KIF18A INHIBITORS AND USES THEREOF

Abstract

Described herein are KIF18A inhibitors and pharmaceutical compositions comprising the inhibitors. The compounds and compositions are useful for treating KIF18A-related diseases or disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of International Application No. PCT / CN2023 / 073384, filed January 20, 2023, International Application No. PCT / CN2023 / 096044, filed May 24, 2023, International Application No. PCT / CN2023 / 119748, filed September 19, 2023, and International Application No. PCT / CN2023 / 140730, filed December 21, 2023, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is thought to regulate the correct intranuclear positioning of chromosomes and spindle tension by affecting the dynamics of the plus ends of kinetochore microtubules. Depletion of human KIF18A results in longer spindles, increased chromosome oscillations during metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology 17, 488-98, 2007). KIF18A is a viable target for cancer treatment. KIF18A is overexpressed in various types of cancer, including, but not limited to, colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, and ovarian cancer. Furthermore, gene deletion or knockdown, or inhibition of KIF18A affects the spindle apparatus in cancer cell lines. More specifically, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote cell death in mitosis via apoptosis, mitotic catastrophe, or multipolarity-driven lethality or death after mitotic slippage in interphase. Therefore, there is strong interest in finding inhibitors of the KIF18A protein.

[0003] Therefore, inhibition of KIF18A activity is a promising approach for the development of novel anticancer agents. Summary of the Invention

[0004] One embodiment is a compound of formula (I)

[0005] [ka] or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is represented by Formula (Ia), (Ia-1), (Ib), or (Ic):

[0007] [ka] It has the following structure.

[0008] In some embodiments, formula (III)

[0009] [ka] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, formula (IV)

[0011] [ka] or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, disclosed herein are pharmaceutical compositions comprising a compound of Formula (III), (IIIa), (IV), (IVa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] In some embodiments, disclosed herein is a method of modulating kinase-like protein 18A (KIF18A) in a subject in need of modulation of kinase-like protein 18A (KIF18A), comprising administering to the subject a compound of Formula (III), (IIIa), (IV), (IVa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of inhibiting kinase-like protein 18A (KIF18A) in a subject in need of inhibition of kinase-like protein 18A (KIF18A), comprising administering to the subject a compound of Formula (III), (IIIa), (IV), (IVa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof.

[0014] Disclosed herein, in some embodiments, is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein are methods of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, wherein the cancer is (a) a solid tumor or a hematologically derived tumor selected from bladder, endometrial, squamous cell lung, breast, colon, kidney, liver, lung, small cell lung cancer, esophageal, gallbladder, brain, head and neck, ovarian, pancreatic, stomach, cervical, thyroid, prostate, and skin cancer. (b) hematopoietic malignancies of the lymphoid system selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; (c) hematopoietic malignancies of the myeloid system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; and (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, pigment epithelioma, keratinoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0015] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout this specification and the following claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be construed in an inclusive sense, i.e., "including," without limitation. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0017] Throughout this specification, a reference to "some embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0018] As used herein, the following terms have the following meanings unless otherwise indicated.

[0019] "Oxo" refers to C=O.

[0020] "Carboxyl" refers to --COOH.

[0021] "Cyano" refers to -CN.

[0022] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever appearing herein, "C1-C6 alkyl" or "C 1-6 Numerical ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C 1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3and alkyl. Unless otherwise specified in the specification, alkyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl can be substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl can be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl can be substituted with halogen.

[0023] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. As used herein, the terms "C2-C6 alkenyl" or "C 2-6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkenyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl can be substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkenyl can be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen. As used herein, "alkenylene" refers to a divalent alkenyl. Unless stated otherwise in the specification, an alkenylene group may be optionally substituted.

[0024] "Heteroalkenylene" refers to an alkenylene group in which one or more skeletal atoms of the alkenylene is selected from an atom other than carbon, for example, oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. Unless stated otherwise specifically in the specification, a heteroalkenylene group can be optionally substituted.

[0025] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl can be substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl can be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen. As used herein, "alkynylene" refers to a divalent alkynyl. Unless stated otherwise in the specification, an alkynylene group may be optionally substituted.

[0026] "Heteroalkynylene" refers to an alkynylene group in which one or more skeletal atoms of the alkynylene is selected from an atom other than carbon, for example, oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. Unless stated otherwise specifically in the specification, a heteroalkynylene group can be optionally substituted.

[0027] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene can be substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkylene can be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0028] "Alkoxy" means a group of the formula -OR a where Ra is an alkyl radical as defined. Unless otherwise stated in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy can be substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy can be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0029] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in the specification, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl can be substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl can be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl can be substituted with halogen. As used herein, "arylene" refers to a divalent aryl. Unless otherwise specified in the specification, an arylene group can be optionally substituted.

[0030] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spirocyclic, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl). In some embodiments, the cycloalkyl is a 3-10 membered fully saturated cycloalkyl or a 3-10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-6 membered fully saturated cycloalkyl or a 3-6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-6 membered fully saturated cycloalkyl or a 5-6 membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a cycloalkyl can be substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen. As used herein, "cycloalkylene" refers to a divalent cycloalkyl. Unless otherwise specified in this specification, cycloalkylene is optionally substituted.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0032] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0033] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CH2CHOCH3, -CH2CHOCH2CHOCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen. As used herein, "heteroalkylene" refers to a divalent heteroalkyl. Unless stated otherwise specifically in the specification, heteroalkylene can be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0036] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spirocyclic, or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and the like. Examples of heterocycloalkyl include, but are not limited to, cyclohexane, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise stated specifically in the specification, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl can be substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen. As used herein, "heterocycloalkylene" refers to a divalent heterocycloalkyl. Unless otherwise stated specifically in the specification, a heterocycloalkylene is optionally substituted.

[0037] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, heteroaryl is a 5-10 membered heteroaryl. In some embodiments, heteroaryl is a 5-6 membered heteroaryl. In some embodiments, heteroaryl is a 6 membered heteroaryl. In some embodiments, heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl can be substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl can be substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, heteroaryl is optionally substituted with halogen. As used herein, "heteroarylene" refers to a divalent heteroaryl. Unless stated otherwise specifically in the specification, a heteroarylene group can be optionally substituted.

[0038] The terms "optional" or "optionally" mean that the event or circumstance described below may or may not occur, and that the description includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, it is not intended that such groups introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0039] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce a desired therapeutic effect.

[0040] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment involves administration of a pharmaceutical composition after the onset of a pathological event or contact with a pathogenic agent, and includes stabilization of disease (e.g., disease does not worsen) or remission of disease.

[0041] As used herein, the terms "treat," "treating," or "treatment" include alleviating, ameliorating, or reversing at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., halting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition.

[0042] compound In one aspect, provided herein are inhibitors of kinase-like protein 18A (KIF18A).

[0043] In some embodiments, Formula (I)

[0044] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is a C3-C7 cycloalkyl, a 4-12 membered heterocycloalkyl, a phenyl, or a 5-10 membered heteroaryl, each of which is selected from the group consisting of one or more R a optionally substituted with Ring B is phenyl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 5- to 12-membered heterocycloalkyl, each of which may be one or more R b optionally substituted with L 1is a bond or linker moiety connecting ring A and ring B, the linker moiety comprising a linear sequence ranging from 1 to 20 non-hydrogen atoms, and one or more R c optionally substituted with L 2 is a bond, -O-, -S-, -N(R 8 )-, -N(R 8 )CO-, -CON(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; L 3 is a bond, -O-, -S-, -N(R 8 )CO-, -CON(R 8 )-, -N(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; X 1 is N or CR 1 and X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and R 1 , R 2 , and R 4 are each independently selected from hydrogen, —CN, —OH, —SH, halogen, amino, C-C alkyl, C-C alkoxyl, C-C heteroalkyl, C-C alkenyl, and C-C alkynyl, and each of alkyl, alkoxyl, heteroalkyl, alkenyl, and alkynyl is selected from one or more R 6 optionally substituted with Each R 6 are independently halogen, -CN, -NO2, -OH, oxo, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 8 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 3 is -CN or a group -ZR 5 and or R 4 and R 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -ZR 5 and one or more R d optionally substituted with or R 3 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -ZR 5 and one or more R d optionally substituted with or R 2 and R 1together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d optionally substituted with Z is a bond, C1-C8 alkylene, C1-C8 heteroalkylene, -NR 8 -, -S(=O)C0-C6 alkylene-, -NR 8 SO2-(C0-C6 alkylene)-, -SO2NR 8 -(C0-C6 alkylene)-, -NR 8 SO2NR 8 -, -NR 8 SO2NR 8 C(=O)O-, -(C0-C6 alkylene)-S(=O)(=NH)-, -(C0-C6 alkylene)-NR 8 -S(=O)(=NH)-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-S(=O)-, -(C0-C6 alkylene)-SO2-, -O-, -P(=O)-, -P(=O) 2- , -P(=O)(OR 8 )-, -(C=O)-, -(C=O)NR 8 -, or -NR 8 (C═O)—, wherein the alkylene or heteroalkylene is optionally substituted with one or more R; R 5 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R e optionally substituted with Group-ZR 5 is -N=S(=O)-(R 5 )2 and two R 5 may alternatively be combined with the sulfur atom to which they are attached to form one or more Re can form a heterocycloalkyl optionally substituted with R a , R b , R c , and R d are each independently halogen, oxo, -CN, -NO2, -OH, or -OR. 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; or two R's ctogether with the atom to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R e are independently halogen, oxo, -CN, -NO2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, -OR 7 , -OC1-C4 haloalkyl, -CN, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)N(R 8 )2, -C(=NR 8 )N(R 8 )2, -OC(=O)R 7 , -OC(=O)N(R 8 )2, -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -OC2-C6 alkylene)N(R 8 )2, -OC2-C6 alkylene OR 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2N(R 8 )2, -N(R 8 )C(=O)R 7 , -NR 8 C(=O)OR 7 , -N(R 8 )C(=O)N(R 8 )2, -N(R 8 )C(=NR 8 )N(R 8 )2, -N=S(=O)(R 7 )2, -N(R 8 )S(=O)2R 7 , -N(R 8 )S(=O)2N(R 8 )2, -NR 8 C2-C6 alkyleneN(R 8 )2, -NR 8 C2-C6 alkylene OR8 , -C1-C6 alkyleneN(R 8 )2, -C1-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )C(=O)R 7 , -C1-C6 alkyleneOC(=O)R 8 , -C1-C6 alkylene C(=O)N(R 8 )2, and -C1-C6 alkylene C(=O)OR 7 wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R 7 is C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 8 are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R; or Two R on the same atom 8 together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O )OH, —C(═O)OCi-C3 alkyl, —C(═O)NH2, —C(═O)NHCi-C3 alkyl, —C(═O)N(Ci-C3 alkyl)2, —P(═O)(Ci-C3 alkyl)2, Ci-C3 alkyl, Ci-C3 alkoxy, Ci-C3 haloalkyl, Ci-C3 haloalkoxy, Ci-C3 hydroxyalkyl, Ci-C3 aminoalkyl, Ci-C3 heteroalkyl, or C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (Ia):

[0046] [ka] It has the following structure.

[0047] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the formula (Ia-1):

[0048] [ka] having the structure During the ceremony, Y 1 is N, CH, or CR b and Y 2 is N, CH, or CR b and Y 5 is N or CR b2 and Y 4 is N or CR b1 and R b2 is H or R b and R b1 is H or R b is.

[0049] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (Ib):

[0050] [ka] having the structure During the ceremony, Y 1 is N, CH, or CR b and Y 2 is N, CH, or CR b and R b1 is H or R b and R b2 is H or R b is.

[0051] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the formula (Ic):

[0052] [ka] having the structure During the ceremony, Y 2 is N, CH, or CR b and Y 3 is N, CH, or CR b and R b1 is H or R b and R b2 is H or R b is.

[0053] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the formula (Id):

[0054] [ka] having the structure During the ceremony, Y 2 is N, CH, or CR b and Y 4 is N, CH, or CR b and R b1 is H or R b and R b2 is H or R b is.

[0055] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (Ie):

[0056] [ka] having the structure During the ceremony, Y 2 is N, CH, or CR b and Y 5 is N, CH, or CR b and R b1 is H or R b and R b2 is H or R b is.

