stirring, 80 mL of concentrated hydrochloric acid was added dropwise over 10 minutes to adjust the pH to 4. The mixture was filtered and the filter cake was washed with water (100 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (100 mL×2). The precipitate was dried under reduced pressure to give 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3B).

[0670] Example 8: Preparation of (R)-1-(3-fluorophenyl)ethyl(1-methyl-4-(4-(2,2,2-trifluoroacetamido)benzene 1H-1,2,3-triazol-5-yl)carbamate (Compound 1)

[0671]

[0672] Step 1: (R)-1-(3-fluorophenyl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl) Carbamate

[0673] A mixture of (R)-1-(3-fluorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D) (0.370 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.407 mmol), tetrakis(triphenylphosphine)palladium(0) (0.037 mmol) and sodium carbonate (1.11 mmol) in 1,4-dioxane / water (3:1, 3.0 mL) was degassed with argon for 10 minutes. The vessel was sealed and heated to 100°C for 18 hours. The reaction was cooled to room temperature, diluted with saturated aqueous NH4Cl solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to afford (R)-1-(3-fluorophenyl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8C).

[0674] Step 2: (R)-1-(3-Fluorophenyl)ethyl(1-methyl-4-(4-(2,2,2-trifluoroacetamido)phenyl)-1H- 1,2,3-Triazol-5-yl)carbamate (Compound 1)

[0675] To a solution of (R)-1-(3-fluorophenyl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8C) (0.082 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic anhydride (0.122 mmol). The solution was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and purified by reverse phase chromatography to give (R)-1-(3-fluorophenyl)ethyl(1-methyl-4-(4-(2,2,2-trifluoroacetamido)phenyl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS (m / z) 452.0 [M+H] + ). 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 11.36 (s, 1H), 9.97 (major) and 9.55 (minor) (s, 1H), 7.73 (s, 4H), 7.53-6.66 (m, 4H), 5.89-5.60 (m, 1H), 3.85 (s, 3H), 1.56 (major) and 1.24 (minor) (s, 3H).

[0676] Example 9: Preparation of [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-[5-[(1-cyanocyclopropanecarbonyl)amino]- 1-Methyl-2-pyrimidin-2-yl]-3-methyl-triazol-4-yl]carbamate (Compound 2)

[0677]

[0678] Step 1: [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazole- 4-amino]carbamate

[0679] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (1.39 mmol) in tetrahydrofuran (14 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.53 mmol) in THF at -78°C. After 10 minutes, a 2.5 M solution of n-butyllithium (2.77 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (4.30 mmol) in 2-MeTHF was added, and the reaction was stirred at room temperature for 45 minutes. At this point, 2-bromopyrimidin-5-amine (1.94 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride complexed with dichloromethane (0.139 mmol) were added to the reaction, and the reaction mixture was heated to 70°C for 1 hour. After the reaction is complete, the mixture is cooled and quenched with saturated aqueous ammonium chloride solution. The mixture is diluted with ethyl acetate and the organic matter is separated. The aqueous layer is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to obtain [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate.

[0680] Step 2: [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-[5-[(1-cyanocyclopropanecarbonyl)amino]pyrimidine [2-pyridinyl]-3-methyl-triazol-4-yl]carbamate (Compound 2)

[0681] A mixture of [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate (0.08mmol), 1-cyanocyclopropanecarboxylic acid (0.096mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.096mmol) in pyridine (1.0mL) was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to obtain [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-[5-[(1-cyanocyclopropanecarbonyl)amino]pyrimidin-2-yl]-3-methyl-triazol-4-yl]carbamate. (MS(m / z)468.1[M+H] + ). 1H NMR (400 MHz, mid-alcohol-d4) δ 9.04 (s, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 6.08 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.82-1.75 (m, 2H), 1.73-1.67 (m, 2H), 1.59 (s, 3H).

[0682] Example 10: Preparation of compounds 3 and 4

[0683] Compounds 3 and 4 were generally synthesized according to Scheme B, Step 1. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(6-(3-methylureido)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 3) was prepared as follows.

[0684]

[0685] A mixture of 1-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (1.67 mmol), (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (0.556 mmol) and sodium carbonate (1.67 mmol) in 3:1 1,4-dioxane / water (7 mL) was heated to 100° C. for 1 hour. The mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(6-(3-methylureido)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 3). (MS (m / z) 432.1 [M+H] + ).1H NMR (400MHz, DMSO-d6) δ10.05 (bs, 1H), 9.41 (bs, 1H), 8.47 (d, J=2.4Hz, 1H), 8.40 (bs, 1H), 8.03-7.85 (m, 3H), 7.54 (bs, 1H), 7.42 (d, J=8.7Hz, 1H), 5.93 (m, 1H), 3.85 (s, 3H), 2.75 (d, J=4.2Hz, 3H), 1.60 (bs, 3H).

[0686]

[0687] Following the general procedure described for compound 3, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (Example 3) was reacted with 1-ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-(3-ethylureido)pyridin-3-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 4), which was similarly prepared according to Scheme C, Step 2. (MS (m / z) 444.2 [M+H] + ).1H NMR (400MHz, DMSO-d6) δ10.01 (s, 1H), 9.35 (s, 1H), 8.49 (d, J=2.3Hz, 1H), 8.09-7.81 (m, 2H), 7.6 9-7.17 (m, 5H), 6.01 (m, 1H), 3.85 (s, 3H), 3.31-3.09 (m, 2H), 1.57 (bs, 3H), 1.11 (t, J=7.2Hz, 3H).

[0688] Example 11: Preparation of [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(5-acetamido-6-fluoro-2-pyridinyl] 4-[(1-[(1-((1-methyl-3 ...triazol-4-yl-1-yl-3-methyl-triazol-4-yl-)carbamate) (Compound 5)

[0689]

[0690] Step 1: N-(6-bromo-2-fluoro-3-pyridyl)acetamide

[0691] To a solution of 6-bromo-2-fluoro-pyridin-3-amine (5.24mmol) in dichloromethane (17mL) was added pyridine (26.2mmol), followed by acetyl chloride (22.9mmol). The reactant was stirred overnight. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3×10mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain N-(6-bromo-2-fluoro-3-pyridyl)acetamide.

[0692] Step 2: 5-(5-Acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid

[0693] A mixture of N-(6-bromo-2-fluoro-3-pyridyl)acetamide (0.485 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and dichloromethane complex (0.0485 mmol), bis(pinacolato)diboron (0.728 mmol) and potassium acetate (0.728 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. for 1 hour. At this point, the reactants were cooled to room temperature and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1) (0.485 mmol), potassium carbonate (0.971 mmol) and water (1.5 mL) were added to the reactants. The reactants were purged with nitrogen and heated to 100° C. for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid.

[0694] Step 3: [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(5-acetamido-6-fluoro-2-pyridinyl)-3- Methyl-triazol-4-yl]carbamate (Compound 5)

[0695] To a mixture of 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid (0.372 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.559 mmol) and trimethylsilylazide (0.559 mmol) in THF (1.9 mL) was added triethylamine (0.745 mmol) dropwise. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.559 mmol) was added and the flask was heated at 70° C. for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazol-4-yl]carbamate (Compound 5). (MS (m / z) 434.1 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.54 (dd, J=9.8, 8.3Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.85 (d, J=8.2H z, 1H), 7.45 (s, 1H), 6.09 (q, J=6.4Hz, 1H), 3.96 (s, 3H), 2.21 (s, 3H), 1.57 (d, J=48.3Hz, 3H).

[0696] Example 12: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-aminophenyl)-1-methyl-1H-1,2- 3-Triazol-5-yl)carbamate (Intermediate 8B)

[0697]

[0698] Step 1: 4-(4-((tert-Butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0699] To a mixture of (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (2.7 mmol) and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (2.4 mmol) were added potassium carbonate (7.3 mmol) and Pd(PPh3)4 (0.24 mmol). The mixture was suspended in 20 mL of a 10:1 mixture of dioxane / water and bubbled with argon for 5 minutes. The reaction was sealed and heated to 100°C for 16 hours. The reaction was diluted with 1M aqueous HCl and brine and extracted with ethyl acetate (25 mL×2). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid.

[0700] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl- 1H-1,2,3-triazol-5-yl)carbamate

[0701] 4-(4-((tert-Butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (1 mmol), a 50% solution of 1-propanephosphonic anhydride (1.4 mmol) in DMF, and trimethylsilylazide (1.4 mmol) were suspended in THF (3 mL). Triethylamine (1.4 mmol) was added, and the resulting solution was stirred at room temperature for 30 minutes. (1R)-1-(2-chloro-3-pyridyl)ethanol (1.4 mmol) was added, and the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, and the THF was removed under vacuum. The resulting crude material was purified by silica gel column chromatography to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-((tert-Butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-yl)carbamate.

[0702] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazole- 5-amino)carbamate (Intermediate 8B)

[0703] A 4M solution of HCl in 1,4-dioxane (1 mL) was added to (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.5 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to afford (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) as the hydrochloride salt.