[0057] In some embodiments, formula (III)

[0058] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is a C3-C7 cycloalkyl, a 4-12 membered heterocycloalkyl, a phenyl, or a 5-10 membered heteroaryl, each of which is selected from the group consisting of one or more R a optionally substituted with Ring B is phenyl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 5- to 12-membered heterocycloalkyl, each of which may be one or more R b optionally substituted with Ring C is phenyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, 5-7 membered heterocycloalkyl, each of which may be one or more R f optionally substituted with L 1 is a bond or linker moiety connecting ring A and ring B, the linker moiety comprising a linear sequence ranging from 1 to 20 non-hydrogen atoms, and one or more R c optionally substituted with L 2 is a bond, -O-, -S-, -N(R 8 )-, -N(R 8 )CO-, -CON(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; L 3 is a bond, -O-, -S-, -N(R 8 )CO-, -CON(R 8 )-, -N(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and R 2 , and R 4are each independently selected from hydrogen, —CN, —OH, —SH, halogen, amino, C-C alkyl, C-C alkoxyl, C-C heteroalkyl, C-C alkenyl, and C-C alkynyl, and each of alkyl, alkoxyl, heteroalkyl, alkenyl, and alkynyl is selected from one or more R 6 optionally substituted with Each R 6 are independently halogen, -CN, -NO2, -OH, oxo, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 8 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 3 is -CN or a group -ZR 5 and Z is a bond, C1-C8 alkylene, C1-C8 heteroalkylene, -NR 8 -, -S(=O)C0-C6 alkylene-, -NR8 SO2-(C0-C6 alkylene)-, -SO2NR 8 -(C0-C6 alkylene)-, -NR 8 SO2NR 8 -, -NR 8 SO2NR 8 C(=O)O-, -(C0-C6 alkylene)-S(=O)(=NH)-, -(C0-C6 alkylene)-NR 8 -S(=O)(=NH)-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-S(=O)-, -(C0-C6 alkylene)-SO2-, -O-, -P(=O)-, -P(=O) 2- , -P(=O)(OR 8 )-, -(C=O)-, -(C=O)NR 8 -, or -NR 8 (C═O)—, wherein the alkylene or heteroalkylene is optionally substituted with one or more R; R 5 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R e optionally substituted with Group-ZR 5 is -N=S(=O)-(R 5 )2 and two R 5 may alternatively be combined with the sulfur atom to which they are attached to form one or more R e can form a heterocycloalkyl optionally substituted with R a , R b , R c , R d , and R f are each independently halogen, oxo, -CN, -NO2, -OH, or -OR. 7, -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; or two R's c together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R eare independently halogen, oxo, -CN, -NO2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, -OR 7 , -OC1-C4 haloalkyl, -CN, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)N(R 8 )2, -C(=NR 8 )N(R 8 )2, -OC(=O)R 7 , -OC(=O)N(R 8 )2, -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -OC2-C6 alkylene)N(R 8 )2, -OC2-C6 alkylene OR 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2N(R 8 )2, -N(R 8 )C(=O)R 7 , -NR 8 C(=O)OR 7 , -N(R 8 )C(=O)N(R 8 )2, -N(R 8 )C(=NR 8 )N(R 8 )2, -N=S(=O)(R 7 )2, -N(R 8 )S(=O)2R 7 , -N(R 8 )S(=O)2N(R 8 )2, -NR 8 C2-C6 alkyleneN(R 8 )2, -NR 8 C2-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )2, -C1-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )C(=O)R7 , -C1-C6 alkyleneOC(=O)R 8 , -C1-C6 alkylene C(=O)N(R 8 )2, and -C1-C6 alkylene C(=O)OR 7 wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R 7 is C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 8 are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R; or two R on the same atom 8 together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O )OH, —C(═O)OCi-C3 alkyl, —C(═O)NH2, —C(═O)NHCi-C3 alkyl, —C(═O)N(Ci-C3 alkyl)2, —P(═O)(Ci-C3 alkyl)2, Ci-C3 alkyl, Ci-C3 alkoxy, Ci-C3 haloalkyl, Ci-C3 haloalkoxy, Ci-C3 hydroxyalkyl, Ci-C3 aminoalkyl, Ci-C3 heteroalkyl, or C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof has the formula (IIIa):

[0060] [ka] It has the following structure.

[0061] In some embodiments, formula (IV)

[0062] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is a C3-C7 cycloalkyl, a 4-12 membered heterocycloalkyl, a phenyl, or a 5-10 membered heteroaryl, each of which is selected from the group consisting of one or more R a optionally substituted with Ring B is phenyl, 5-10 membered heteroaryl, C3-C 12cycloalkyl, or 5- to 12-membered heterocycloalkyl, each of which may be one or more R b optionally substituted with Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L 1 is a bond or linker moiety connecting ring A and ring B, the linker moiety comprising a linear sequence ranging from 1 to 20 non-hydrogen atoms, and one or more R c optionally substituted with L 2 is a bond, -O-, -S-, -N(R 8 )-, -N(R 8 )CO-, -CON(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; L 3 is a bond, -O-, -S-, -N(R 8 )CO-, -CON(R 8 )-, -N(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R; Each R 2 are each independently selected from hydrogen, —CN, —OH, —SH, halogen, amino, C-C alkyl, C-C alkoxyl, C-C heteroalkyl, C-C alkenyl, and C-C alkynyl, and each of alkyl, alkoxyl, heteroalkyl, alkenyl, and alkynyl is selected from one or more R 6 optionally substituted with Each R 6 are independently halogen, -CN, -NO2, -OH, oxo, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 8 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; k2 is 0, 1, 2, or 3; R 3 is -CN or a group -ZR 5 and k1 is 0, 1, 2, or 3; Z is a bond, C1-C8 alkylene, C1-C8 heteroalkylene, -NR 8 -, -S(=O)C0-C6 alkylene-, -NR 8 SO2-(C0-C6 alkylene)-, -SO2NR 8 -(C0-C6 alkylene)-, -NR 8 SO2NR 8 -, -NR 8 SO2NR 8 C(=O)O-, -(C0-C6 alkylene)-S(=O)(=NH)-, -(C0-C6 alkylene)-NR 8 -S(=O)(=NH)-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-S(=O)-, -(C0-C6 alkylene)-SO2-, -O-, -P(=O)-, -P(=O) 2- , -P(=O)(OR 8)-, -(C=O)-, -(C=O)NR 8 -, or -NR 8 (C═O)—, wherein the alkylene or heteroalkylene is optionally substituted with one or more R; R 5 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R e optionally substituted with Group-ZR 5 is -N=S(=O)-(R 5 )2 and two R 5 may alternatively be combined with the sulfur atom to which they are attached to form one or more R e can form a heterocycloalkyl optionally substituted with R a , R b , R c , R d , and R f are each independently halogen, oxo, -CN, -NO2, -OH, or -OR. 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or two R's c together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R e are independently halogen, oxo, -CN, -NO2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, -OR 7 , -OC1-C4 haloalkyl, -CN, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)N(R 8 )2, -C(=NR 8 )N(R 8 )2, -OC(=O)R 7 , -OC(=O)N(R 8 )2, -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -OC2-C6 alkylene)N(R 8 )2, -OC2-C6 alkylene OR 8 , -SH, -SR7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2N(R 8 )2, -N(R 8 )C(=O)R 7 , -NR 8 C(=O)OR 7 , -N(R 8 )C(=O)N(R 8 )2, -N(R 8 )C(=NR 8 )N(R 8 )2, -N=S(=O)(R 7 )2, -N(R 8 )S(=O)2R 7 , -N(R 8 )S(=O)2N(R 8 )2, -NR 8 C2-C6 alkyleneN(R 8 )2, -NR 8 C2-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )2, -C1-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )C(=O)R 7 , -C1-C6 alkyleneOC(=O)R 8 , -C1-C6 alkylene C(=O)N(R 8 )2, and -C1-C6 alkylene C(=O)OR 7 wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R 7 is C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 8are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R; or Two R on the same atom 8 together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O )OH, —C(═O)OCi-C3 alkyl, —C(═O)NH2, —C(═O)NHCi-C3 alkyl, —C(═O)N(Ci-C3 alkyl)2, —P(═O)(Ci-C3 alkyl)2, Ci-C3 alkyl, Ci-C3 alkoxy, Ci-C3 haloalkyl, Ci-C3 haloalkoxy, Ci-C3 hydroxyalkyl, Ci-C3 aminoalkyl, Ci-C3 heteroalkyl, or C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound of formula (IV) has the structure of formula (III). In some embodiments, the compound of formula (IV) has the structure of formula (IIIa). In some embodiments, the compound of formula (IV) has the structure of formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic). In some embodiments,

[0064] [ka] teeth,

[0065] [ka] and rings C and X 2 , X 3 , and X 4 is defined in formula (III). In some embodiments,

[0066] [ka] teeth,

[0067] [ka] In some embodiments,

[0068] [ka] teeth,

[0069] [ka] and X 1 , X 2 , X 3 , and X 4is defined in formula (I). In some embodiments, k1 is 0. In some embodiments, k1 is 1. In some embodiments, k1 is 2. In some embodiments, k1 is 3. In some embodiments, k2 is 0. In some embodiments, k2 is 1. In some embodiments, k2 is 2. In some embodiments, k2 is 3. In some embodiments, R 3 L 3 In some embodiments, R 3 L 2 In some embodiments, R 3 L 2 It is in the ortho position relative to the attachment point of

[0070] In some embodiments, the compound of formula (IV) has the formula (IVa):

[0071] [ka] It has the following structure.

[0072] In some embodiments of the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, Ring D is aryl. In some embodiments, Ring D is phenyl. In some embodiments, Ring D is phenyl fused to a cycloalkyl. In some embodiments, Ring D is phenyl fused to a 5-6 membered cycloalkyl. In some embodiments,

[0073] [ka] teeth,

[0074] [ka] In some embodiments, ring D is phenyl fused to a heterocycloalkyl. In some embodiments, ring D is phenyl fused to a 5-6 membered heterocycloalkyl. In some embodiments,

[0075] [ka] teeth,

[0076] [ka] In some embodiments,

[0077] [ka] teeth,

[0078] [ka] is.

[0079] In some embodiments of the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, Ring D is naphthyl.

[0080] [ka] teeth,

[0081] [ka] is.

[0082] In some embodiments, Ring D is heterocycloalkyl. In some embodiments, Ring D is cycloalkyl.

[0083] In some embodiments of a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, Ring D is heteroaryl. In some embodiments, Ring D is monocyclic heteroaryl. In some embodiments, Ring D is bicyclic heteroaryl. In some embodiments, Ring D is a 5-6, 6-6, or 6-5 fused bicyclic heteroaryl. In some embodiments, Ring D is a 6-5 fused bicyclic heteroaryl. In some embodiments, Ring D contains 1-3 nitrogens, 0-1 sulfur, and 0-1 oxygen. In some embodiments, Ring D contains 1-3 nitrogens. In some embodiments, Ring D contains 0-2 nitrogens and 1 oxygen. In some embodiments,

[0084] [ka] teeth,

[0085] [ka] In some embodiments,

[0086] [ka] teeth,

[0087] [ka] In some embodiments,

[0088] [ka] teeth,

[0089] [ka] In some embodiments, R 3 L 3In some embodiments, R 3 L 2 In some embodiments,

[0090] [ka] teeth,

[0091] [ka] is.

[0092] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, X 1 is N.

[0093] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, X 1 is CR 1 In some embodiments of the compound or pharmaceutically acceptable salt thereof, R 1 is hydrogen or C1-C3 alkyl. In some embodiments of the compound, or a pharmaceutically acceptable salt thereof, R 1 is hydrogen.

[0094] In some embodiments of the compound of Formula (III), (IIIa), or (I), or a pharmaceutically acceptable salt thereof, X 3 is N.

[0095] In some embodiments of the compound of Formula (III), (IIIa), or (I), or a pharmaceutically acceptable salt thereof, X 3 is CR 3 is.

[0096] In some embodiments of compounds of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), R 3 is CN.

[0097] In some embodiments of the compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), R3 is -ZR 5 In some embodiments, Z is a bond, C1-C8 alkylene, -NR 8 -, -NR 8 SO2-(C0-C6 alkylene)-, -SO2NR 8 -(C0-C6 alkylene)-, -NR 8 SO2NR 8 In some embodiments, Z is selected from the group consisting of -, and -(C0-C6 alkylene)-SO2-. In some embodiments, Z is -NHSO2-, -CH2SO2-, -NH-, or -SONH-. In some embodiments, Z is -NHSO2-. In some embodiments, Z is -CH2SO2-. In some embodiments, Z is -NH-. In some embodiments, Z is -SONH-. In some embodiments, Z is -NR 8 In some embodiments, Z is NR 8 In some embodiments, Z is a C1-C8 heteroalkylene, which can be substituted with one or more R. In some embodiments, the C1-C8 heteroalkylene is

[0098] [ka] is.

[0099] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, the group -ZR 5 is -N=S(=O)-(R 5 )2 and two R 5can alternatively be combined with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 nitrogen atoms and 0, 1, or 2 atoms selected from O and S.

[0100] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C4 haloalkyl, and C1-C6 hydroxyalkyl.

[0101] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, -ZR 5 are -NHSO2CH2CH2OH, -NHSO2CH2CH3, -NHSO2CH3, -NHC(CH3)2CH2OH, and

[0102] [ka] is selected from the group consisting of:

[0103] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, -ZR 5 is selected from the group consisting of -SO2NHCH2CH2OH, -SO2NHC(CH3)3, -SO2NHCH3, and -SO2NH2.

[0104] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, -ZR5 is -CH2SO2CH2CH2OH.

[0105] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 3 teeth,

[0106] [ka] In some embodiments, R 3 teeth,

[0107] [ka] In some embodiments, R 3 teeth,

[0108] [ka] In some embodiments, R 3 teeth,

[0109] [ka] In some embodiments, R 3 teeth,

[0110] [ka] In some embodiments, R 3 teeth,

[0111] [ka] In some embodiments, R 3 teeth,

[0112] [ka] In some embodiments, R 3 teeth,

[0113] [ka] In some embodiments, R 3 teeth,

[0114] [ka] In some embodiments, R 3 teeth,

[0115] [ka] In some embodiments, R 3 teeth,

[0116] [ka] is.

[0117] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof,

[0118] [ka] teeth,

[0119] [ka] is.

[0120] In some embodiments of a compound of Formula (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, X 2 is N.

[0121] In some embodiments of a compound of Formula (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, X 2 is CR 2 In some embodiments of the compound or pharmaceutically acceptable salt thereof, R 2 is hydrogen or C1-C3 alkyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is F.

[0122] In some embodiments of a compound of Formula (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, X 4 is N.

[0123] In some embodiments of a compound of Formula (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, X 4 is CR 4 In some embodiments of the compound or pharmaceutically acceptable salt thereof, R 4 is hydrogen or C1-C3 alkyl. In some embodiments of the compound, or a pharmaceutically acceptable salt thereof, R 4 is hydrogen.

[0124] In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 4 and R 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d In some embodiments, R 4 and R 3together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -ZR 5 and optionally one or more R d In some embodiments, R 4 and R 3 are taken together to form an optionally substituted heteroaryl. In some embodiments,

[0125] [ka] is -ZR 5 and optionally one or more R d is replaced by

[0126] [ka] is. In some embodiments,

[0127] [ka] teeth,

[0128] [ka] is.

[0129] In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 3 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d is optionally replaced by

[0130] In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 4 and R 3 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d is optionally replaced by

[0131] In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 3 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d is optionally replaced by

[0132] In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 3 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -ZR 5 and one or more R d In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R 3 and R 2 together form a heterocycloalkyl or heteroaryl, each of which is -ZR 5 and one or more R d In some embodiments, R 3 and R 2 together form a 5- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, each of which is -ZR 5and one or more R d In some embodiments,

[0133] [ka] teeth,

[0134] [ka] and each of these is -ZR 5 and one or more R d In some embodiments,

[0135] [ka] teeth,

[0136] [ka] is. In some embodiments,

[0137] [ka] teeth,

[0138] [ka] In some embodiments,

[0139] [ka] teeth,

[0140] [ka] In some embodiments,

[0141] [ka] teeth,

[0142] [ka] In some embodiments,

[0143] [ka] teeth,

[0144] [ka] is.

[0145] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 2 and R 1 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be joined by one or more R d In some embodiments, R 2 and R 1 together with one or more R d In some embodiments, R 2 and R 1 together with one or more R d In some embodiments, R 2 and R 1 together with one or more R d In some embodiments, R 2 and R 1 are taken together as one or more R containing one oxygen atom. d In some embodiments, R 2 and R1 together with one or more R d In some embodiments, R 2 and R 1 together with one or more R d to form a heteroaryl optionally substituted with

[0146] In some embodiments of the compound of Formula (Ia-1) or (Ib), or a pharmaceutically acceptable salt thereof, Y 1 is N, CH, or CR b In some embodiments, Y 1 is N. In some embodiments, Y 1 is CH. In some embodiments, Y 1 is CR b is.

[0147] In some embodiments of the compound of Formula (Ia-1), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt thereof, Y 2 is N, CH, or CR b In some embodiments, Y 2 is N. In some embodiments, Y 2 is CH. In some embodiments, Y 2 is CR b is.

[0148] In some embodiments of the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, Y 3 is N, CH, or CR b In some embodiments, Y 3 is N. In some embodiments, Y 3 is CH. In some embodiments, Y 3 is CR b is.

[0149] In some embodiments of the compound of Formula (Ia-1) or a pharmaceutically acceptable salt thereof, Y 4 is N or CR b1In some embodiments, Y 4 is N. In some embodiments, Y 4 is CR b1 In some embodiments of the compound of Formula (Ia-1) or a pharmaceutically acceptable salt thereof, Y 5 is N or CR b2 In some embodiments, Y 5 is N. In some embodiments, Y 5 is CR b2 is.

[0150] In some embodiments of the compound of Formula (Id) or a pharmaceutically acceptable salt thereof, Y 4 is N, CH, or CR b In some embodiments, Y 4 is N. In some embodiments, Y 4 is CH. In some embodiments, Y 4 is CR b is.

[0151] In some embodiments of the compound of Formula (Ie) or a pharmaceutically acceptable salt thereof, Y 5 is N, CH, or CR b In some embodiments, Y 5 is N. In some embodiments, Y 5 is CH. In some embodiments, Y 5 is CR b is.

[0152] In some embodiments of a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, Ring C is phenyl, 5-6 membered heteroaryl, C-C cycloalkyl, 5-7 membered heterocycloalkyl, each of which is selected from the group consisting of one or more R fIn some embodiments of a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, Ring C is phenyl, a 5-6-membered heteroaryl, a C5-C6 cycloalkyl, or a 5-6-membered heterocycloalkyl, each of which is optionally substituted. In some embodiments, Ring C is an optionally substituted phenyl. In some embodiments, Ring C is an optionally substituted C5-C6 cycloalkyl or a 5-6-membered heterocycloalkyl. In some embodiments, Ring C is an optionally substituted 5-6-membered heterocycloalkyl. In some embodiments, Ring C is an optionally substituted heteroaryl. In some embodiments, Ring C is an optionally substituted 5-7-membered heterocycloalkyl. In some embodiments, Ring C is an optionally substituted 5-membered heterocycloalkyl. In some embodiments, Ring C is an optionally substituted 6-membered heterocycloalkyl. In some embodiments, Ring C is an optionally substituted 7-membered heterocycloalkyl. In some embodiments, Ring C is a 6-membered heterocycloalkyl, which is selected from one or more R f In some embodiments, Ring C is a 7-membered heterocycloalkyl, which is optionally substituted with one or more R f is optionally replaced by

[0153] In some embodiments of the compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, Ring C is a 6-membered heteroaryl, which may be one or more R f In some embodiments,

[0154] [ka] teeth,

[0155] [ka] In some embodiments of the compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, Ring C is selected from the group consisting of one or more R f In some embodiments,

[0156] [ka] teeth,

[0157] [ka] is.

[0158] In some embodiments of the compound of Formula (III),

[0159] [ka] teeth,

[0160] [ka] In some embodiments,

[0161] [ka] teeth,

[0162] [ka] and

[0163] [ka] represents a double bond or a single bond. In some embodiments,

[0164] [ka] represents a double bond. In some embodiments,

[0165] [ka] represents a single bond. In some embodiments of the compound of formula (III),

[0166] [ka] teeth,

[0167] [ka] In some embodiments,

[0168] [ka] teeth,

[0169] [ka] In some embodiments,

[0170] [ka] teeth,

[0171] [ka] is.

[0172] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is represented by formula (II)

[0173] [ka] The structure of During the ceremony, L 11 , L 12 , L 13 , L 14 , and L 15 each independently represents a substituted or unsubstituted C-C 20 Alkylene, substituted or unsubstituted C1-C 19 Heteroalkylene, substituted or unsubstituted C-C 20 Heteroalkenylene, substituted or unsubstituted C-C 20 Heteroalkynylene, substituted or unsubstituted C-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -(CH2CH2O) p -, -(OCH2CH2) p -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, -N(OR LK )-, and a bond; Each R LK are independently hydrogen or substituted or unsubstituted C1-C6 alkyl; P is an integer selected from 1 to 6.

[0174] In some embodiments, L 11 , L 12 , L 13, L 14 , and L 15 each independently represents a substituted or unsubstituted C-C 20 Alkylene, substituted or unsubstituted C1-C 19 Heteroalkylene, substituted or unsubstituted C-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -(CH2CH2O) p -, -(OCH2CH2) p -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, -N(OR LK )-, and a bond.

[0175] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is represented by formula (II)

[0176] [ka] The structure of During the ceremony, L 11 , L 12 , L 13 , L 14 , and L15 each independently represents a substituted or unsubstituted C-C 20 Alkylene, substituted or unsubstituted C1-C 19 Heteroalkylene, substituted or unsubstituted C-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -(CH2CH2O) p -, -(OCH2CH2) p -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C (=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, -N(OR LK )-, and a bond, wherein alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are substituted and then are selected from one or more R c is replaced by Each Rc is independently hydrogen, halogen, -CN, -NO2, -OR b , -SR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C9 heterocycloalkyl, aryl, and heteroaryl; Each R LK are independently hydrogen or substituted or unsubstituted C1-C6 alkyl; p is an integer selected from 1 to 6.

[0177] In some embodiments, R LK is one or more R c is replaced by

[0178] In some embodiments, the linker L 1 is represented by formula (II)

[0179] [ka] The structure of During the ceremony, L 11 , L 12 , L 13 , L 14 , and L 15 Each of the is a substituted or unsubstituted C1-C 20 Alkylene, substituted or unsubstituted C1-C 19 Heteroalkylene, substituted or unsubstituted C-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -(CH2CH2O) p -, -(OCH2CH2) p -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, -N(OR LK)-, and bonds, Each R LK are independently hydrogen, -CN, or -C(=O)R 7 , -C(=O)OR 7 , -C(=O)NR 8 R 8 C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; p is an integer selected from 1 to 6.

[0180] In some embodiments, L 11 is attached to ring B. In some embodiments, L 11 is attached to ring A. In some embodiments, L 11 , L 12 , L 13 , L 14 , and L 15 In some embodiments, at least one of L 11 , L 12 , L 13 , L 14 , and L 15 In some embodiments, one of L 11 , L 12 , L 13 , L 14 , and L 15 In some embodiments, two of L 11 , L 12 , L 13 , L 14 , and L 15 In some embodiments, three of L 11 , L 12 , L 13 , L 14 , and L 15In some embodiments, four of the linkers L 1 -L 11 -L 12 -, -L 11 -L 12 -L 13 -, -L 11 -L 12 -L 13 -L 14 -, -L 11 -L 12 -L 13 -L 14 -L 15 -, -L 13 -L 14 -L 15 -, or -L 11 -L 15 In some embodiments, the linker L 1 -L 11 -L 12 - has the structure.

[0181] In some embodiments, L 11 is a bond, -O-, -NR LK -, -C(=O), NR LK -, C1-C 20 Alkylene, C2-C 19 In some embodiments, L is selected from heteroalkylene, heterocycloalkylene, and heterocycloalkylene. 11 is -NH-. In some embodiments, L 11 is a substituted or unsubstituted heterocycloalkylene. In some embodiments, the heterocycloalkylene is a 4- to 6-membered ring. In some embodiments, the heterocycloalkylene is a 6-membered ring.

[0182] In some embodiments, L 12 is a bond, -O-, C1-C 20 Alkylene, C1-C 19 In some embodiments, L is selected from heteroalkylene, C-C alkylene (cycloalkyl), and cycloalkylene. 12 is C-C cycloalkylene. In some embodiments, L 12is a substituted or unsubstituted C1-C 20 In some embodiments, L is alkylene. 12 is a substituted or unsubstituted C1-C6 alkylene. In some embodiments, L 12 is a substituted or unsubstituted C1-C 19 In some embodiments, L is heteroalkylene. 12 is a substituted or unsubstituted C1-C6 heteroalkylene. In some embodiments, L 12 is a substituted or unsubstituted C1-C3 heteroalkylene.

[0183] In some embodiments, L 13 is a bond, -O-, C1-C 20 Alkylene, C1-C 19 In some embodiments, L is selected from heteroalkylene, C-C alkylene (cycloalkyl), and cycloalkylene. 13 is C1-C6 alkylene or C1-C6 heteroalkylene. In some embodiments, L 13 is C1-C3 alkylene or C1-C3 heteroalkylene.

[0184] In some embodiments, L 14 is a bond, -O-, C1-C 20 Alkylene, and C1-C 19 In some embodiments, L is selected from heteroalkylene. 14 is a bond.

[0185] In some embodiments, L 15 are bonds, O-, and C1-C 20 In some embodiments, L is selected from alkylene. 15 is a bond.

[0186] In some embodiments, L 11 , L 12 , L 13 , L 14 , and L 15each independently represents a bond, -O-, -CH2-, -CH2CH2-, -CH = CH-, -CH2CH2CH2-, -NH-, -C(=O)-,

[0187] [ka] is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -NH-,

[0188] [ka] each of which is selected from one, two, or three CH3 (e.g., CD3), halogen, -CH2CF3, -OCH3, -CF3, -OH, or

[0189] [ka] is optionally replaced by

[0190] In some embodiments, each R LK is independently C-C alkyl optionally substituted with one or more R, and each R is independently halogen, oxo, —CN, —OH, —OCH, —S(═O)CH, —S(═O)CH, —S(═O)NH, —S(═O)NHCH, —S(═O)N(CH), —NH, —NHCH, —N(CH), —C(═O)CH, —C(═O)OH, —C(═O)OCH, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, and C-C heteroalkyl, or two R together form oxo.

[0191] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1is -heterocycloalkyl-C1-C6 alkylene-, -heterocycloalkyl-C1-C6 heteroalkylene-, -cycloalkyl-C1-C6 alkylene-, -cycloalkyl-C1-C6 heteroalkylene, -C1-C6 alkylene-heterocycloalkyl-, -C1-C6 heteroalkylene-heterocycloalkyl-, -C1-C6 alkylene-cycloalkyl-, -C1-C6 heteroalkylene-cycloalkyl-, -C1-C6 heteroalkylene-cycloalkyl-C1-C6 heteroalkylene, -C1-C6 alkylene-cycloalkyl-C1-C6 alkylene, C1-C 6 heteroalkylene-cycloalkyl-C1-C6 alkylene, C1-C6 alkylene-cycloalkyl-C1-C6 heteroalkylene, -C1-C6 heteroalkylene-heterocycloalkyl-C1-C6 heteroalkylene, -C1-C6 heteroalkylene-heterocycloalkyl-C1-C6 alkylene, -C1-C6 alkylene-heterocycloalkyl-C1-C6 heteroalkylene, or -C1-C6 alkylene-heterocycloalkyl-C1-C6 alkylene, and each of the cycloalkyl, heterocycloalkyl, alkylene, and heteroalkylene may be selected from the group consisting of one or more R c is optionally replaced by

[0192] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is -heterocycloalkyl-C-C heteroalkylene-, and each of the heterocycloalkyl and heteroalkylene is selected from one or more R c In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 6 membered heterocycloalkyl. In some embodiments, the C1-C6 heteroalkylene contains 1-2 oxygen atoms. In some embodiments, the C1-C6 heteroalkylene is a C1-C4 heteroalkylene. In some embodiments, L 1 teeth,

[0193] [ka] is.