[0704] Example 13: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-acetamidophenyl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Compound 6)

[0705]

[0706] Step 4: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-acetamidophenyl)-1-methyl-1H-1,2,3-triazol-2-yl)-1-yl)-1-methyl-2-nitro-1 ... oxazol-5-yl)carbamate (Compound 6)

[0707] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.16 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to afford (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-acetamidophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS(m / z)415.08[M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.65 (s, 4H), 7.56-6.99 (m, 1H), 6.11 (s, 1H), 3.95 (s, 3H), 2.17 (s, 3H), 1.82-1.19 (m, 3H).

[0708] Example 14: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-((methoxycarbonyl)amino)phenyl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7)

[0709]

[0710] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Methyl chloroformate chloride (0.16 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-((methoxycarbonyl)amino)phenyl)1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7). (MS (m / z) 431.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.60-8.13 (m, 1H), 8.06 (s, 1H), 7.77-7.10 (m, 5H), 6.23-5.90 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 1.80-1.38 (m, 3H).

[0711] Example 15: Preparation of (S)-2-fluoro-1-phenethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-trifluoromethyl) oxazol-5-yl)carbamate (Intermediate 8D)

[0712]

[0713] Step 1: (S)-(6-(5-(((2-Fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazole- tert-Butyl 4-yl)pyridin-3-yl)carbamate

[0714] Following the procedure described in Example 12 for the preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate and using (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (0.73 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, tert-butyl (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate was obtained.

[0715] Step 2: (S)-2-Fluoro-1-phenethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl) (Intermediate 8D)

[0716] 4M HCl in 1,4-dioxane (1 mL) was added to tert-butyl (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.34 mmol). The resulting suspension was stirred at room temperature for 3 hours. The reaction was concentrated to afford (S)-2-fluoro-1-phenylethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8D) as the hydrochloride salt.

[0717] Example 16: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido) Pyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 8)

[0718]

[0719] Step 1; (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyrazin-2-yl)-1- Methyl-1H-1,2,3-triazol-5-yl)carbamate

[0720] To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (0.42 mmol) in 3 mL of THF was added dropwise a 1N solution of lithium bis(trimethylsilyl)amide in THF (0.50 mmol, 1 M) at -78°C. After 15 minutes, a 1.6 M solution of n-butyllithium (nBuLi) (0.83 mmol) in hexanes was added dropwise. After 15 minutes, a 1.9 M solution of zinc chloride (ZnCl2) in THF (1.0 mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 20 minutes. A solution of tert-butyl (5-bromopyrazin-2-yl)carbamate (Br-pyrazine) (0.50 mmol) and (2-dicyclohexylphosphino-2′, 4′, 6′triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (XPhosPd G3) (0.042 mmol) in THF was added and the reaction was heated to 70° C. for 2 hours. The reaction was then cooled to room temperature, quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. This was purified by silica gel chromatography (0-20% DCM / MeOH) to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate.

[0721] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyrazin-2-yl)-1-methyl-1H-1,2,3- triazol-5-yl)carbamate

[0722] A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.126 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to provide (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate.

[0723] Step 3; (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrazine-2-yl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 8)

[0724] A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0729 mmol) in 0.2 mL of DMF was treated with pyridine (0.729 mmol), 1-cyanocyclopropane-1-carboxylic acid (0.114 mmol) and EDC (0.0875 mmol) and stirred at room temperature for 3 hours. It was diluted with aqueous MeCN and purified by RP HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 27). (MS (m / z) 467.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) d 9.01 (s, 1H), 8.84 (s, 1H), 8.51-7.91 (m, 2H), 7.46 (s, 1H), 6.30-5.74 (m, 1H), 3.97 (s, 3H), 1.84-1.38 (m, 7H).

[0725] Example 17: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-acetamido-3-fluoropyridin-2-yl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 9)

[0726]

[0727] Step 1: N-(6-bromo-5-fluoro-3-pyridyl)acetamide

[0728] To a solution of 6-bromo-5-fluoro-pyridine-3-amine (5.24mmol) in dichloromethane (17mL) was added pyridine (26.2mmol), followed by acetyl chloride (22.9mmol). The reactant was stirred overnight. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-bromo-5-fluoro-pyridine-3-amine.

[0729] Step 2: 4-(5-Acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0730] To a mixture of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (1.3 mmol) in tetrahydrofuran (20 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.3 mmol) in THF at 78°C. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexane was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-MeTHF was added, and the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was sparged with argon for 5 minutes, followed by the addition of N-(6-bromo-5-fluoro-3-pyridyl)acetamide (0.84 mmol) and a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.08 mmol). The reaction was heated at 70°C for 2 hours, after which it was cooled and diluted with 1M aqueous hydrogen chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to give 4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, which was used in the next step without further purification.

[0731] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl- 1H-1,2,3-triazol-5-yl)carbamate (Compound 9)

[0732] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.14 mmol), a 50% DMF solution of 1-propanephosphonic anhydride (0.29 mmol), and trimethylsilylazide (0.29 mmol) were suspended in THF (2 mL). Triethylamine (0.43 mmol) was added, and the resulting solution was stirred at room temperature for 30 minutes. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.29 mmol) was added, and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, and the THF was removed under vacuum. The crude material was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29). (MS (m / z) 434.0 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.33 (s, 1H), 8.19-7.76 (m, 2H), 7.48 (s, 1H), 6.20-5.90 (m, 1H), 4.01 (s, 3H), 2.21 (s, 3H), 1.60 (s, 3H).

[0733] Example 18: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-amino-4-fluoropyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B)

[0734]

[0735] Step 1: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)4-fluoropyridin-2-yl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate

[0736] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (1 mmol) in tetrahydrofuran (15 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in tetrahydrofuran at -78°C. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-methyltetrahydrofuran was added, and the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was bubbled with argon for 5 minutes, and then tert-butyl (6-chloro-4-fluoropyridin-3-yl)carbamate (1.2mmol) and a complex (0.1mmol) of [1,1′-bis(diphenylphosphino)ferrocene] palladium (II) dichloride and dichloromethane were added. The reaction mixture was heated to 70°C for 1 hour. After the reaction was complete, the mixture was cooled and quenched with 1N aqueous hydrochloric acid solution (20mL). The aqueous layer was extracted with ethyl acetate (3×10mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)carbamate, which was used in the next step without further purification.

[0737] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1, 2,3-Triazol-5-yl)carbamate (Intermediate 7B)

[0738] A 4M solution of HCl in 1,4-dioxane (1 mL) was added to (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.49 mmol). The resulting suspension was stirred at room temperature for 4 hours. The reaction was concentrated to afford (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B) as the hydrochloride salt.

[0739] Example 19: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-acetamido-4-fluoropyridin-2-yl)-1- Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 10)

[0740]

[0741] The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B) (0.05 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.1 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 30) (MS (m / z) 434.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 9.17 (d, J = 9.8 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J = 11.5 Hz, 1H), 7.48 (s, 1H), 6.18-6.00 (m, 1H), 3.99 (s, 3H), 2.24 (s, 3H), 1.62 (s, 3H).

[0742] Example 20: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyridine-2-yl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 11)

[0743]

[0744] To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (9.4 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 14.1 mmol), and trimethylsilylazide (14.1 mmol) in THF (100 mL) was added triethylamine (23.5 mmol) dropwise. The reaction mixture was heated at 70° C. for 1 hour, followed by the addition of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (18.8 mmol) at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 11) (MS (m / z) 474.12 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.67 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.94 (dd, J=8.7, 2.6Hz, 1H), 7.8 4 (dd, J=8.6, 0.8Hz, 1H), 7.47 (s, 1H), 6.07 (d, J=6.7Hz, 1H), 3.98 (s, 3H), 1.75-1.46 (m, 12H).

[0745] Example 21: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Intermediate 5A)

[0746]

[0747] A 4M solution of HCl in 1,4-dioxane (20 mL) was added to (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (6.9 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to afford (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) as the hydrochloride salt.

[0748] Example 22: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B)

[0749]

[0750] Step 1: (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H- tert-Butyl 1,2,3-triazol-4-yl)pyridin-3-yl)carbamate

[0751] To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (10.6 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 16 mmol), and trimethylsilylazide (16 mmol) in THF (15 mL) was added triethylamine (27 mmol) dropwise. The reaction mixture was heated at 70° C. for 0.5 h, followed by the addition of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (21 mmol) at the same temperature. After heating for 24 h, the reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to provide tert-butyl (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate.

[0752] Step 2: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1, 2,3-Triazol-5-yl)carbamate (Intermediate 5B)

[0753] A 4M solution of HCl in 1,4-dioxane (15 mL) was added to tert-butyl (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (4.2 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to afford (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as the hydrochloride salt.

[0754] Example 23: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5C)

[0755]

[0756] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (1.7 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5C) was obtained.

[0757] Example 24: Preparation of (R)-1-(2-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Intermediate 5D)

[0758]

[0759] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (7.0 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5D) was obtained.

[0760] Example 25: Preparation of (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1- Methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5E)

[0761]

[0762] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethan-1-ol (6.4 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5E) was obtained.

[0763] Example 26: Preparation of (R)-1-(2-chloropyridinyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2, 3-Triazol-5-yl)carbamate (Intermediate 6A)

[0764]

[0765] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (3.2 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chloropyridin-ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) was obtained.

[0766] Example 27: Preparation of (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Intermediate 6B)

[0767]

[0768] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (2.3 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (S)-2-fluoro-1-(3-fluorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B) was obtained.

[0769] Example 28: Preparation of 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol

[0770]

[0771] 2-Chloro-6-fluoronicotinaldehyde (2.51 mmol) dissolved in methyltetrahydrofuran (20 mL) was cooled in an ice / acetonitrile bath and then methylmagnesium bromide solution (3.0 M, 7.20 mmol) was added dropwise. The reaction mixture was quenched by adding ethanol, then diluted with ethyl acetate and washed with 10% citric acid. The organic layer was concentrated. The residue was purified by column chromatography to obtain 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol.

[0772] Example 29: Preparation of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol:

[0773]

[0774] A 20mL THF solution of 2-fluoro-4-iodo-5-methylpyridine (4.22mmol) was cooled to 0°C and treated with a hexane solution (5.06mmol) of 1.6M nBuLi. After 15 minutes, DMF (12.7mmol) was added dropwise. The reactant was stirred for 30 minutes, then warmed to room temperature and quenched with saturated NH4Cl. The mixture was extracted with EtOAc, dried and concentrated with MgSO4 to give 2-fluoro-5-methylisonicotinaldehyde. 2-fluoro-5-methylisonicotinaldehyde (5.5mmol) was absorbed in 25mL THF and cooled to -15°C in an ice-acetone bath. It was treated with a THF solution (11.2mmol) of 3M MeMgBr and stirred for 20 minutes. Quenched with saturated NH4Cl and extracted with EtOAc, dried over MgSO4, filtered and concentrated to give 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol (MS (m / z) 155.9 [M+H]+).

[0775] Example 30: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

[0776]

[0777] Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 2,5-difluoroisonicotinaldehyde (11.9 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(2,5-difluoropyridin-4-yl)ethan-1-ol was obtained. (MS (m / z) 160.11 [M+H]+).

[0778] Example 31: Preparation of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol

[0779]

[0780] Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 5-bromo-2-fluoronicotinaldehyde (7.35 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol was obtained (MS (m / z) 220.01 [M+H]).

[0781] Example 32: Preparation of 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol

[0782]

[0783] Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 5-bromo-2-chloronicotinaldehyde (10.6 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol was obtained (MS (m / z) 235.99 [M+H]).

[0784] Example 33: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

[0785]

[0786] Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 5-bromo-2-fluoronicotinaldehyde (7.4 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol was obtained (MS (m / z) 220.01 [M+H]).

[0787] Example 34 Preparation of 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Intermediate 5F)

[0788]

[0789] Following the procedure described in Example 22 for the preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) and using 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol (0.34 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, 1-(2-chloro-6-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5F) was obtained.

[0790] Example 35: Preparation of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamide) 1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate (Compound 12)

[0791]

[0792] Step 1: (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2- tert-Butyl 3-(3-triazol-4-yl)pyridin-3-yl)carbamate

[0793] A solution of tert-butyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.125 mmol) in 0.2 mL of THF was treated with T3P (0.25 mmol), trimethylsilyl azide (TMS-N3) (0.25 mmol) and triethylamine (TEA) (0.25 mmol) and stirred at room temperature for 20 minutes. A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol in 200 μL of THF was added, and the mixture was heated at 65° C. for 90 minutes. The mixture was then diluted with DCM and washed with a NaHCO3 aqueous solution. It was purified by silica gel chromatography to give tert-butyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate.

[0794] Step 2: 2,2,2-Trifluoroacetic acid, 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)- 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-ammonium salt

[0795] By (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl) ethoxy) carbonyl) amino)-1-methyl isophthalic acid H-1,2,3-triazol-4-yl) pyridin-3-yl) t-butyl carbamate (0.125mmol) is absorbed in 2mL DCM and 2mL trifluoroacetic acid (TFA).Stir 5 minutes, then concentrate.Be absorbed in 15mL ethylene dichloride, and concentrate again.This step is repeated 2 times, and the gained oily matter is placed under high vacuum and spend the night.The 2,2,2-trifluoroacetic acid obtained, 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl) ethoxy) carbonyl) amino)-1-methyl isophthalic acid H-1,2,3-triazol-4-yl) pyridine-3-ammonium salt are used for next step as crude product.

[0796] Step 3: 1-(5-bromo-2-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyrrolidone) pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 12)

[0797] 2,2,2-Trifluoroacetic acid, 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-ammonium salt (0.125 mmol) was taken up in 2 mL of DCM and cooled to 0°C. The solution was treated with pyridine (0.36 mmol) and methanesulfonic anhydride (0.156 mmol). It was warmed to room temperature and stirred for 30 minutes. The reaction was concentrated and the residue was taken up in MeCN and water. It was purified by RP HPLC to give 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. (Compound 12) (MS (m / z) 532.04 [M+H]+). 1H NMR (400 MHz, DMSO-d6) 810.08 (s, 1H), 9.85 (m, 1H), 8.37-8.32 (m, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.69 (dd, J=8.6, 2.7 Hz, 1H), 5.80 (s, 1H), 3.89 (s, 3H), 3.08 (s, 3H), 1.77-1.38 (m, 3H).

[0798] Example 36: Preparation of 1-(5-bromo-2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamide 1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate (Compound 13)

[0799]

[0800] Following the procedure described in Example 35 for the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate and using 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol (0.143 mmol) instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol, 1-(5-bromo-2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 13) was obtained. (MS(m / z)548.03[M+H]+).1H NMR (400MHz, DMSO-d6) δ11.54 (s, 1H), 9.94 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J=8 .6, 2.6Hz, 1H), 8.02 (d, J=8.6Hz, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 3.91 (s, 3H), 1.58 (s, 3H).

[0801] Example 37: Preparation of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 14)

[0802]

[0803] Step 1: (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyridine-2-yl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate

[0804] Following the procedure described in Step 1 of Example 35 for the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate, using (R)-1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol (0.43 mmol) instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol, (R)-1-(5-bromo-2-fluoropyridin-3-yl)ethyl(4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was obtained. (MS (m / z) 492.03 [M+H]+).

[0805] Step 2: (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1, 2,3-Triazol-5-yl)carbamate hydrochloride

[0806] A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.193 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to provide (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride as an oil.

[0807] Step 3: (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 14)

[0808] A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.193 mmol) in 0.5 mL of DCM was treated with pyridine (2.9 mmol) and cooled to 0° C. Acetyl chloride (0.212 mmol) was added, and the mixture was stirred at 0° C. for 45 minutes. The reaction was concentrated in vacuo and purified by RP HPLC to give (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 14) (MS (m / z) 434.0 [M+H]+). H NMR (400 MHz, acetonitrile-d3) δ 8.98-8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24-8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62-1.55 (m, 3H).

[0809] Example 38: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)- 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 15)

[0810]

[0811] The procedure for the synthesis of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed as described in Step 3 of Example 39 using (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.23 mmol) was used instead of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 15). (MS (m / z) 434.0 [M+H]+) H NMR (400 MHz, acetonitrile-d3) δ 8.98-8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24-8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62-1.55 (m, 3H).

[0812] Example 39: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-formamidopyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Compound 16)

[0813]

[0814] Under an argon atmosphere, formic acid (5 mmol) was added to acetic anhydride (3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Then, a THF (0.33 mL) solution of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (intermediate 5A) (0.37 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction mixture was concentrated to dryness and then co-evaporated with toluene. The residue was purified by reverse HPLC to obtain (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-formamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 41) (MS (m / z) 402.0 [M + H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.89 (d, 1H), 8.37 (d, 2H), 8.19-8.03 (m, 1H), 8.02-7.89 (m, 1H), 7.80-7.59 (m, 1H), 7.49 (s, 1H), 6.09 (m, 1H), 4.00 (d, 3H), 1.63 (s, 3H).

[0815] Example 40: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((methoxycarbonyl)amino)pyridine-2-yl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 17)

[0816]

[0817] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5A) (0.78 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Methyl chloroformate chloride (0.14 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 17) (MS (m / z) 432.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.70 (s, 1H), 8.31 (s, 1H), 8.13-7.92 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 6.21-5.92 (m, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 1.61 (s, 3H).