[0194] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety that includes cyclic moieties, each of which may be one or more R c is optionally replaced by

[0195] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety that includes acyclic moieties, and each acyclic moiety is one or more R c is optionally replaced by

[0196] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety that includes an aromatic moiety, and each aromatic moiety is linked to one or more R c is optionally replaced by

[0197] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety that includes a non-aromatic moiety, and each non-aromatic moiety is one or more R c is optionally replaced by

[0198] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety consisting of a linear sequence ranging from 1 to 20 non-hydrogen atoms.

[0199] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is a linker moiety consisting of a linear sequence ranging from 1 to 8 non-hydrogen atoms.

[0200] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is selected from the group consisting of one or more R c In some embodiments, L 1 is C1-C8 alkylene or C1-C8 heteroalkylene, each of which is selected from the group consisting of one or more R c is optionally replaced by

[0201] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is one or more R c In some embodiments, L is C-C alkylene optionally substituted with 1 is —(CH)—, —(CH)—, —(CH)—, or —(CH)—. In some embodiments, L 1 is -(CH2)3-. In some embodiments, L 1is -(CH2)4-. In some embodiments, L 1 is -(CH2)5-. In some embodiments, L 1 is -(CH2)6-.

[0202] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 is one or more R c In some embodiments, the C1-C6 heteroalkylene contains 1, 2, or 3 heteroatoms selected from N, O, and S, which are optionally substituted with one or more R c In some embodiments, the C1-C6 heteroalkylene contains 1 or 2 heteroatoms selected from N and O, which are optionally substituted with one or more R c In some embodiments, the C1-C6 heteroalkylene comprises one nitrogen atom. In some embodiments, the C1-C6 heteroalkylene comprises two nitrogen atoms. In some embodiments, the C1-C6 heteroalkylene comprises one oxygen atom. In some embodiments, the C1-C6 heteroalkylene comprises two oxygen atoms. In some embodiments, the C1-C6 heteroalkylene comprises one nitrogen and one oxygen. In some embodiments, the C1-C6 heteroalkylene comprises one nitrogen and two oxygen atoms.

[0203] In some embodiments of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), each R c are independently halogen, oxo, -CN, -NO2, -OH, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7, -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R or two R c together with the atoms to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, two R c are united,

[0204] [ka] and R is defined herein. In some embodiments, two R c are united,

[0205] [ka] and each R is independently halogen, —C1-C3 alkyl, —C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, two R c are united,

[0206] [ka] Form.

[0207] In some embodiments of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), each R c are independently hydrogen, halogen, -CN, -NO2, -OR b , -SR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C9 heterocycloalkyl, aryl, and heteroaryl. In some embodiments, each R c is independently selected from hydrogen, halogen, —CN, —NO2, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl.

[0208] In some embodiments of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), each R c are independently halogen, oxo, -OH, -OR 7 , C1-C6 haloalkyl, C1-C6 alkyl, and cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more R.

[0209] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R c is halogen. In some embodiments, R c is F.

[0210] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R c is oxo.

[0211] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R c is -OH.

[0212] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R c HA-OR 7 In some embodiments, R c is -OCH3.

[0213] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R c is C1-C6 haloalkyl. In some embodiments, R c is —CF. In some embodiments, R c is -CH2CF3.

[0214] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), R cis C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R c is —CH3. In some embodiments, R c is -CD3.

[0215] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), at least one R c is cycloalkyl, and the cycloalkyl is optionally substituted with one or more R. In some embodiments, R c is a C-C cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R. In some embodiments, R c is optionally substituted with one or more R

[0216] [ka] is.

[0217] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), L 1-OCH2CH2OCH2- H2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2CH2OCH2-, -CH2OCH(CH3)CH2OCH2-, -CH2OCH2CH2-, -N(CH3)CH2CH2OCH2-, -N(cyclopropyl)CH2CH2CH2OCH2- 、-N(CH3)CH2CH2CH2OCH2-、-NHCH2CH2OCH2-、-NHCH2CH2CH2OCH2-、-NHCH2CH(CH3)CH2OCH2-、-N(CH3)CH2CH2OCH2CH2-、-NHCH2CH2OCH2CH2-、-NH(CH2) )4-、-NH(CH2)5-、-NHCH2CH(CH3)(CH2)3-、-N(CH3)(CH2)4-、-N(CH3)(CH2)5-、-NHCH2CH2CH2CH2O-、-NHCH2C(=O)N(CH3)CH2CH2-、-NHCH2CH2CH2NHCH 2-、-NHCH(CH3)CH2OCH2CH2-、-NHCH2CH(CH3)OCH2CH2-、-N(CH3)CH2CH(CH3)OCH2CH2-、-NHCH2CF2CH2OCH2-、-N(CH3)CH2CF2CH2OCH2-、-NHCH2CH(CH3) )CH2OCH2-、-N(CH3)CH2CH(CH3)CH2OCH2-、-NHCH(CH3)CH2CH2OCH2-、-NHCH2CH2CH(CH3)OCH2-、-NHCH2CH(CH3)CH2OCH2-、-NHCH2CHFCH2OCH2-、-NHCH 2CH(OCH3)CH2OCH2-、-NHCH2CH(CF3)CH2OCH2-、-NHCH2CF2CH2OCH2-、-NHCH2CH(OH)CH2OCH2-、-N(CH3)CH2CH(CH3)CH2OCH2-、-N(CH3)CH2CH2OCH2 -、-N(CH3)CH2CH(OCH3)CH2OCH2-、-N(CH3)CH2CH(CF3)CH2OCH2-、-N(CH3)CH2CF2CH2OCH2-、-N(CH3)CH2CH(OH)CH2OCH2-、-C(=O)N(CH3)CH2CH2OCH2-、In some embodiments, -N(CH)(CH)- is -N(CD)(CH)-. In some embodiments, -N(CH)(CH)- is -N(CD)(CH)-. In some embodiments, -N(CH)(CH)- is -N(CD)(CH)-.

[0218] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -OCH2CH2OCH2-, -OCH2CH2CH2OCH2-, -OCH2CH2CH2CH2CH2-, -OCH(CH3)CH2CH2OCH2-, -OCH2CH(CH3)CH2OCH2-, -OCH2CH(CH3)CH2OCH2-, -OCH2CH(CH3)OCH2CH2-, and -OCH(CH3)CH2OCH2CH2-.

[0219] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -CH2OCH2-, -CH2CH2OCH2-, -CH2CH2CH2CH2OCH2-, and -CH2OCH2CH2-.

[0220] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -N(CH3)CH2CH2OCH2-, -N(CH3)CH2CH2CH2OCH2-, -NHCH2CH2OCH2-, or -NHCH2CH2CH2OCH2-.

[0221] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -N(CH3)CH2CH2OCH2CH2-, -NHCH2CH2OCH2CH2-, -NH(CH2)4-, -NH(CH2)5-, -NHCH2CH2CH2CH2O-, and -NHCH2CH2CH2NHCH2-.

[0222] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -NHCH(CH3)CH2OCH2CH2-, -NHCH2CH(CH3)OCH2CH2-, and -N(CH3)CH2CH(CH3)OCH2CH2-.

[0223] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -NHCHCFCHOCH-, -N(CH)CHCFCHOCH-, -N(CH)CHCH(CH)CHOCH-, -NHCH(CH)CHCHOCH-, and -NHCHCHCH(CH)OCH-.

[0224] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1is selected from the group consisting of -NHCH2CH(CH3)CHOCH2-, -NHCH2CHFCHOCH2-, -NHCH2CH(OCH3)CHOCH2-, -NHCH2CH(CF3)CHOCH2-, -NHCH2CF2CH2OCH2-, -NHCH2CH(OH)CHOCH2-, -N(CH3)CH2CH(CH3)CHOCH2-, -N(CH3)CH2CHFCHOCH2-, -N(CH3)CH2CH(OCH3)CHOCH2-, -N(CH3)CH2CH(CF3)CHOCH2-, -N(CH3)CH2CF2CH2OCH2-, and -N(CH3)CH2CH(OH)CHOCH2-.

[0225] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, L 1 is selected from the group consisting of -C(=O)N(CH3)CH2CH2OCH2-, -C(=O)N(CH3)CH2CH2CH2OCH2-, and -C(=O)N(CH3)CH2CH2CH2CH2-.

[0226] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), two R c together with the atoms to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R.

[0227] In some embodiments of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, two R c together with the atom to which they are attached form a cycloalkyl optionally substituted with one or more R. In some embodiments, two R ctogether with the atoms to which they are attached form a C3-C6 cycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, two R c are optionally substituted, together with the atoms to which they are attached, with one or more R

[0228] [ka] In some embodiments, L 1 teeth,

[0229] [ka] is.

[0230] In some embodiments of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), or a pharmaceutically acceptable salt thereof, two R c together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R (e.g., L 1 teeth

[0231] [ka] (It is).

[0232] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), two R c together with the intervening atoms form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted. In some embodiments, two R ctaken together with the intervening atoms form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, the intervening atoms include two or more carbons. In some embodiments, the intervening atoms include two carbons. In some embodiments, the intervening atoms include three carbons. In some embodiments, the intervening atoms include at least one carbon and at least one heteroatom. In some embodiments, the heteroatom is nitrogen. In some embodiments, the intervening atoms include one carbon and one nitrogen. In some embodiments, the intervening atoms include two carbons and one nitrogen.

[0233] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), L 1 is a C1-C6 heteroalkylene, which is a group consisting of one or more R c and optionally substituted with two R c may be taken together with the intervening atoms to form a ring (e.g., L 1 teeth

[0234] [ka] In some embodiments, L 1 is a C1-C6 heteroalkylene, which is a group consisting of one or more R c and two R attached to adjacent atoms c together to form a bond (e.g., L 1 teeth

[0235] [ka] (It is).

[0236] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), two R c together with the intervening atoms form a cycloalkyl optionally substituted with one or more R. In some embodiments, two R c together with the intervening atoms form a C-C cycloalkyl optionally substituted with one or more R. In some embodiments, two R c is combined with the intervening atom,

[0237] [ka] each of which is optionally substituted with one or more R. In some embodiments, two R c is, together with any intervening atoms, optionally substituted with one or more R

[0238] [ka] In some embodiments, two R c is, together with any intervening atoms, optionally substituted with one or more R

[0239] [ka] In some embodiments, L 1 teeth,

[0240] [ka] In some embodiments, L 1 teeth,

[0241] [ka] In some embodiments, L 1 teeth,

[0242] [ka] In some embodiments, L 1 teeth,

[0243] [ka] In some embodiments, L 1 teeth,

[0244] [ka] is.

[0245] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), two R c together with the intervening atoms form a heterocycloalkyl optionally substituted with one or more R. In some embodiments, two R c together with the intervening atoms form a 4- to 6-membered heterocycloalkyl optionally substituted with one or more R, containing one or two heteroatoms selected from N and O. In some embodiments, two R c is combined with the intervening atom,

[0246] [ka] each of which is optionally substituted with one or more R. In some embodiments, two R c is, together with any intervening atoms, optionally substituted with one or more R

[0247] [ka] In some embodiments, two Rc is, together with any intervening atoms, optionally substituted with one or more R

[0248] [ka] In some embodiments, two R c is, together with any intervening atoms, optionally substituted with one or more R

[0249] [ka] In some embodiments, L 1 teeth,

[0250] [ka] In some embodiments, L 1 teeth,

[0251] [ka] In some embodiments, L 1 teeth,

[0252] [ka] In some embodiments, L 1 teeth,

[0253] [ka] is.

[0254] In some embodiments of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), (Ic), or (II), two R c together form a bond. In some embodiments, L 1 teeth,

[0255] [ka] In some embodiments, L 1 teeth,

[0256] [ka] In some embodiments, L 1 teeth,

[0257] [ka] In some embodiments, L 1 teeth,

[0258] [ka] In some embodiments, L 1 teeth,

[0259] [ka] In some embodiments, L 1 teeth,

[0260] [ka] In some embodiments, L 1 teeth,

[0261] [ka] is.

[0262] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0263] [ka] is selected from the group consisting of:

[0264] In some embodiments, L 1 connects ring B to ring B from left to right, for example, L 1 is -OCH2CH2OCH2-,

[0265] [ka] part is,

[0266] [ka] In some embodiments, L 1 connects ring B and ring A from right to left, for example, L 1 is -OCH2CH2OCH2-,

[0267] [ka] part is,

[0268] [ka] is.

[0269] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 2 is a bond, -N(R 8 )CO-, -CON(R8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R. In some embodiments, L 2 is C1-C3 alkylene or C1-C3 heteroalkylene, each of which is optionally substituted. In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 2 is selected from a bond, —OCH—, or —CHO—. In some embodiments, L 2 is a bond. In some embodiments, L 2 is —OCH—. In some embodiments, L 2 is CH2O-.

[0270] In some embodiments of the compound of Formula (IV), (IVa), (III), (IIIa), or (I) (or a pharmaceutically acceptable salt thereof), L 3 is a bond, -N(R 8 )CO-, -CON(R 8 )-, C1-C6 alkylene, or C1-C6 heteroalkylene, wherein the alkylene and heteroalkylene are optionally substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, L 3 is -NHCO-. In some embodiments, L 3 is —NHCO— or —C(═O)O—. In some embodiments, L 3 is C1-C3 heteroalkylene (e.g., -C(=O)O-). In some embodiments, L 3 -N(R 8 )CO-, and -N(R 8 )- is attached to ring B, and -CO- is

[0271] [ka] In some embodiments, L 3 -N(R 8 )CO—, where —CO— is bonded to ring B, and —N(R 8 )-teeth

[0272] [ka] In some embodiments, L 3 is —NHCO—, and —NH— is attached to ring B. In some embodiments, L 3 is —NHCO—, and —CO— is attached to ring B. In some embodiments, L 3 -N(R 8 In some embodiments, L 3 is -NH-.

[0273] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, Ring A is a C4-C7 cycloalkyl, a monocyclic 4-7 membered heterocycloalkyl, or a bicyclic 6-10 membered heterocycloalkyl, each of which is selected from the group consisting of one or more R a In some embodiments, ring A is optionally substituted with one or more R a In some embodiments, ring A is a C-C cycloalkyl optionally substituted with one or more R a In some embodiments, ring A is a 4-6 membered heterocycloalkyl optionally substituted with one or more R a In some embodiments, ring A is a 4-6 membered heterocycloalkyl optionally substituted with one or more R aand 6-membered heterocycloalkyl optionally substituted with , wherein the heterocycloalkyl contains 1-3 nitrogens, 0-1 oxygens, and 0-1 sulfurs.

[0274] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring A is

[0275] [ka] where * represents L 2 indicates the point of attachment to L 1 indicates the point of attachment to Each R a1 , R a2 , and R a3 are each independently hydrogen, halogen, oxo, -CN, -NO2, -OH, or -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 9-membered cycloalkyl, and 3- to 9-membered heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.

[0276] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R a1 , R a2 , and R a3 are each independently selected from hydrogen, halogen, oxo, —CN, —NO, —OH, C1-C3 alkyl, C1-C3 haloalkyl, 3- to 6-membered cycloalkyl, and 5- to 6-membered heterocycloalkyl. a1 , R a2 , and R a3 are each independently selected from hydrogen, halogen, oxo, —CN, —NO 2 , —OH, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.

[0277] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring A is selected from the group consisting of one or more R a In some embodiments, ring A is a monocyclic 4-7 membered heterocycloalkyl optionally substituted with one or more R a In some embodiments, ring A is a monocyclic 5-6 membered heterocycloalkyl containing 1 or 2 nitrogens, optionally substituted with: In some embodiments, ring A is an optionally substituted piperidine. In some embodiments, ring A is

[0278] [ka] In some embodiments, the hetero ring atom of ring A is selected from the group consisting of L 2 In some embodiments, ring A is an optionally substituted piperidine, and the nitrogen of the piperidine is bonded to L 2 In some embodiments, ring A is directly bonded to

[0279] [ka] In some embodiments, ring A is

[0280] [ka] In some embodiments, ring A is

[0281] [ka] In some embodiments, ring A is

[0282] [ka] In some embodiments, ring A is

[0283] [ka] In some embodiments, ring A is

[0284] [ka] In some embodiments, ring A is

[0285] [ka] is.

[0286] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring A is selected from the group consisting of one or more R a

[0033] In some embodiments, ring A is a bicyclic 6-10 membered heterocycloalkyl optionally substituted with

[0287] [ka] is.

[0288] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R a each independently represents a halogen, oxo, -CN, -NO2, -OH, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7, -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R a each independently represents a halogen, -CN, -NO2, -OH, -OR 7 , -SH, -SR 7 , -NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R a are each independently selected from halogen, —CN, —NO, —OH, amino, C-C alkyl, C-C alkoxyl, C-C haloalkoxyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, and C-C cycloalkyl, wherein cycloalkyl is optionally substituted with one or more R. In some embodiments, R a are independently selected from halogen, —CN, —NO, C-C alkyl, C-C haloalkyl, and cycloalkyl, wherein the alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R. In some embodiments, R ais independently selected from -CN, -C1-C6 alkyl, C1-C6 haloalkyl, and cycloalkyl, wherein the alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R. In some embodiments, R a is -CN. In some embodiments, R a is -C1-C6 alkyl. In some embodiments, R a is -C1-C3 alkyl. In some embodiments, R a is —CH3. In some embodiments, R a is C1-C6 haloalkyl. In some embodiments, R a is C1-C3 haloalkyl. In some embodiments, R a is —CF. In some embodiments, R a is -CFH. In some embodiments, R a is cycloalkyl. In some embodiments, R a is C-C cycloalkyl. In some embodiments, R a teeth

[0289] [ka] is.

[0290] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring A is

[0291] [ka] In some embodiments, ring Ah is selected from the group consisting of L 1 and L 2 and connect from top to bottom, for example, ring A is

[0292] [ka] If

[0293] [ka] part is,

[0294] [ka] is.

[0295] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring A is selected from the group consisting of one or more R a In some embodiments, ring A is a C4-C7 cycloalkyl optionally substituted with one or more R a In some embodiments, Ring A is an optionally substituted C5-C6 cycloalkyl. In some embodiments, Ring A is an optionally substituted cyclopentyl or cyclohexyl. In some embodiments, Ring A is

[0296] [ka] In some embodiments, ring A is

[0297] [ka] In some embodiments, ring A is

[0298] [ka] is.

[0299] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, Ring B is phenyl, a 5-10 membered heteroaryl, or a 5-12 membered heterocycloalkyl, each of which is selected from the group consisting of one or more R b is optionally replaced by

[0300] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of one or more R b In some embodiments, Ring B is an optionally substituted 5-12 membered heterocycloalkyl. In some embodiments, Ring B is an optionally substituted monocyclic heterocycloalkyl. In some embodiments, Ring B is an optionally substituted bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, Ring B is substituted with one or more R b C3-C optionally substituted with 12 In some embodiments, Ring B is an optionally substituted C5-C6 cycloalkyl. In some embodiments, Ring B is an optionally substituted bicyclic cycloalkyl.

[0301] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I) or (Ia), or a pharmaceutically acceptable salt thereof, Ring B is phenyl, a 5- to 6-membered heteroaryl, or a 9- to 10-membered heterocycloalkyl, each of which may be selected from the group consisting of one or more R b is optionally replaced by

[0302] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, ring B is phenyl or 6-membered heteroaryl, each of which may contain one or more R bIn some embodiments, Ring B is optionally substituted with phenyl. In some embodiments, Ring B is

[0303] [ka] is.

[0304] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of one or more R b In some embodiments, Ring B is a 5- or 6-membered heteroaryl optionally substituted with. In some embodiments, Ring B is an optionally substituted 6-membered heteroaryl. In some embodiments, Ring B is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring B is pyridine, pyrimidine, pyrazine, pyridazine, or triazine, each of which is optionally substituted. In some embodiments, Ring B is an optionally substituted pyridine. In some embodiments, Ring B is an optionally substituted pyrimidine. In some embodiments, Ring B is an optionally substituted imidazole, an optionally substituted pyrazole, or an optionally substituted triazole. In some embodiments, Ring B is

[0305] [ka] In some embodiments, ring B is

[0306] [ka] In some embodiments, ring B is

[0307] [ka] In some embodiments, ring B is

[0308] [ka] In some embodiments, ring B is

[0309] [ka] In some embodiments, ring B is

[0310] [ka] In some embodiments, ring B is

[0311] [ka] In some embodiments, ring B is

[0312] [ka] In some embodiments, ring B is

[0313] [ka] In some embodiments, ring B is

[0314] [ka] In some embodiments, ring B is

[0315] [ka] In some embodiments, ring B is

[0316] [ka] In some embodiments, ring B is

[0317] [ka] In some embodiments, ring B is

[0318] [ka] In some embodiments, ring B is

[0319] [ka] In some embodiments, ring B is

[0320] [ka] In some embodiments, ring B is

[0321] [ka] In some embodiments, ring B is

[0322] [ka] is.

[0323] In some embodiments of the compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, ring B (or

[0324] [ka] )teeth,

[0325] [ka] In some embodiments, ring B is L 1 and L 3 and connect from top to bottom, for example, ring B

[0326] [ka] If

[0327] [ka] part is,

[0328] [ka] In some embodiments, ring B is L 1 and L 3 and connect from top to bottom, for example, ring B

[0329] [ka] where * is L 1 represents the point of attachment to L 3 Represents the attachment point to

[0330] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of one or more R b In some embodiments, ring B is a 9-10 membered heteroaryl optionally substituted with one or more R b In some embodiments, ring B is a 9-10 membered heteroaryl optionally substituted with

[0331] [ka] is. In some embodiments, ring B is

[0332] [ka] In some embodiments, ring B is

[0333] [ka] In some embodiments, ring B is

[0334] [ka] In some embodiments, ring B is

[0335] [ka] In some embodiments, ring B is

[0336] [ka] In some embodiments, ring B is

[0337] [ka] In some embodiments, ring B is

[0338] [ka] In some embodiments, Ring B is an optionally substituted 9-10 membered heteroaryl, including a heteroaryl fused to a heterocycloalkyl. In some embodiments, Ring B is

[0339] [ka] In some embodiments, ring B is

[0340] [ka] is.

[0341] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), or (Ia), or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of one or more R b In some embodiments, ring B is a 9-10 membered heterocycloalkyl optionally substituted with one or more R b In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl optionally substituted with

[0342] [ka] is.

[0343] In some embodiments of the compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), or (Ib), or a pharmaceutically acceptable salt thereof, ring B (or

[0344] [ka] )teeth,

[0345] [ka] is selected from the group consisting of:

[0346] In some embodiments of a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R b each independently represents a halogen, oxo, -CN, -NO2, -OH, -OR 7 , -OC(=O)R 7 , -OC(=O)OR7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R a , R b , Rc, Rd, and Rf are each a halogen, oxo-CN, -NO2, -OH, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8, -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.

[0347] In some embodiments, R b each independently represents a halogen, oxo, -CN, -NO2, -OH, -OR 7 , -SH, -SR 7 , -NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R bis independently selected from halogen, oxo, —CN, —NO, —OH, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R b are independently selected from halogen, —OH, oxo, —CN, C-C alkyl, and C-C haloalkyl. b is halogen (e.g., F and Cl). In some embodiments, R b is OH or oxo. In some embodiments, R b is OH. In some embodiments, R b is oxo. In some embodiments, R b Ha-NR 8 R 8 In some embodiments, R b is NH, —NH(C-C alkyl), or —N(C-C alkyl). In some embodiments, R b is -CN. In some embodiments, R b is C1-C6 alkyl. In some embodiments, R b is C1-C3 alkyl. In some embodiments, R b is —CH3. In some embodiments, R b is C1-C6 haloalkyl. In some embodiments, R b is C1-C3 haloalkyl. In some embodiments, R b is —CF. In some embodiments, R b is a 5- to 6-membered heteroaryl.

[0348] In some embodiments of a compound of Formula (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R b1 is hydrogen, C-C alkyl, or C-C haloalkyl. In some embodiments, R b1 is hydrogen. In some embodiments, R b1 is C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, R b1 is methyl. In some embodiments, R b1 is hydrogen, halogen, -CN, -NO2, -OH, -OR 7 , -SH, -SR 7 , -NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R b1 is hydrogen, halogen, —CN, —NO, —OH, —SH, NH, —NH(C-C alkyl), —N(C-C alkyl), —O—C-C alkyl, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, and heterocycloalkyl, where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R b1 is hydrogen, halogen, —CN, C-C alkyl, or C-C haloalkyl. b1 is heteroaryl. In some embodiments, R b1 is a 5- to 6-membered heteroaryl.

[0349] In some embodiments of the compound of Formula (Ia-1), (Ib), (Id), (Ie) or (Ic) or a pharmaceutically acceptable salt thereof, R b2 is hydrogen, C-C alkyl, or C-C haloalkyl. In some embodiments, R b2 is hydrogen. In some embodiments, R b2 is C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, R b2 In some embodiments of a compound of Formula (Ia-1), (Ib), (Id), (Ie), or (Ic), or a pharmaceutically acceptable salt thereof, R b2 is hydrogen, halogen, -CN, -NO2, -OH, -OR 7 , -SH, -SR 7 , -NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R b2 is hydrogen, halogen, —CN, —NO, —OH, —SH, NH, —NH(C-C alkyl), —N(C-C alkyl), —O—C-C alkyl, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, and heterocycloalkyl, where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R b2 is hydrogen, halogen, —CN, C1-C3 alkyl, or C1-C3 haloalkyl. 1 is CH and X 2 is CH and X 3 Ga-ZR 5 and X4 is CH and Y 1 is N and Y 2 Provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein L is N and ring A is an optionally substituted 6-membered heteroalkyl. In some embodiments, L 1 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is selected from the group consisting of one or more R c In some embodiments, each Rc is independently hydrogen, halogen, —CN, —NO, —OR b , -SR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C9 heterocycloalkyl, aryl, and heteroaryl, or two R c together with the intervening atoms form a heterocycloalkyl or cycloalkyl, which is optionally substituted with one or more R.