[0818] Example 41: Preparation of (S)-2-fluoro-1-phenylethyl (4-(4-((methoxycarbonyl)amino)phenyl)-1-methyl- 1H-1,2,3-triazol-5-yl)carbamate (Compound 18)

[0819]

[0820] Following the procedure described in Example 40 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate and using (S)-2-fluoro-1-phenylethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8D) (0.06 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, (S)-2-fluoro-1-phenylethyl(4(4-(methoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was obtained. (Compound 18) (MS (m / z) 414.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) 87.87-6.82 (m, 9H), 6.03 (s, 1H), 4.81-4.56 (m, 2H), 3.92 (s, 3H), 3.78 (s, 3H).

[0821] Example 42: Preparation of (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-((methoxycarbonyl)amino)pyridine-2-yl)-1-(3-fluorophenyl)ethyl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 19)

[0822]

[0823] The procedure for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using (S)-2-fluoro-1-(3-fluorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate ( Intermediate 6B) (0.05 mmol) was used instead of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (S)-2-fluoro-1-(3-fluorophenyl)ethyl(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 19) (MS (m / z) 433.2 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.69 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57-6.62 (m, 4H), 6.09-5.77 (m, 1H), 4.80-4.47 (m, 2H), 3.97 (s, 3H), 3.79 (s, 3H).

[0824] Example 43: Preparation of (R)-1-(2-chlorophenyl)ethyl(4-(5-(methoxycarbonyl)amino)pyridin-2-yl)-1- Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 20)

[0825]

[0826] The procedure for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate described in Example 40 was followed using (R)-1-(2-chlorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) (0.03 mmol) was added instead of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (R)-1-(2-chlorophenyl)ethyl(4-(5-(methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 20). (MS (m / z) 431.2 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.74 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.83 (d, J = 8.7Hz, 1H), 7.74-7.00 (m, 4H), 6.14 (d, J=6.7Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.42 (s, 3H).

[0827] Example 44: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((ethoxycarbonyl)amino)pyridine-2-yl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21)

[0828]

[0829] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5A) (0.10mmol) suspended in dichloromethane (1mL) was treated with N,N-diisopropylethylamine (30uL, 0.17mmol) and then treated with ethyl chloroformate (0.210mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated. The residue was purified by HPLC and the fractions were dried by lyophilization. The lyophilized solid was dissolved in methyltetrahydrofuran (1mL) and treated with 1N sodium hydroxide solution (400μL). The reaction mixture was heated at 55°C for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21). (MS (m / z) 446.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.65 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0830] Example 45: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((isobutoxycarbonyl)amino)pyridine-2-yl) 1-Methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 22)

[0831]

[0832] Following the procedure described in Example 44 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, using isobutyl chloroformate (0.2 mmol) instead of methyl chloroformate, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((isobutoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 22) was obtained. (MS (m / z) 474.1 [M+H] + ). 1H NMR (400MHz, methanol-d4) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 8.9Hz, 2H), 7.90 (d, J = 8.6Hz, 1H), 7.51 (s, 1H), 6.09 (d, J=7.1Hz, 1H), 4.01 (d, J=6.7Hz, 2H), 4.00 (s, 4H), 2.04 (dq, J=13.4, 6.7Hz, 1H), 1.65 (s, 3H), 1.03 (d, J=6.7Hz, 6H).

[0833] Example 46: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Compound 23)

[0834]

[0835] The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) (0.07 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.14 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 23) (MS (m / z) 416.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.31 (s, 1H), 8.21-7.95 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 6.08 (m, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 1.61 (s, 3H).

[0836] Example 47: Preparation of (R)-1-(2-chlorophenyl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)carbamate (Compound 24)

[0837]

[0838] The procedure for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate described in Example 46 was followed using (R)-1-(2-chlorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6 A) (0.03 mmol) was added to replace (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (R)-1-(2-chlorophenyl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 24). (MS (m / z) 415.2 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.88 (s, 1H), 8.10 (dd, J=8.6, 2.6Hz, 1H), 7.86 (d, J=8.6Hz, 1H), 7.71-7.05(m, 4H), 6.29-5.90(m, 1H), 3.96(s, 3H), 2.18(s, 3H), 1.55(s, 3H).

[0839] Example 48: Preparation of (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl 1H-1,2,3-triazol-5-yl)carbamate (Compound 25)

[0840]

[0841] The procedure for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using (S)-2-fluoro-1-(3-fluorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate ( Intermediate 6B) (0.05 mmol) was used instead of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (S)-2-fluoro-1-(3-fluorophenyl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 25) (MS (m / z) 417.2 [M+H] +).1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.56-6.58 (m, 4H), 6.11-5.70 (m, 1H), 4.79-4.30 (m, 2H), 3.98 (s, 3H), 2.18 (s, 3H).

[0842] Example 49: Preparation of 1-(2-fluoro-5-methylpyridin-4-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-yl)carboxylate (amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26)

[0843]

[0844] Step 1: 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-trifluoromethanesulfonyl)pyridin-2-yl Methyl oxadiazole-5-carboxylate

[0845] To a mixture of methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A) (4.3 mmol) in a 5:1 mixture of DCM:pyridine (25 mL) was added 3,3-difluorocyclobutane-1-carboxylic acid (5.1 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mmol). The reaction mixture was magnetically stirred for 2 hours, at which time the reaction was concentrated to give crude methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate, which was used directly in the next step.

[0846] Step 2; 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-trifluoromethanesulfon ... oxazole-5-carboxylic acid

[0847] The crude product 4-(5-(3,3-difluorocyclobutane-1-formamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester (4.3 mmol) was treated with 2M NaOH aqueous solution (50 mL) and THF (25 mL) and stirred vigorously for 30 minutes. Next, the reaction was treated with concentrated HCl until pH=5. The precipitate was filtered and dried under vacuum to give 4-(5-(3,3-difluorocyclobutane-1-formamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, which was used in the next step without further purification.

[0848] Step 3; 1-(2-fluoro-5-methylpyridin-4-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyrrolidone pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26)

[0849] A solution of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.0889 mmol) in 100 μL DMF was treated with a 50% solution of T3P in DMF (0.178 mmol), TMS-N3 (0.156 mmol), and TEA (0.267 mmol), and the mixture was stirred for 20 minutes. 1-(2-Fluoro-5-methylpyridin-4-yl)ethan-1-ol (0.156 mmol) was added, and the reaction was heated at 65° C. for 2 hours. The reaction was cooled to room temperature and purified by RPHPLC to give 1-(2-fluoro-5-methylpyridin-4-yl)ethyl (4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26). (MS(m / z)490.04)[M+H]+)1H NMR (400MHz, acetonitrile-d3) δ9.00-8.89 (m, 1H), 8.88-8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J=9.1, 5.8, 2.8Hz, 1H), 8.07-7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J=6.7Hz, 1H), 3.96 (s, 3H), 3.18-3.06 (m, 1H), 3.02-2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J=6.7Hz, 3H).

[0850] Example 50: Preparation of 1-(2-fluoro-5-methylpyridin-4-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamide) 1-Methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate (Compound 27)

[0851]

[0852] Step 1: 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole- 5-Methyl formate

[0853] Following the procedure described in Step 1 of Example 49 for the synthesis of methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate and using 1-cyanocyclopropane-1-carboxylic acid (5.1 mmol) instead of 3,3-difluorocyclobutane-1-carboxylic acid, methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate was obtained.

[0854] Step 2: 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole- 5-Formic acid

[0855] Following the procedure for the synthesis of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid described in Step 2 of Example 49, using methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (5.1 mmol) instead of methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate, 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate to obtain methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate.

[0856] Step 3: 1-(2-Fluoro-5-methylpyridin-4-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrrolidone) pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 27)

[0857] The procedure for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl1H-1,2,3-triazol-5-yl)carbamate. 2,3-Triazole-5-carboxylic acid (0.0961 mmol) was used instead of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid to obtain 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Compound 27). (MS(m / z)465.12[M+H]+).1H NMR (400MHz, acetonitrile-d3) δ9.00-8.89 (m, 1H), 8.88-8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J=9.1, 5.8, 2.8Hz, 1H), 8.07-7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J=6.7Hz, 1H), 3.96 (s, 3H), 3.18-3.06 (m, 1H), 3.02-2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J=6.7Hz, 3H).

[0858] Example 51: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3, 3 -Difluorocyclobutane-1-methane (amido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28)

[0859]

[0860] To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) (0.07 mmol) in pyridine (0.5 mL) was added 3,3-difluorocyclobutanecarbonyl chloride (0.07 mmol). The reaction mixture was magnetically stirred for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to afford (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28). (MS (m / z) 494.1 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.21-7.67 (m, 4H), 5.95 (s, 1H), 4.00 (s, 3H), 3.21-3.05 (m, 1H), 3.05-2.68 (m, 4H), 1.62 (s, 3H).

[0861] Example 52: Preparation of compounds 29 to 37

[0862] Compounds 29 to 37 were generally synthesized according to Scheme C, Step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29) was prepared as follows.