[0350] In any of the above embodiments, each R 6 are independently halogen, -CN, -NO2, -OH, oxo, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 8 , -NR 8 C(=O)OR 7, -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl. In some embodiments, R 6 is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0351] In any of the above embodiments, each R d is halogen, oxo, -CN, -NO2, -OH, -OR 7 , -OC(=O)R 7 , -OC(=O)OR 7 , -OC(=O)NR 8 R 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2NR 8 R 8 , -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -NR 8 C(=O)NR 8 R 8 , -NR 8 C(=O)R 7 , -NR 8 C(=O)OR 7 , -NR 8 S(=O)2R 7 , -N=S(=O)(R 7 )2, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)NR 8 R 8, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R d is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0352] In any of the above embodiments, each R e are independently halogen, oxo, -CN, -NO2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl-OR 7 , -OC1-C4 haloalkyl, -CN, -C(=O)R 7 , -C(=O)OR 8 , -C(=O)N(R 8 )2, -C(=NR 8 )N(R 8 )2, -OC(=O)R 7 , -OC(=O)N(R 8 )2, -S(=O)(=NR 8 )R 7 , -NR 8 R 8 , -OC2-C6 alkylene)N(R 8 )2, -OC2-C6 alkylene OR 8 , -SH, -SR 7 , -S(=O)R 7 , -S(=O)2R 7 , -S(=O)2N(R 8 )2, -N(R 8 )C(=O)R 7 , -NR 8 C(=O)OR 7 , -N(R 8 )C(=O)N(R 8)2, -N(R 8 )C(=NR 8 )N(R 8 )2, -N=S(=O)(R 7 )2, -N(R 8 )S(=O)2R 7 , -N(R 8 )S(=O)2N(R 8 )2, -NR 8 C2-C6 alkyleneN(R 8 )2, -NR 8 C2-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )2, -C1-C6 alkylene OR 8 , -C1-C6 alkyleneN(R 8 )C(=O)R 7 , -C1-C6 alkyleneOC(=O)R 8 , -C1-C6 alkylene C(=O)N(R 8 )2, and -C1-C6 alkylene C(=O)OR 7 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R e is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0353] In any of the above embodiments, R 7 is C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, R 7 is C-C alkyl, C-C haloalkyl, and cycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7is C1-C3 alkyl.

[0354] In any of the above embodiments, each R 8 are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R. In some embodiments, R 8 is hydrogen or C1-C6 alkyl. Alternatively, in any of the above embodiments, two R on the same atom 8 together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0355] In any of the above embodiments, each R is independently selected from the group consisting of halogen, —CN, —OH, oxo, —SF, —SH, —S(═O)C1-C3 alkyl, —S(═O)2C1-C3 alkyl, —S(═O)2NH, —S(═O)2NHC1-C3 alkyl, —S(═O)2N(C1-C3 alkyl), —S(═O)(═NC1-C3 alkyl)(C1-C3 alkyl), —NH, —NHC1-C3 alkyl, —N(C1-C3 alkyl), —N═S(═O)(C1-C3 alkyl). )2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R is halogen, -CN, -OH, oxo, -SF, -SH, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl. In some embodiments, R is halogen, -CN, -OH, oxo, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl. In some embodiments, R is halogen, —CN, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R is halogen, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R is halogen or —C1-C3 alkyl.

[0356] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0357] In some embodiments, disclosed herein is a compound selected from the compounds provided in Table 1, or a pharmaceutically acceptable salt thereof.

[0358] [Table 1-1]

[0359] [Table 1-2]

[0360] [Table 1-3]

[0361] [Table 1-4]

[0362] [Table 1-5]

[0363] [Table 1-6]

[0364] [Table 1-7]

[0365] [Table 1-8]

[0366] [Table 1-9]

[0367] [Table 1-10]

[0368] [Table 1-11]

[0369] [Table 1-12]

[0370] In some embodiments, disclosed herein is a compound selected from the compounds provided in Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments of Table 2,

[0371] [ka] represents a double bond. In some embodiments of Table 2,

[0372] [ka] represents a single bond.

[0373] [Table 2-1]

[0374] [Table 2-2]

[0375] [Table 2-3]

[0376] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0377] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, for example, 2 H(D), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability.

[0378] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100 mole %. In some embodiments, one or more of the substituents disclosed herein contain deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more 1 H is substituted with one or more deuterium atoms in one or more of the substituents disclosed herein.

[0379] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0380] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0381] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salt thus formed.

[0382] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a compound described herein with a mineral acid, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutylene, hydroxybenzoate ... ester, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0383] Additionally, the compounds described herein can be prepared by dissolving the free base form of the compound in various solutions with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoylbenzoic acid, ... The compounds may be prepared as pharmaceutically acceptable salts by reaction with pharmaceutically acceptable inorganic or organic acids, including organic acids such as hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0384] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines of pharmaceutically acceptable metal cations. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4.

[0385] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0386] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, the present disclosure provides methods for treating diseases by administering compounds in the form of such solvates. In some embodiments, the present disclosure provides methods for treating diseases by administering compositions containing compounds in the form of such solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the process of crystallization using pharmaceutically acceptable solvents.

[0387] tautomers In some situations, compounds exist as tautomers.The compounds described herein include all possible tautomers within the formulas described herein.Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, with the switch of a single bond and an adjacent double bond.In bonding configurations where tautomerization is possible, there is a chemical equilibrium of tautomers.All tautomeric forms of the compounds disclosed herein are contemplated.The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0388] Treatment method Disclosed herein is a method for treating a disease in which inhibition of KIF18A is beneficial, the method comprising administering a compound of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0389] Disclosed herein is a method for treating a disease or disorder associated with KIF18A, the method comprising administering to a subject a compound of formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0390] Disclosed herein are methods of treating cancer in a subject, the methods comprising administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the methods of treating cancer in a subject, the methods comprise administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating cancer, the method comprises administering to a subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from (a) a solid tumor or a hematologically derived tumor selected from bladder cancer, endometrial cancer, squamous cell lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) leukemia, acute lymphocytic ... (c) hematopoietic tumors of the lymphoid lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma; (f) tumors selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, pigment epithelioma, keratinoma, follicular thyroid carcinoma or Karposi's sarcoma.In some embodiments of the method of treating a solid tumor or a hematologically derived tumor selected from the group consisting of a solid tumor or a hematologically derived tumor selected from bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophageal, gallbladder, brain, head and neck, ovarian, pancreatic, stomach, cervical, thyroid, prostate, and skin cancer in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method for treating a hematopoietic tumor of myeloid lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method for treating a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof.In some embodiments of a method for treating a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method for treating melanoma, seminoma, teratocarcinoma, osteosarcoma, pigment epithelioma, keratinoma, follicular thyroid carcinoma, or Karposi's sarcoma in a subject, the method comprises administering to the subject a compound of Formula (IV), (IVa), (III), (IIIa), (I), (Ia), (Ia-1), (Ib), (Id), (Ie), or (Ic) disclosed herein, or a pharmaceutically acceptable salt thereof. Administration In certain embodiments, the composition containing the compound(s) described herein is administered for therapeutic treatment.In certain therapeutic applications, the composition is administered to a patient who already suffers from a disease or illness in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or illness.The amount effective for this use depends on the severity and course of the disease or illness, previous treatment, the patient's health, weight, and response to drugs, and the judgment of the treating physician.

[0391] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof either alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

[0392] Pharmaceutical compositions are formulated in a conventional manner, using one or more pharmaceutically acceptable excipients, which facilitate the processing of active compound into pharmaceutically usable preparations.Suitable formulation depends on the route of administration selected.The summary of pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0393] Example The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0394] I. Chemical synthesis As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH acetic acid Ac Acetyl Bn Benzyl BOC or Boc tert-butyl carbamate i Bu isobutyl t But tert butyl CDI 1,1-carbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0] Undec-7-ene DCE Dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIBAL-H Diisobutylaluminum hydride DIPEA or DIEA Diisopropylethylamine DMAP 4(N,N-dimethylamino)pyridine DM 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMPU N,N'-Dimethylpropyleneurea DMSO dimethyl sulfoxide DPPA Diphenylphosphoryl azide Dppf or dppf 1,1'bis(diphenylphosphino) Ferrocene EDC or EDCI N-(3-dimethylaminopropyl)- N'-Ethylcarbodiimide Hydrochloride eq equivalent quantity(s) Et Ethyl Et2O diethyl ether EtOH ethanol EA or EtOAc Ethyl acetate HATU 1-[bis(dimethylamino)methylene] -1H-1,2,3-triazolo[4,5 -b]pyridinium 3-oxide hexa Fluorophosphate HOBt 1-hydroxybenzotriazole HPLC High-Performance Liquid Chromatography KOAc Potassium Acetate KOtBu Potassium tert-butoxide KHMDS Potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl) amide LiHMDS Lithium bis(trimethylsilyl)amide LAH / LiAlH4 Lithium Aluminum Anhydrous LCMS Liquid Chromatography Mass Spectrometry Me methyl MeOH Methanol MS mass spectrometry MTBE Methyl tert-butyl ether NBS N-Bromosuccinimide NMP N-methylpyrrolidin-2-one NMR nuclear magnetic resonance PE Petroleum Ether Ph Phenyl iPr / i-Pr isopropyl PyAOP 7-azabenzotriazol-1-yl Oxy)tripyrrolidinophosphonium Hexafluorophosphate RP HPLC Reversed Phase High Pressure Liquid Chromatography rt room temperature SEM 2-(trimethylsilyl)ethoxymethyl TBS tert-butyldimethylsilyl TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl

[0395] Example 1 (EX01)

[0396] [ka]

[0397] Step 1: To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (5.0 g, 21.8 mmol) in THF (100 mL) was added NaH (1.04 g, 26.16 mmol) and ethyl bromoacetate (3.64 g, 21.8 mmol). The reaction was stirred at 25 °C for 2 hours. The reaction was diluted with EtOAc (200 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX01-1 (2.43 g).

[0398] Step 2: To a solution of EX01-1 (1.02 g, 3.23 mmol) in MeOH (50 mL) was added NaBH4 (367 mg, 9.70 mmol) at 0 °C. The reaction was stirred at 25 °C for 24 h. The reaction was diluted with water (10 mL) and DCM (50 mL). The organic layer was separated, washed with brine (50 mL), and concentrated under reduced pressure to give EX01-2 (800 mg).

[0399] Step 3: To a solution of compound EX01-2 (200 mg, 0.732 mmol) in THF (2.00 mL) was added 6-fluoropyridin-2-amine (73.8 mg, 0.658 mmol) and t BuOK (180 mg, 1.61 mmol) was added. The reaction was stirred at 80° C. for 2 hours. The reaction was diluted with EtOAc (10 mL) and water (3 mL). The organic layer was separated, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX01-3 (150 mg). LCMS [M+H] + :366.4.

[0400] Step 4: To a solution of compound EX01-3 (150 mg, 0.41 mmol) in EtOAc (2 mL) was added HCl (12 M, 0.21 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give EX01-4 (105 mg). LCMS [M+H] + :266.4.

[0401] Step 5: To a solution of EX01-4 (140 mg, 0.528 mmol) in DMSO (1.0 mL) was added methyl 2-fluoro-4-iodobenzoate (221 mg, 0.792 mmol) and K2CO3 (182 mg, 1.32 mmol). The reaction was stirred at 100 °C for 2 h. The reaction was diluted with EtOAc (10 mL) and water (4 mL). The organic layer was separated, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX01-5 (100 mg). LCMS [M+H] + :526.6.

[0402] Step 6: To a solution of compound EX01-5 (100 mg, 0.19 mmol) in MeOH (5.0 mL) was added aqueous NaOH (1 M, 0.57 mL, 0.57 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with DCM (10 mL) and water (2 mL). The organic layer was separated, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX01-6 (95 mg). LCMS [M+H] + :512.3.

[0403] Step 7: To a solution of EX01-6 (80.0 mg, 0.156 mmol) in DCM (2 mL) was added POCl (0.044 mL, 0.469 mmol) and pyridine (0.126 mL, 1.56 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (20 mL) at 25 °C and then extracted with EtOAc (30 mL × 3). The combined organic layer was concentrated and purified by preparative TLC to give EX01-7 (40 mg). LCMS [M+H] + :494.2.

[0404] Step 8: A mixture of EX01-7 (35 mg, 0.06 mmol), 2-hydroxyethane-1-sulfonamide (26.63 mg, 0.213 mmol), CuI (2.32 mg, 0.012 mmol), CsCO (13.87 mg, 0.043 mmol), and 2,5-diazahexane (2.14 mg, 0.024 mmol) in DMF (1 mL) was degassed and purged with N three times. The mixture was stirred at 100 °C for 3 h under a N atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC to give EX01 (5 mg). 1 H NMR(400MHz,CD3OD)δ8.02(d,J=8.5Hz,1H),7.88(d,J=7.8Hz,1H),7.64(t,J=8.0Hz,1H),7.21 (d,J=2.1Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),6.49(d,J=8.0Hz,1H),4.63(t,J=4.7Hz,2H),3. 95(t,J=6.2Hz,2H),3.77(t,J=4.8Hz,2H),3.37(t,J=6.2Hz,2H),3.19(s,2H),3.10-3.03(m,2 H),2.99(t,J=12.2Hz,2H),2.65(td,J=13.1,4.9Hz,2H),1.19(d,J=13.1Hz,2H),0.94(s,3H). LCMS[M+H] + :491.3.

[0405] Example 2 (EX02)

[0406] [ka]

[0407] Step 1: To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (5.0 g, 21.0 mmol) in THF (15 mL) was added NaH (1.31 g, 32.7 mmol) and 3-bromoprop-1-ene (1.32 mg, 109 mmol). The reaction was stirred at 25 °C for 2 hours. The reaction was diluted with EtOAc (20 mL) and water (10 mL). The organic layer was separated, washed with brine (5 mL), and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX02-1 (4.0 g).

[0408] Step 2: To a solution of EX02-1 (2.0 g, 7.42 mmol) in THF (50 mL) was added 9-borabicyclo[3.3.1]nonan-9-yl (0.5 M in THF, 32.7 mL, 16.334 mmol) at 0 °C under an argon atmosphere. The reaction was stirred at 0 °C for 1 h and then at room temperature for 10 h. The reaction was cooled to 0 °C, followed by the sequential addition of water (20 mL), aqueous NaOH (3 M, 13.6 mL, 40.8 mmol), and HO (13 mL, 4.82 mmol). The reaction was stirred at 0 °C for 1 h and then at room temperature for 12 h. The reaction was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and dried over anhydrous sodium sulfate. The organic solution was concentrated under reduced pressure and purified by silica gel chromatography to give EX02-2 (1.5 g).

[0409] Step 3: EX02 (5.53 mg) was prepared as described in Example 1 (EX01) steps 3-8, except that EX02-2 was used instead of EX01-2 in step 3. 1H NMR(400MHz,CD3OD)δ8.08(d,J=8.7Hz,1H),7.90(d,J=7.8Hz,1H),7.63(t,J=8.0Hz,1H),7.2 9(d,J=2.2Hz,1H),7.11(dd,J=8.6,2.1Hz,1H),6.46(d,J=8.0Hz,1H),4.79(t,J=6.8Hz,2H), 3.95(t,J=6.3Hz,2H),3.46(t,J=5.3Hz,2H),3.37(t,J=6.3Hz,2H),3.18(s,2H),3.09-2.98( m,4H),2.60(td,J=12.8,5.4Hz,2H),1.95-1.86(m,2H),1.23(d,J=13.4Hz,2H),0.97(s,3H). LCMS[M+H] + :505.3.

[0410] Example 3 (EX03)

[0411] [ka]

[0412] Step 1: EX03 (1.0 mg) was prepared as described in Example 1 (EX01) steps 3-8, except that in step 3, 2-chloro-6-methylpyrimidin-4-amine was used instead of 6-fluoropyridin-2-amine. 1 H NMR(400MHz,CD3OD)δ8.03(d,J=8.5Hz,1H),7.85(s,1H),7.22(d,J=2.1Hz,1H),7.15-7.10(m,1H),4.74-4.67(m,2H),3.97(t,J=6.2Hz,2H),3.84- 3.77(m,2H),3.40(t,J=6.3Hz,2H),3.19(s,2H),3.09-2.96(m,4H),2.60( td,J=12.9,5.2Hz,2H),2.45(s,3H),1.21(d,J=13.4Hz,2H),0.96(s,3H). LCMS[M+H] + :506.4.

[0413] Example 4 (EX04)

[0414] [ka]

[0415] Step 1: To a solution of EX01-2 (0.700 g, 2.56 mmol) in DCM (20 mL) was added MsO (1.34 g, 7.68 mmol) and TEA (1.06 mL, 7.68 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h under a N atmosphere. The mixture was diluted with water (10.0 mL) and extracted with DCM (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give EX04-1 (800 mg).

[0416] Step 2: To a solution of EX04-1 (0.80 g, 2.27 mmol) in EtOH (8.00 mL) was added methanamine (10.0 g, 321 mmol) at 25° C. The mixture was stirred at 80° C. for 12 hours under a N atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give EX04-2 (600 mg). LCMS [M+H] + :2872.

[0417] Step 3: To a solution of EX04-2 (700 mg, 2.44 mmol) and 2-chloro-6-methylpyrimidin-4-amine (351 mg, 2.44 mmol) in DMF (10 mL) was added K2CO3 (1.01 g, 7.33 mmol) at 25 °C. The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give EX04-3 (600 mg). LCMS [M+H] + :394.3.

[0418] Step 4: EX04 (11.42 mg) was prepared as described in Example 1 (EX01) steps 4-8, except that EX04-3 was used instead of EX01-3 in step 4. 1 H NMR(400MHz,CD3OD)δ8.02(s,1H),7.39(s,1H),7.21(s,1H),7.11(s,1H),4.08-3.91(m,2H),3.91-3.81(m,2H),3.73(t,J=5.3Hz,2 H),3.40(s,2H),3.22(s,2H),3.19(s,3H),3.11-2.95(m,4H),2.68-2.52(m,2H),2.37(s,3H),1.20(d,J=13.1Hz,2H),0.94(s,3H). LCMS[M+H] + :519.4.

[0419] Example 5 (EX05)

[0420] [ka]

[0421] Step 1: EX05 (70 mg) was prepared as described in Example 1 (EX01) steps 3-8, except that in step 3, EX02-2 and 2-chloro-6-methylpyrimidin-4-amine were used instead of EX01-2 and 6-fluoropyridin-2-amine. 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.35(s,1H),7.95(d,J=8.7Hz,1H),7.79(s ,1H),7.15(s,1H),7.00(d,J=8.7Hz,1H),4.70(t,J=7.0Hz,2H),4.36(brs,1H),3. 74(t,J=6.5Hz,2H),3.16(s,2H),2.99-2.88(m,4H),2.41-2.31(m,4H),2.08(s,3 H),1.89-1.81(m,2H),1.23(d,J=11.0Hz,2H),1.06(t,J=7.0Hz,2H),0.92(s,3H). LCMS[M+H] + :520.3.

[0422] Example 6 (EX06)

[0423] [ka]

[0424] Step 1: EX06 (15.89 mg) was prepared as described in Example 4 (EX04), except that EX02-2 was used instead of EX01-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.7Hz,1H),7.44(s,1H),7.30(d,J=2.2Hz,1H),7. 12(dd,J=8.7,2.2Hz,1H),3.94(td,J=7.2,6.7,3.0Hz,4H),3.46-3.41(m,2H),3.37 (t,J=6.2Hz,2H),3.18(s,2H),3.10(s,3H),3.02(dd,J=7.9,2.3Hz,4H),2.61(dt,J =13.6,9.4Hz,2H),2.34(s,3H),1.86-1.77(m,2H),1.28-1.19(m,2H),0.98(s,3H). LCMS[M+H] + :533.4.

[0425] Example 7 (EX07)

[0426] [ka]

[0427] Step 1: A mixture of methyl 4-bromo-2-fluorobenzoate (5.0 g, 21.5 mmol), phenylmethanethiol (7.99 g, 64.4 mmol), DIEA (10.6 mL, 64.4 mmol), Xantphos (1.24 g, 2.15 mmol), and Pd(dba) (0.98 g, 1.07 mmol) in dioxane (10 mL) was degassed and purged with N three times. The mixture was stirred at 100 °C for 18 h under a N atmosphere. The reaction mixture was quenched with aqueous NaClO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give EX07-1 (7.0 g). LCMS [M+H] + :277.2.

[0428] Step 2: To a solution of EX07-1 (10.0 g, 36.2 mmol) in AcOH (100 mL) and HO (10 mL) was added NCS (14.5 g, 108 mmol). The mixture was then stirred at 25 °C for 3 h. The reaction mixture was diluted with saturated aqueous NaHCO (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give EX07-2 (8.60 g).

[0429] Step 3: To a solution of EX07-2 (8.00 g, 31.7 mmol) in DCM (80 mL) was added DIEA (26.2 mL, 158 mmol) and 2-methylpropan-2-amine (11.6 g, 158 mmol) at 0° C. The mixture was then stirred at 25° C. for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The organic solution was concentrated under reduced pressure and purified by silica gel chromatography to give EX07-3 (1.10 g).

[0430] Step 4: EX07 (5.0 mg) was prepared as described in steps 3 to 7 of Example 1 (EX01), except that EX02-2 was used instead of EX01-2 in step 3 and EX07-3 was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.21(d,J=8.1Hz,1H),7.95-7.87(m,2H),7.77-7.65(m,3H),6.53(d,J=8.0Hz,1H),4.74(t,J=6.9Hz,2H) ,3.41(t,J=5.2Hz,2H),3.15(s,2H),3.07-2.97(m,4H),2.46-2.34(m,2 H),1.89-1.78(m,2H),1.21(d,J=13.1Hz,2H),1.11(s,9H),0.93(s,3H). LCMS[M+H] + :517.3.

[0431] Example 8 (EX08)

[0432] [ka]

[0433] Step 1: EX08 (2.75 mg) was prepared as described in Steps 3-8 of Example 1 (EX01), except that EX02-2 was used instead of EX01-2 in Step 3 and methanesulfonamide was used instead of 2-hydroxyethane-1-sulfonamide in Step 8. 1H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.90(d,J=7.8Hz,1H),7.63(t,J=7.9H z,1H),7.27(d,J=2.2Hz,1H),7.11(dd,J=8.6,2.1Hz,1H),6.46(d,J=8.0Hz,1H),4 .79(t,J=6.8Hz,2H),3.46(t,J=5.3Hz,2H),3.19(s,2H),3.10-2.97(m,7H),2.61( td,J=12.8,5.3Hz,2H),1.91(p,J=6.4Hz,2H),1.24(d,J=13.5Hz,2H),0.97(s,3H). LCMS[M+H] + :475.4.

[0434] Example 9 (EX09)

[0435] [ka]

[0436] Step 1: EX09 (2.64 mg) was prepared as described in Example 4 (EX04), except that EX09-1 was used instead of EX01-2 in step 1. 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),7.89(d,J=8.6Hz,1H),7.36(s,1H),7.20(d ,J=2.1Hz,1H),7.04(dd,J=8.5,2.1Hz,1H),3.78-3.71(m,4H),3.59-3.53(m,4H) ,3.06(s,3H),2.92(d,J=8.5Hz,4H),2.28(s,3H),2.25-2.14(m,2H),2.04-1.95( m, 1H), 1.49 (t, J=5.4Hz, 2H), 1.23-1.18 (m, 4H), 0.99 (s, 3H), 0.88-0.81 (m, 1H). LCMS[M+H] + :533.5.

[0437] Example 10 (EX10)

[0438] [ka]

[0439] Step 1: To a solution of EX04-2 (2.10 g, 7.33 mmol) in DCM (20 mL) was added DIEA (3.64 mL, 22.0 mmol) and 3-nitrobenzoyl chloride (1.60 g, 8.80 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (25 mL) and extracted with DCM (15 mL x 3). The combined organic layer was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The organic solution was concentrated under reduced pressure and purified by silica gel chromatography to give EX10-1 (1.60 g). LCMS [M-Boc+H] + :336.4.

[0440] Step 2: To a solution of EX10-1 (1.60 g, 3.67 mmol) in MeOH (20 mL) was added NH4Cl (1.0 g, 18.4 mmol) and iron powder (1.0 g, 18.4 mmol) in HO (6.5 mL). The mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give EX10-2 (1.40 g). LCMS [M-Boc+H] + :306.4.

[0441] Step 3: EX10 (10 mg) was prepared as described in Example 1 (EX01) steps 4 to 8, except that EX10-2 was used instead of EX01-3 in step 4. 1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.45(d,J=8.0Hz,1H),7.97(d,J=8.4H z,1H),7.41(t,J=8.0Hz,1H),7.20(brs,2H),6.97-7.11(m,2H),3.75(t,J=6 .4Hz,2H),3.50-3.61(m,2H),3.41-3.49(m,2H),3.13-3.22(m,3H),2.87-3. 01(m,8H),2.24(td,J=12.8,5.2Hz,2H),1.25(d,J=13.2Hz,2H),0.94(s,3H). LCMS[M+H] + :531.4.

[0442] Example 11 (EX11)

[0443] [ka]

[0444] Step 1: EX11 (14.02 mg) was prepared as described in Example 2 (EX02), except that in step 1, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate. 1 H NMR(400MHz,CD3OD)δ8.09(dd,J=8.6,1.7Hz,1H),7.91(d,J=7.8Hz,1H),7.64(t,J=8.0Hz,1H) ,7.24(t,J=2.1Hz,1H),7.11(dt,J=8.8,1.6Hz,1H),6.46(d,J=8.0Hz,1H),4.76(t,J=6.8Hz,2H ),3.94(t,J=6.3Hz,2H),3.54(d,J=1.8Hz,2H),3.52-3.47(m,2H),3.36(t,J=6.3Hz,2H),3.28 -3.21(m,2H),2.83(t,J=12.0Hz,2H),2.47-2.33(m,2H),1.96-1.86(m,2H),1.70-1.55(m,3H). LCMS[M+H] + :491.2.

[0445] Example 12 (EX12)

[0446] [ka]

[0447] Step 1: EX12-1 (5.4 g) was prepared as described in Step 1 of Example 4 (EX04), except that EX02-2 was used instead of EX01-2. LCMS [M- t Bu+H] + :310.0.

[0448] Step 2: To a solution of EX12-1 (2.6 g, 7.11 mmol) and 4-methoxybenzylamine (2.00 g, 14.22 mmol) in DMSO (25 mL) was added CsF (2.2 g, 14.22 mmol) and DIEA (3.53 mL, 21.34 mmol) under N2 protection. The mixture was stirred at 120 °C for 2 hours. The reaction mixture was quenched with water (200 mL). The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give EX12-2 (1.8 g). LCMS [M+H] + :407.2.