[0863]

[0864] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5A) (0.07 mmol) in pyridine (0.5 mL) was added benzoyl chloride (0.07 mmol). The reaction mixture was magnetically stirred for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to afford (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29). (MS (m / z) 478.1 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.46-7.88 (m, 6H), 7.88-7.01 (m, 4H), 6.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 3H).

[0865] Following the general procedure described for compound 29, compounds 30 to 37 (Table 1) were similarly prepared according to Scheme C, Step 4 by reacting (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A, Example 21) with the reagents listed in Table 1.

[0866]

[0867]

[0868]

[0869]

[0870]

[0871] Example 53: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-azetidine-3-carboxamido)pyridine (2-pyridin-1-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compounds 38)

[0872]

[0873] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H11,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5A) (0.06 mmol) in pyridine (0.5 mL) was added 1-Boc-azetidine-3-carboxylic acid (0.067 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.064 mmol). The reaction mixture was stirred magnetically for 2 hours, at which time it was concentrated in vacuo and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was magnetically stirred for 0.5 h, at which time water (1 mL) and pyridine (0.5 mL) were added and the crude mixture was purified by HPLC to afford (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(azetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 38). (MS (m / z) 457.1 [M+H] + ). 1H NMR (400MHz, methanol-d4) δ8.86 (s, 1H), 8.61-7.76 (m, 4H), 7.59 (d, J=90.0Hz, 1H), 6.07 (s, 1 H), 4.53-4.18 (m, 4H), 4.00 (s, 3H), 3.87 (tt, J=8.9, 7.1Hz, 1H), 1.66 (d, J=36.7Hz, 3H).

[0874] Example 54: Preparation of compounds 39 to 184 and 195 to 296

[0875] Compounds 39 to 184 and 195 to 296 were generally synthesized according to Scheme C, Step 4. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39) was prepared as follows.

[0876]

[0877] To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5B) (0.06 mmol) in pyridine (0.5 mL) was added 1-cyanocyclopropane-1-carboxylic acid (0.067 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.067 mmol). The reaction mixture was magnetically stirred for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39). (MS(m / z)469.1[M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.33-7.46 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.82-1.36 (m, 7H).

[0878] Compounds 40 to 160 and 195 to 206 (Table 2) were prepared analogously according to Scheme C, Step 4, following the general procedure described for compound 39 by reacting (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A, Example 21) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0879]

[0880] To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (1.0 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.082 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was stirred magnetically for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to afford (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 251). (MS (m / z) 550.0 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ9.47 (s, 2H), 8.95 (s, 1H), 8.25 (dd, J=8.6, 2.6Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J=8.7, 0.7Hz, 1H), 7.87 (s, 1H), 5.95 (d, J=7.1Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H).

[0881] Following the general procedure described for compound 39, compounds 161 to 165 and 207 to 284 (Table 2) were prepared analogously according to Scheme C, Step 4 by reacting (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B, Example 22) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0882]

[0883] To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (0.5 mL) were added 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (0.080 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.080 mmol). The reaction mixture was stirred magnetically for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to afford (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 162). LCMS ((m / z) 495.175 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.22-7.58 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H).

[0884] Following the general procedure described for compound 39, compounds 166 to 168, 285 and 288 to 290 (Table 2) were similarly prepared according to Scheme C, Step 4 by reacting (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5C, Example 23) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0885]

[0886] To a mixture of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5C) (0.070 mmol) in pyridine (1.0 mL) was added 6-(trifluoromethyl)nicotinic acid (0.077 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.084 mmol). The reaction mixture was magnetically stirred for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to afford (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 288). (MS(m / z)565.0[M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 9.26 (d, J = 2.1 Hz, 1H), 8.97 (s, 1H), 8.64-8.52 (m, 1H), 8.34-8.15 (m, 2H), 8.11-7.68 (m, 3H), 6.03 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H).

[0887]

[0888] To a mixture of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5C) (0.054 mmol) in pyridine (2.0 mL) was added 1-(difluoromethyl)cyclopropane-1-carboxylic acid (0.081 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.107 mmol). The reaction mixture was magnetically stirred for 2 h, concentrated, and purified by HPLC to afford (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 166). (MS(m / z)510.15[M+H] + ). 1H NMR (400MHz, DMSO-d6) δ9.86 (bs, 1H), 9.63 (s, 1H), 8.73 (s, 1H), 8.42 (bs, 1H), 8.10-7.82 (m, 3H), 6. 58(t, J=56.9Hz, 1H), 5.83(bs, 1H), 3.89(s, 3H), 1.57(bs, 3H), 1.43-1.27(m, 2H), 1.24-1.03(m, 2H).

[0889] Following the general procedure described for compound 39, compounds 169 to 174 and 290 to 296 (Table 2) were prepared analogously according to Scheme C, Step 4 by reacting (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5D, Example 24) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0890] Following the general procedure described for compound 39, compounds 175 to 180 (Table 2) were similarly prepared according to Scheme C, Step 4 by reacting (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5E, Example 25) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0891] Following the general procedure described for compound 39, compounds 181 to 182 (Table 2) were similarly prepared according to Scheme C, Step 4 by reacting 1-(2-chloro-6-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5F, Example 34) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0892] Following the general procedure described for compound 39, compounds 183 to 184 (Table 2) were similarly prepared according to Scheme C, Step 4 by reacting (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B, Example 18) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

[0893] Compounds 201 to 204, 245 to 246, and 265 to 270 (Table 2) were prepared using racemic mixtures of the reagents listed in Table 2 and purified by chiral SFC purification to afford single stereoisomers.

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013] Example 55: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((1r,3R)-3-cyano-3-fluorocyclobutane) (alkane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 185)

[1014]

[1015] To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((1s,3S)-3-cyano-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 139) (0.04 mmol) in dichloromethane (1 mL) at 0°C was added (diethylamino)sulfur trifluoride (0.04 mmol). This was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution and brine. The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give the title compound as a light yellow oil. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((1r,3R)-3-cyano-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 185). (MS (m / z) 499.1 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.21-7.78 (m, 3H), 7.39 (d, 1H), 6.21-5.92 (m, 1H), 5.01-4.65 (m, 2H), 4.00 (s, 3H), 2.76 (m, 1H), 1.94-1.79 (m, 2H), 1.55 (d, 3H).

[1016] Example 56: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyano-3,3-difluorocyclobutane-1- (formamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 186)

[1017]

[1018] To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyano-3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (20 mg, 0.04 mmol) in dichloromethane (1 mL) was added (diethylamino)sulfur trifluoride (30 mg, 0.19 mmol) at 0°C. The mixture was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-cyano-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 186). (MS (m / z) 517.0 [M+H] +). 1 H NMR (400 MHz, methanol-d4) δ 9.10-8.82 (m, 1H), 8.33 (s, 1H), 8.29-8.02 (m, 2H), 7.97 (d, 1H), 7.51 (s, 1H), 6.09 (d, 1H), 4.02 (d, 3H), 3.57 (m, 2H), 3.33 (m, 2H), 1.65 (s, 3H).

[1019] Example 57: Preparation of (S)-2-fluoro-1-(3-fluorophenyl)ethyl(1-methyl-4-(5-(3-methylureido)pyridine- 2-methyl)-1H-1,2,3 - triazol-5-yl)carbamate (Compound 187)

[1020]

[1021] (S)-2-Fluoro-1-(3-fluorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 6B) (0.05 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Triphosgene (0.1 mmol) was added, followed by a 2M solution of methylamine (0.5 mmol) in THF after 10 minutes. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (S)-2-fluoro-1-(3-fluorophenyl)ethyl(1-methyl-4-(5-(3-methylureido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 187). (MS (m / z) 432.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61-6.59 (m, 4H), 6.14-5.62 (m, 1H), 4.78-4.39 (m, 2H), 3.98 (s, 3H), 2.80 (s, 3H).

[1022] Example 58: Preparation of compounds 188 to 194

[1023] Compounds 188 to 194 were generally synthesized according to Scheme C, Step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(azetidine-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 188) was prepared as follows.

[1024]

[1025] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)carbamate (Intermediate 5A) (Example 21) (0.07mmol) was dissolved in 0.2mL DCM and 0.1mL DMF and treated with triethylamine (0.183mmol) and phenylchloroformate (0.08mmol). The reaction was stirred for 15 minutes and a THF solution of azetidine (0.112mmol) was added. After 15 minutes, the reaction was concentrated, dissolved in a MeCN aqueous solution and acidified with TFA. Purification by RP-HPLC gave (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(azetidine-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a TFA salt (Compound 188). (MS(m / z)457.1[M+H]+).1H NMR (400MHz, acetonitrile-d3) δ8.93 (s, 1H), 8.59 (bs, 1H), 8.34 (dd, J=4.8, 1.9Hz, 1H), 8.14 (ddd, J=8.8, 2.6, 1.2Hz, 1H), 7.97 (d, J=8.8Hz, 1H ), 7.39 (d, J = 15.7Hz, 2H), 6.04 (q, J = 6.6Hz, 1H), 4.14-4.05 (m, 4H), 3.96 (s, 3H), 2.31 (dq, J = 8.2, 7.4Hz, 2H), 1.59 (d, J = 6.6Hz, 3H).

[1026] Following the general procedure described for compound 188, compounds 188 to 194 (Table 3) were similarly prepared according to Scheme C, Step 4 by reacting (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A, Example 21) with the reagents listed in Table 3 instead of azetidine.

[1027]

[1028]

[1029]

[1030]

[1031] Example 59: Preparation of compounds 297 to 303

[1032] Compounds 297 to 304 were generally synthesized according to Scheme C, Step 4, followed by removal of the protecting groups. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 297) was prepared as follows.

[1033]

[1034] Step 1: (R)-3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)- tert-Butyl (1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[1035] To a vial was added (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5B) (0.12 mmol), 1-(tert-butoxycarbonyl)-3-cyanoazetidine-3-carboxylic acid (0.15 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford tert-butyl (R)-3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)azetidine-1-carboxylate, which was used without further purification. (MS (m / z) 584.3 [M+H] + ).

[1036] Step 2: (R)-1-(2,5 - difluoropyridin-3-yl)ethyl (4-(5-(3-cyanoazetidine-3-carboxamide 1-Methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate

[1037] A solution of (R)-tert-butyl 3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)azetidine-1-carboxylate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyanoazetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a trifluoroacetate salt. (MS (m / z) 484.0 [M+H] + ).1HNMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 9.85 (bs, 1H), 9.31 (bs, 2H), 8.69 (bs, 1H), 8.20 ( bs, 1H), 8.11-7.83 (m, 3H), 5.80 (bs, 1H), 4.53 (q, J=11.4Hz, 4H), 3.90 (s, 3H), 1.41 (bs, 3H).

[1038] Compounds 298 to 303 (Table 4) were prepared analogously according to Scheme C, Step 4 by reacting (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5B) (Example 22) with the reagents listed in Table 4 instead of 1-(tert-butoxycarbonyl)-3-cyanoazetidine-3-carboxylic acid.

[1039]

[1040]

[1041]

[1042]

[1043] Example 60: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-(1-aminomethyl)-3,3-diol) Fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 304)

[1044]

[1045] Step 1: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-((tert-butyloxycarbonyl)amino)methyl) Base)-3,3 - (difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1046] To a vial was added (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 5C) (0.19 mmol), 1-(((tert-butoxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxylic acid (0.25 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated, diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to afford (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-(1-(((tert-butoxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, which was used without further purification. (MS (m / z) 639.1. [M+H] + ).

[1047] Step 2: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-aminomethyl)-3,3-difluorocyclobutane) (alkane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1048] A solution of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-(1-((tert-butoxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-(1-(aminomethyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the trifluoroacetate salt. (MS (m / z) 539.0 [M+H] + ).1H NMR (400MHz, DMSO-d6) δ10.24 (s, 1H), 9.87 (bs, 1H), 8.76 (s, 1H), 8.44 (bs, 1H), 8.15-7.68 (m, 5H), 5.84 (bs, 1H), 3.90 (s, 3H), 3.51-3.22 (m, 2H), 3.21 (q, J=13.3Hz, 2H), 2.90 (q, J=13.0Hz, 2H), 1.57 (bs, 3H).

[1049] Example 61: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyano-1-(2,2,2-trifluoro)pyridin-3-yl)ethyl) (ethyl)azetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate ( Compound 305)

[1050]

[1051] To a vial was added (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.03 mmol) as the trifluoroacetate salt, triethylamine (0.15 mmol), and ACN (2 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.09 mmol) was added, and the solution was heated at 60° C. for 2 hours. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyano-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m / z) 565.9 [M+H] + ).1H NMR (400MHz, DMSO-d6) δ10.77 (bs, 1H), 9.84 (bs, 1H), 8.70 (bs, 1H), 8.19 (bs, 1H), 8.13-7.91 (m, 3 H), 5.80 (bs, 1H), 3.96 (d, J=7.6Hz, 2H), 3.93-3.86 (m, 5H), 3.37 (q, J=10.1Hz, 2H), 1.58 (bs, 3H).

[1052] Example 62: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1r,3R)-3-((2,2, (2-(trifluoroethyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 306)

[1053]

[1054] Step 1: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-((tert-butyloxycarbonyl)amino)cyclohexyl)-1-(2-chloropyridin-3-yl)ethyl) (butane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1055] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.146 mmol) suspended in dimethylformamide (2 mL) was treated with (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 mmol) and pyridine (0.869 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give a crude product.

[1056] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-aminocyclobutane-1-carboxamide 1-Methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate

[1057] (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((1r,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.105 mmol) dissolved in dichloromethane (2 mL) was treated with trifluoroacetic acid (10.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give the crude product.

[1058] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl) (4-(2-Yl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate

[1059] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-aminocyclobutane-1-formamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425mmol) dissolved in acetonitrile (4mL) was treated with triethylamine (0.215mmol) and then with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl)amino)cyclobutane-1-formamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. (MS(m / z)553.1[M+H]+).1H NMR (400MHz, methanol-d4) δ8.86 (s, 1H), 8.39-8.24 (m, 2H), 8.09 (dd, J=8.5, 2.8Hz, 1H), 7.90 (d, J=8.8Hz, 1H), 7.45 (dd, J=7.7, 4.8Hz, 1H), 6.07 (s, 1H) , 4.16 (p, J=8.0Hz, 1H), 3.99 (s, 3H), 3.94 (t, J=9.1Hz, 1H), 2.74 (td, J=8 .6, 8.1, 4.1Hz, 2H), 2.57 (dt, J=13.6, 9.3Hz, 2H), 1.55 (dt, J=46.0Hz, 3H).

[1060] Example 63: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1s,3S)-3-((2,2, (2-(trifluoroethyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 307)

[1061]

[1062] The title compound was prepared in analogy to Example 62 using (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS(m / z)553[M+H]+).1H NMR (400MHz, methanol-d4) δ 8.84 (s, 1H), 8.31 (s, 1H), 8.09 (dd, J = 8.7, 2.6Hz, 1H), 7.90 (d, J = 8.6Hz, 1H), 7.46 (s, 2H), 6.07 ( s, 1H), 3.99 (s, 3H), 3.82-3.69 (m, 2H), 3.11 (d, J=8.5Hz, 2H), 2.74-2.60 (m, 2H), 2.43 (d, J=10.6Hz, 2H), 1.61 (s, 3H).

[1063] Example 64: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1R,5S,6r)-3-(2, (2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl) Carbamate (Compound 308)

[1064]

[1065] The title compound was prepared in analogy to Example 62 using exo-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS(m / z)565.1[M+H]+).1H NMR (400MHz, methanol-d4) δ8.95 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.8Hz, 2H), 7.90 (d, J = 8.8Hz, 1H), 7.48 (s, 1H), 6.09 (d, J = 6.9Hz, 1H), 4.00 (s, 2H), 3.24 (dt, J=19.5, 9.5Hz, 4H), 2.87-2.76 (m, 2H), 2.21 (t, J=2.9Hz, 1H), 2.10 (t, J=2.7Hz, 2H), 1.63 (s, 3H).

[1066] Example 65: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(1-(2,2,2-trifluoroethyl) (4-(2-Yl)azetidine-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 309)

[1067]

[1068] The title compound was prepared in analogy to Example 62 using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m / z) 539.1 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.90 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 7.8 Hz, 2H), 4.13 (d, J = 9.1 Hz, 2H), 4.00 (s, 2H), 3.86 (q, J = 8.0 Hz, 1H), 1.62 (s, 3H).

[1069] Example 66: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-amino-3,3 - Difluorocyclobutane-1- Formamido)pyridin-2-yl)-1-methyl-1H-1,2,3 - triazol-5-yl)carbamate (Compound 310)

[1070]

[1071] Step 1: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-((tert-butyloxycarbonyl)amino)-3,3-difluorocyclohexane) (butane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1072] A mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (25 mg, 0.061 mmol), 1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid (31 mg, 0.122 mmol), and EDCI (20 mg, 0.1 mmol) in pyridine (1 mL) was stirred at room temperature for 1 hour. The residue was purified by preparative HPLC using a Gilson preparative HPLC (Gemini column, 30%-85% CHCN in H0 containing 0.1% TFA) to provide the intermediate. MS: 607.15 (M+1).

[1073] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-amino-3,3-difluorocyclobutane-1-carboxamide) 1-Methyl-1H-1,2,3-pyridin-2-yl)-1-methyl-1H-1,2,3- - triazol-5-yl)carbamate

[1074] The above intermediate (20 mg) was treated with 2 mL of 4N HCl in dioxane, and the mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by preparative HPLC using a Gilson preparative HPLC (Gemini column, 30%-85% CH3CN in H2O with 0.1% TFA) to give the product. (MS (m / z) 507 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.89 (s, 1H), 8.32 (s, 1H), 8.15 (m, 1H), 7.95 (m, 1H), 7.68-7.25 (m, 2H), 6.08 (s, 1H), 4.00 (s, 3H), 3.72 (m, 2H), 3.19 (m, 2H), 1.86-1.40 (m, 3H).

[1075] Example 67: Synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-(cyclopropylamino)cyclobutane-1-yl) (formamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 311)

[1076]

[1077] Step 1. (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido) Pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate

[1078] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.0975 mmol) suspended in dimethylformamide (2 mL) was treated with 3-oxocyclobutane-1-carboxylic acid (0.131 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.292 mmol) and pyridine (0.621 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The layers were separated. The organic layer was concentrated to give crude (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate.

[1079] Step 2. (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido) Pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate

[1080] (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (0.0638 mmol) suspended in dichloromethane (1 mL)

[1081] It is treated with cyclopropylamine (0.144mmol) and triethylamine (0.215mmol). After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.330mmol) is added. The reaction mixture is stirred at room temperature for 30 minutes. Trifluoroacetic acid (6.53mmol) is added to quench the reaction. The reaction mixture is then concentrated and purified by HPLC to obtain (R) -1- (2- chloropyridin-3-yl) ethyl (1- methyl -4- (5- (3- oxocyclobutane -1- formamido) pyridin-2-yl) -1H-1,2,3- triazole -5-yl) carbamate. (MS (m / z) 511.2 [M + H] +). 1H NMR (400MHz, methanol-d4) δ8.88 (s, 1H), 8.32 (s, 1H), 8.20-8.00 (m, 2H), 7.91 (d, J =8.6Hz, 1H), 7.48 (s, 1H), 6.08 (d, J = 7.1Hz, 1H), 4.00 (s, 3H), 3.98-3.91 (m, 1H), 3.29-3.17(m, 1H), 2.75(ddt, J=15.7, 12.1, 8.4Hz, 3H), 2.65-2.48(m, 2 H), 1.78-1.37 (m, 3H), 0.95 (dtt, J=7.4, 5.2, 2.8Hz, 2H), 0.92-0.84 (m, 2H).

[1082] Example 68: Synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-acetamidobicyclo[1.1.1]pentyl) (alkane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 312)

[1083]

[1084] Step 1. (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1] (pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1085] Prepared according to the procedure described in Step 1 of Example 62 using 3-(tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid.

[1086] Step 2. (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-aminobicyclo[1.1.1]pentane-1-carboxamide) 1-Methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)carbamate

[1087] Prepared according to the procedure described in Step 2 of Example 62.

[1088] Step 3. (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-acetamidobicyclo[1.1.1]pentane-1-yl)- (amido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[1089] (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-aminobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425 mmol) dissolved in acetonitrile was treated with triethylamine (0.287 mmol) and subsequently with acetic anhydride (0.212 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by HPLC to give a bis-acylated product. The bis-acylated product was dissolved in tetrahydrofuran (2 mL) and treated with 1N sodium hydroxide solution (800 μL). The reaction mixture was stirred at room temperature for 100 minutes. The reaction mixture was concentrated and purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-acetamidobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS(m / z)525.1[M+H]+).1H NMR (400MHz, methanol-d4) δ8.93 (s, 1H), 8.32 (s, 1H), 8.13 (dd, J=8.6, 2.6Hz, 1H), 7.92 (d, J=8.8Hz, 1H) , 7.55 (s, 2H), 6.08 (d, J = 6.4Hz, 1H), 3.99 (s, 3H), 2.44 (s, 6H), 1.94 (d, J = 8.8Hz, 3H), 1.62 (s, 3H).

[1090] Example 69: Preparation of (R)-1-(2,5 - difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-yl) (amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 313)

[1091]

[1092] Step 1: (R)-(6-(5-(...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in: R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ) and –NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A Alkyl and heteroaryl are optionally substituted by 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 Alkyl; or R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen, C 1-6 Alkyl, where each C 1-6 The alkyl group is optionally substituted with 1 to 4 R 1E Replace, the R 1E may be the same or different, wherein each R 1E independently selected from halogen; R 2 is hydrogen or C 1-6 alkyl; Each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; n is 0, 1, or 2; R 4 C 1-6 alkyl; X 1 、X 2 、X 3 and X 4 Each of is independently selected from CH and N; Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, said substituents may be the same or different and are independently selected from deuterium, halogen; and Z is phenyl or pyridyl, which is optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from halogen, C 1-4 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia):

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH3.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Y 2 For hydrogen.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIa):

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIb): Each R 3 Can be the same or different.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIc):

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IId):

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIe):

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIf): Each R 3 Can be the same or different.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIg): Each R 3 Can be the same or different.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIh):

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIi):

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIj):

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIk):

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (III):

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIm):

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIn):

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or Formula (Ia) has Formula (IIo):

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ), and –NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A The alkyl group is optionally substituted with 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl.

23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl or C 2-6 Alkynyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-6 Cycloalkyl.

24. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 -CH3, -CHF2, -CF3, 25. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 Independently C 1-6 Alkyl, where each C 1-6 The alkyl group is optionally substituted with 1 to 4 R 1E Substituted, the R 1E may be the same or different, wherein each R 1E are independently selected from halogen.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 For-OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D and R 1D2 independently -CH3, -C2H5 or -C(CH3)3.

27. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 28. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ) and –NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A The alkyl group is optionally substituted with 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl.

29. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 1 to 4 R 1A Substituted C 3-10 Cycloalkyl, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 and –C(O)N(R 1B1 )(R 1B2 ), where each R 1B1 and R 1B2 are independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, and wherein each R 1A C 1-4 The alkyl group is optionally substituted with 1 to 3 halogens.

30. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, and are independently selected from -F, -Cl, -CN, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2-NH2, -OCH3, -NH-CH2-CF3, -NO2, cyclopropyl and phenyl.

31. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A They may be the same or different and are each independently selected from -F, -Cl, -CN, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2-OH, -CH2-NH2, -OCH3, cyclopropyl and phenyl.

32. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 33. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 34. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 35. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the C 3-10 Cycloalkyl is C 5-10 Bicyclic cycloalkyl.

36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein the C 5-10 Bicyclic cycloalkyl is C 5-8 Bridged bicyclic cycloalkyl.

37. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein the C 5-8 The bridged bicyclic cycloalkyl is bicyclopentyl or bicyclooctyl, each optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3 and -O-CH3.

38. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 for 39. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 for 40. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein the C 5-10 Bicyclic cycloalkyl is C 5-10 Spirobicyclic cycloalkyl.

41. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein the C 5-10 The spirobicyclic cycloalkyl group is spiropentyl, spirohexyl, spiroheptyl or spirodecanyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A Each is independently selected from -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -CN and -O-CH3.

42. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein R 1 for 43. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein R 1 for 44. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclic group being optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ) and –NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A The alkyl group is optionally substituted with 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl.

45. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 3- to 8-membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclic group being optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different and are independently selected from halogen, cyano, oxo or C 1-4 Alkyl, where each R 1A C 1-4 The alkyl group is optionally substituted with 1 to 3 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkoxy, halogen.

46. ​​The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl or morpholinyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, and are independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, -C2H5, -CH2-CF3 and -O-CH3.

47. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 48. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 3- to 10-membered heterocyclyl forms a bicyclic heterocyclyl.

49. The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocyclyl is a bridged bicyclic heterocyclyl.

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein the bridged bicyclic heterocyclic group is optionally substituted by 1 to 4 R 1A Substituted oxabicyclohexyl, the R 1A may be the same or different, wherein each R 1A Independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3 and -O-CH3.

51. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein R 1 for 52. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocyclyl is a fused bicyclic heterocyclyl.

53. The compound according to claim 52, or a pharmaceutically acceptable salt thereof, wherein the fused bicyclic heterocyclic group is optionally substituted by 1 to 4 R 1A Substituted oxabicyclohexyl, the R 1A may be the same or different, wherein each R 1A Independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3 and -O-CH3.

54. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein R 1 for 55. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein R 1 for 56. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 3- to 10-membered heterocyclyl is a spiro bicyclic heterocyclyl.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein the spirobicyclic heterocyclyl is an oxaspiroheptane optionally substituted with 1 to 4 substituents, the substituents being the same or different and each independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3.

58. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein R 1 for 59. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 1 to 4 R 1A Substituted phenyl, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ) and –NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A The alkyl group is optionally substituted with 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl.

60. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 1 to 4 R 1A Substituted phenyl, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, C 1-3 Alkyl or C 1-4 Alkoxy.

61. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 1 to 3 R 1A Substituted phenyl, the R 1A may be the same or different, wherein each R 1A Independently selected from -F, -Cl, -CN or -CH3.

62. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl group being optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl, phenyl, –N(R 1B1 )(R 1B2 ), -OR 1B1 ,–C(O)N(R 1B1 )(R 1B2 ),–NR 1B1 C(O)R 1B2 , where each R 1B1 、R 1B2 and R 1B3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl, Each R 1A The alkyl group is optionally substituted with 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen, -OR 1D1 or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl.

63. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted by 1 to 4 R 1A Substituted, the R 1A may be the same or different, wherein each R 1A independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl, -N(R 1B1 )(R 1B2 ) and -OR 1B1 , where each R 1B1 and R 1B2 Independently C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 4 R 1C Substituted, the R 1C may be the same or different, and wherein each R 1C Independently C 1-4 Alkyl, halogen.

64. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted with 1 to 4 substituents, which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy.

65. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted with 1 to 3 substituents, the substituents being the same or different and each independently selected from -F, -Cl, -CN, -CH3, -CHF2, -CF3, -OCH3, -N(CH3)2, 66. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 for 67. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH3.

68. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen.

69. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is -F.

70. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 are each independently hydrogen, deuterium or C optionally substituted with 1 to 3 substituents 1-6 Alkyl, the substituents may be the same or different and are independently selected from halogen.

71. The compound according to claim 70 or a pharmaceutically acceptable salt thereof, wherein Y 1 is C optionally substituted by 1 to 3 substituents 1-4 alkyl, the substituents may be the same or different, each independently selected from halogen, and Y2 is hydrogen.

72. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, wherein Y 1 It is a methyl group optionally substituted by 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl.

73. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, wherein Y 1 It is -CH3 or -CH2F.

74. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted with 1 to 3 substituents, the substituents being the same or different and each independently selected from halogen and C 1-4 alkyl.

75. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted with 1 to 3 substituents, the substituents being the same or different and each independently selected from -F and -Cl.

76. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is 77. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is pyridinyl optionally substituted with 1 to 3 substituents, the substituents being the same or different and each independently selected from -F, -Cl, -Br and -CH3.

78. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is 79. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y1 is -CH3, and Z is 80. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the group consisting of:

81. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the group consisting of:

82. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 83. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 84. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 85. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 86. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 87. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 88. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 89. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 90. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 91. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 92. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 93. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 94. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 95. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

96. The pharmaceutical composition of claim 95, further comprising an additional therapeutic agent.

97. The pharmaceutical composition of claim 96, wherein the additional therapeutic agent is one, two, three or four additional therapeutic agents.

98. The pharmaceutical composition of claim 96, wherein the additional therapeutic agent comprises an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide 1 receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist.

99. The pharmaceutical composition of claim 98, wherein the ACC inhibitor is fesocostat.

100. The pharmaceutical composition according to claim 98, wherein the ASK-1 inhibitor is selositaxel.

101. The pharmaceutical composition of claim 98, wherein the FXR agonist is cilofistl.

102. The pharmaceutical composition of claim 98, wherein the PPARα agonist is fibrate.

103. The pharmaceutical composition of claim 98, wherein the fish oil is eicosapent ethyl ester.

104. The pharmaceutical composition of claim 98, wherein the glucagon-like peptide 1 receptor agonist is liraglutide or semaglutide.

105. The pharmaceutical composition according to claim 98, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

106. The pharmaceutical composition of claim 98, wherein the TGFβ antagonist is a TGFβ receptor.

107. The pharmaceutical composition of claim 98, wherein the additional therapeutic agents comprise fesocostat and cilofistrazostat.

108. The pharmaceutical composition of claim 98, wherein the additional therapeutic agent comprises fesocostat and liraglutide or semaglutide.

109. The pharmaceutical composition of claim 98, wherein the additional therapeutic agent comprises fibrate or icosapent ethyl.

110. The pharmaceutical composition of claim 98, wherein the additional therapeutic agent comprises cilofemstatin and liraglutide or semaglutide.

111. The pharmaceutical composition of claim 95, wherein the additional therapeutic agent comprises a VEGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, an autotoxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin 3 antibody, an integrin α V -β6 / α V -β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymase inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene / thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors or xanthine oxidase inhibitors.

112. The pharmaceutical composition of claim 95, wherein the additional therapeutic agent is selected from the group consisting of nintedanib, pirfenidone, panrelumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, sitanacoxib, SER150, RDEA3170, pracciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

113. Use of a compound according to any one of claims 1 to 94 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 95 or 96, in the preparation of a medicament for treating, stabilizing, or reducing the severity or progression of an LPAR1 -mediated disease or condition.

114. The use according to claim 113, wherein the LPAR1 mediated disease or condition is selected from the group consisting of wound healing, cancer, pain, respiratory diseases, allergic diseases, neurological diseases, cardiovascular diseases and inflammatory diseases.

115. The use according to claim 113, wherein the LPAR1 mediated disease or disorder is interstitial lung disease (ILD).

116. according to the described purposes of claim 115, wherein said interstitial lung disease (ILD) is nonspecific interstitial pneumonia (NSIP), sarcoidosis, progressive fibrosing ILD, idiopathic interstitial pneumonia (IIP), the interstitial lung disease (CTD-ILD) that connective tissue disease is relevant, the relevant ILD of rheumatoid arthritis, the relevant ILD of scleroderma or extrinsic alveolitis.

117. The use according to claim 115, wherein the interstitial lung disease (ILD) is asbestosis.

118. purposes according to claim 115, wherein said interstitial lung disease (ILD) is the ILD relevant to occupational exposure.

119. The use according to claim 113, wherein the LPAR1 mediated disease or disorder is chronic kidney disease (CKD).

120. The use according to claim 119, wherein the CKD is complement glomerulopathy, membranous glomerulopathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS) or Alport syndrome.

121. The use according to claim 113 or 114, wherein the LPAR1 mediated disease or condition comprises fibrosis.

122. The use according to claim 121, wherein the fibrosis is pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, myocardial fibrosis or systemic sclerosis.

123. The use according to claim 122, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or progressive fibrosing interstitial lung disease (PF-ILD).

124. The use according to claim 123, wherein the pulmonary fibrosis is secondary to a systemic inflammatory disease.

125. The use according to claim 124, wherein the systemic inflammatory disease is rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury or acute respiratory distress.

126. The use of claim 122, wherein the renal fibrosis is associated with diabetic nephropathy.

127. The use according to claim 113, wherein the LPAR1 mediated disease or disorder is a liver disease.

128. The use according to claim 127, wherein the liver disease comprises liver fibrosis.

129. The use according to claim 127 or 128, wherein the liver disease comprises non-alcoholic fatty liver disease (NAFLD).

130. The use of claim 127 or 128, wherein the liver disease comprises steatosis.

131. The use of claim 127 or 128, wherein the liver disease comprises non-alcoholic steatohepatitis (NASH).

132. The use of claim 127 or 128, wherein the liver disease comprises cirrhosis.

133. The use according to claim 132, wherein the liver cirrhosis is compensated liver cirrhosis.

134. The use according to claim 132, wherein the liver cirrhosis is decompensated liver cirrhosis.

135. The use of claim 127 or 128, wherein the liver disease comprises hepatocellular carcinoma (HCC).

136. The use according to claim 127 or 128, wherein the liver disease comprises primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

137. The use of claim 127 or 128, wherein the liver disease comprises portal hypertension.

138. The use of claim 113 or 128, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

139. The use of claim 138, wherein the additional therapeutic agent is one, two, three or four additional therapeutic agents.

140. The use of claim 138, wherein the additional therapeutic agent comprises an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide 1 receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist.

141. The use according to claim 140, wherein the ACC inhibitor is fesocostat.

142. The use according to claim 140, wherein the ASK-1 inhibitor is selositaxel.

143. The use according to claim 140, wherein the FXR agonist is cilofemstat.

144. The use according to claim 140, wherein the PPARα agonist is a fibrate.

145. The use according to claim 140, wherein the fish oil is eicosapentaenoic acid ethyl ester.

146. The use according to claim 140, wherein the glucagon-like peptide 1 receptor agonist is liraglutide or semaglutide.

147. The use according to claim 140, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

148. The use according to claim 140, wherein the TGFβ antagonist is a TGFβ receptor.

149. The use of claim 140, wherein the additional therapeutic agent comprises fesocostat and cilofistrazostat.

150. The use of claim 140, wherein the additional therapeutic agent comprises fesocostat and liraglutide or semaglutide.

151. The use of claim 140, wherein the additional therapeutic agent comprises fibrate or icosapent ethyl.

152. The use of claim 140, wherein the additional therapeutic agent comprises cilofem and liraglutide or semaglutide.

153. The use of claim 138, wherein the additional therapeutic agent comprises a VEGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, an autotoxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin 3 antibody, an integrin α V -β6 / α V -β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymase inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene / thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors or xanthine oxidase inhibitors.

154. The use of claim 138, wherein the additional therapeutic agent is selected from the group consisting of nintedanib, pirfenidone, panrelumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, sitanacoxib, SER150, RDEA3170, pracciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

155. Use of a compound according to any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an LPAR1 -mediated disease or condition.

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