[0449] Step 3: EX12-3 (950 mg) was prepared as described in Example 4 (EX04), Step 3, except that EX12-2 was used instead of EX04-2. LCMS [M+H] + :514.4.

[0450] Step 4: EX12-4 (220 mg) was prepared as described in Steps 4-7 of Example 1 (EX01), except that EX12-3 was used instead of EX01-3 in Step 4. LCMS [M+H] + :642.3.

[0451] Step 5: A solution of EX12-4 (200 mg, 0.312 mmol) in TFA (2 mL, 0.312 mmol) was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure, neutralized with aqueous NaCO (pH=8), and extracted with EtOAc (20 mL×3). The combined organic layer was dried over MgSO and concentrated under reduced pressure to give EX12-5 (160 mg). LCMS [M+H] + :522.2.

[0452] Step 6: EX12 (43.98 mg) was prepared as described in Example 1 (EX01), step 8, except that EX12-5 was used instead of EX01-7. 1 H NMR(400MHz,CD3OD)δ8.08(d,J=8.6Hz,1H),7.48(s,1H),7.30(d,J=2.2Hz,1H), 7.13(dd,J=8.7,2.2Hz,1H),3.95(t,J=6.2Hz,2H),3.73(t,J=6.9Hz,2H),3.45(t ,J=5.2Hz,2H),3.38(t,J=6.2Hz,2H),3.19(s,2H),3.07-2.98(m,4H),2.65-2.54 (m,2H),2.32(s,3H),1.76(p,J=6.2Hz,2H),1.24(d,J=13.1Hz,2H),0.97(s,3H). LCMS[M+H] + :519.1.

[0453] Example 13 (EX13)

[0454] [ka]

[0455] Step 1: To a solution of NaOH (2.2 g, 54.51 mmol) in HO (50 mL) was added tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (5.0 g, 21.81 mmol), 1,4-dibromobutane (6.5 mL, 54.51 mmol), and tetrabutylammonium bisulfate (0.2 g, 0.55 mmol). The reaction mixture was stirred at 70 °C for 3 h and then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX13-1 (2 g). LCMS [M- t Bu+H] + :308.0.

[0456] Step 2: To a solution of EX13-1 (2 g, 5.49 mmol) and 6-chloropyridazin-3(2H)-one (1.4 g, 10.98 mmol) in DMF (20 mL) was added K2CO3 (2.3 g, 16.47 mmol) under a N2 atmosphere. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give EX13-2 (2.2 g). LCMS [M-Boc+H] + :314.3.

[0457] Step 3: To a solution of EX13-2 (2 g, 4.83 mmol) and tert-butyl carbamate (1.1 g, 9.66 mmol) in toluene (20 mL), CsCO (4.7 g, 14.5 mmol), Xantphos (0.6 g, 0.97 mmol), and Pd(dba) (0.4 g, 0.48 mmol) were added under a N atmosphere. The reaction mixture was stirred at 100 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX13-3. LCMS [M-Boc+H] + :395.3.

[0458] Step 4: EX13 was prepared as described in Example 1 (EX01) steps 4-8, except that EX13-3 was used instead of EX01-3 in step 4. 1 H NMR(400MHz,CD3OD)δ8.35(d,J=9.8Hz,1H),8.10(d,J=8.7Hz,1H),7.34(d,J=2.2Hz,1H),7.17(dd, J=8.6,2.2Hz,1H),7.04(d,J=9.9Hz,1H),4.21(t,J=6.7Hz,2H),3.95(t,J=6.2Hz,2H),3.48(t,J=5. 4Hz,2H),3.37(t,J=6.2Hz,2H),3.17(s,2H),3.09(t,J=11.7Hz,2H),3.01(d,J=11.3Hz,2H),2.55(t d,J=13.3,4.6Hz,2H),2.12(p,J=7.0Hz,2H),1.55(p,J=6.5Hz,2H),1.33-1.22(m,2H),1.00(s,3H). LCMS[M+H] + :520.1.

[0459] Example 14 (EX14)

[0460] [ka]

[0461] Step 1: EX14 (10.59 mg) was prepared as described in Example 1 (EX01) steps 4 to 7, except that EX13-3 was used instead of EX01-3 in step 4 and EX07-3 was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1H NMR(400MHz,CD3OD)δ8.41(d,J=9.8Hz,1H),8.27(d,J=8.2Hz,1H),7.98(d,J=1.8Hz,1H),7. 80(dd,J=8.2,1.8Hz,1H),7.08(d,J=9.8Hz,1H),4.23(t,J=6.6Hz,2H),3.49(t,J=5.4Hz,2H) ,3.19(s,2H),3.15(d,J=11.7Hz,2H),3.08(d,J=8.8Hz,2H),2.57(td,J=13.1,4.7Hz,2H),2. 15(p,J=6.8Hz,2H),1.56(p,J=6.6Hz,2H),1.31(d,J=12.4Hz,2H),1.23(s,9H),1.03(s,3H). LCMS[M+H] + :532.1.

[0462] Example 15 (EX15)

[0463] [ka]

[0464] Step 1: EX15 (4.27 mg) was prepared as described in Example 1 (EX01) steps 4 to 7, except that EX15-1 was used instead of EX01-3 in step 4 and EX07-3 was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1 H NMR(400MHz,CD3OD)δ8.26(d,J=8.3Hz,1H),7.93(s,1H),7.74(d,J=8.1Hz,1H),7.45(s,1H),3.94(t,J=7.1Hz,2H),3.44(t,J=5.2Hz,2 H),3.19(s,2H),3.13-3.05(m,7H),2.68-2.56(m,2H),2.35(s,3H),1.82(p,J=5.6Hz,2H),1.31-1.23(m,2H),1.21(s,9H),0.99(s,3H). LCMS[M+H] + :545.3.

[0465] Example 16 (EX16)

[0466] [ka]

[0467] Step 1: EX16 (1.87 mg) was prepared as described in Example 1 (EX01) steps 4 to 7, except that EX15-1 was used instead of EX01-3 in step 4 and EX16-1 was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1 H NMR(400MHz,CD3OD)δ8.30(d,J=8.2Hz,1H),7.85(d,J=1.8Hz,1H),7.70(dd,J=8.2,1.7Hz,1H),7.47(s,1H),3.97(t,J=7.1Hz,2H),3.47-3.42(m, 2H),3.20(s,2H),3.11(d,J=10.0Hz,7H),2.68-2.60(m,2H),2.59(s,3H) ,2.37(s,3H),1.84(p,J=6.1Hz,2H),1.28(d,J=13.8Hz,2H),1.01(s,3H). LCMS[M+H] + :503.2.

[0468] Example 17 (EX17)

[0469] [ka]

[0470] Step 1: To a solution of 2-methylpropan-2-yl 4-(methoxycarbonyl)hexahydropyridine-1-carboxylate (10 g, 41.1 mmol) in THF (350 mL) was added LDA (2 M, 41.1 mL, 82.20 mmol) under a N atmosphere at −78° C. The mixture was stirred at −78° C. for 1 hour, followed by the addition of 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (CAS: 129946-88-9, 33.1 g, 82.20 mmol) at −78° C. The mixture was stirred at 25° C. for 16 hours. The reaction was quenched with saturated aqueous NH4Cl (600 mL) and extracted with EtOAc (600 mL × 3). The combined organic layers were washed with brine (500 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give EX17-1 (3.8 g). t Bu+H] + :256.0.

[0471] Process 2 To a solution of EX17-1 (3.8 g, 12.21 mmol) in THF (50 mL) was added LiBHEt (36.6 mL, 36.62 mmol) at 0 °C under N atmosphere. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with MeOH (50 mL) and concentrated under reduced pressure. The residue was diluted with saturated aqueous NH Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX17-2 (2.6 g). LCMS [M- t Bu+H] + :228.0.

[0472] Step 3: EX17-3 (1.6 g) was prepared as described in Steps 1-2 of Example 2 (EX02), except that EX17-2 was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate in Step 1. LCMS [M- t Bu+H] + :286.0.

[0473] Step 4: EX17 (37 mg) was prepared as described in Example 12 (EX12), except that EX17-3 was used instead of EX02-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.10(d,J=8.6Hz,1H),7.49(s,1H),7.29(d,J =2.2Hz,1H),7.17(dd,J=8.8,2.1Hz,1H),3.94(t,J=6.2Hz,2H),3.70(t,J=7.1Hz ,2H),3.49(t,J=5.3Hz,2H),3.43(s,2H),3.37(t,J=6.2Hz,2H),3.16-3.07(m,4H ),2.73-2.61(m,2H),2.33(s,3H),1.94(d,J=14.4Hz,2H),1.78(p,J=6.5Hz,2H). LCMS[M+H] + :573.3.

[0474] Example 18 (EX18)

[0475] [ka]

[0476] Step 1: To a solution of EX18-1 (5 g, 8.73 mmol) and 4-methoxybenzene-1-carbaldehyde (2.4 g, 17.46 mmol) in MeOH (25 mL) was added Na2CO3 (4.6 g, 43.65 mmol). The reaction was stirred at 25 °C for 16 h, followed by the addition of NaBH4 (1.24 g, 32.8 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX18-2 (2 g). LCMS [M+H] + :407.3.

[0477] Step 2: EX18 (20.12 mg) was prepared as described in Example 12 (EX12), steps 3-6, except that EX18-2 was used instead of EX12-2 in step 3. 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),10.25(brs,1H),8.08(d,J=8.6Hz,1H),7.27-7.22( m,2H),7.14(dd,J=8.7,2.1Hz,1H),6.94(t,J=6.7Hz,1H),4.95(s,1H),3.75(t,J=6.5Hz, 2H),3.54-3.43(m,4H),3.38-3.36(m,2H),3.07(d,J=11.4Hz,2H),2.84(d,J=12.6Hz,2H) ,2.44-2.30(m,2H),2.20(s,3H),1.86(d,J=12.4Hz,2H),1.55-1.40(m,4H),1.27(s,3H). LCMS[M+H] + :519.4.

[0478] Example 19 (EX19)

[0479] [ka]

[0480] Step 1: EX19-1 (10 g) was prepared as described in Example 2 (EX02), step 1, except that 3-bromo-2-methylprop-1-ene was used instead of 3-bromoprop-1-ene.

[0481] Step 2: To a solution of EX19-1 (10 g, 35.29 mmol) in THF (200 mL) was added BH3·THF (1 M, 38.8 mL) under N2 atmosphere. The mixture was stirred at 25 °C for 2 h, followed by the addition of aqueous NaOH (3 M, 30 mL, 90 mmol) and H2O2 (83.9 mL, 821.82 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layer was washed with saturated aqueous Na2SO3, dried over MgSO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give EX19-2 (10.5 g). LCMS [M- t Bu+H] + :246.1.

[0482] Step 3: EX19 (122.81 mg) was prepared as described in Example 12 (EX12), except that EX19-2 was used instead of EX02-2. 1 H NMR(400MHz,D2O+DMSO-d6)δ8.02(d,J=8.6Hz,1H),7.31(s,1H),7.27(d,J=2.2Hz,1H),7.10(dd,J=8.6,2.0Hz,1H) ,4.13(dd,J=13.2,3.7Hz,1H),3.75(t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.26(dd,J=9.1,3.6Hz,1H),3.18(d,J= 8.9Hz,1H),3.13-3.04(m,2H),3.03-2.94(m,2H),2.93-2.78(m,2H),2.70(dd,J=13.3,8.0Hz,1H),2.49-2.37(m,2 H),2.21(s,3H),1.70(brs,1H),1.24(d,J=13.0Hz,1H),1.12(d,J=12.9Hz,1H),0.90(s,3H),0.86(d,J=6.9Hz,3H). LCMS[M+H] + :533.2.

[0483] Example 20 (EX20)

[0484] [ka]

[0485] Step 1: EX20-2 (700 mg, crude) was prepared as described in Example 4 (EX04), Step 1, except that EX20-1 was used instead of EX01-2. LCMS [M+Na] + :402.1.

[0486] Step 2: A solution of EX20-2 (700 mg, 1.16 mmol) in ammonium hydroxide (4 mL, 104 mmol) was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure to give EX20-3 (300 mg, crude). LCMS [M+H] + :301.2.

[0487] Step 3: EX20-4 (1.2 g) was prepared as described in Example 4 (EX04) step 3, except that EX20-3 was used instead of EX04-2. LCMS [M+H]: 408.3.

[0488] Step 4: EX20-5 (50 mg) was prepared as described in Steps 4-6 of Example 1 (EX01), except that EX20-4 was used instead of EX01-3 in Step 4. LCMS [M+H] + :554.1.

[0489] Step 5: To a solution of EX20-5 (30 mg, 0.043 mmol) in DCM (0.5 mL) was added POCl (14.7 mg, 0.087 mmol) and DIEA (22 uL, 0.13 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with H O (3 mL) and extracted with DCM (3 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX20-6 (12 mg). LCMS [M+H] + :536.2.

[0490] Step 6: EX20 (1.17 mg) was prepared as described in Example 1 (EX01), step 8, except that EX20-6 was used instead of EX01-7. 1 H NMR(400MHz,CD3OD)δ8.05(d,J=8.63Hz,1H),7.44(s,1H),7.28(d,J=2.13Hz,1H),7.12 (dd,J=8.63,2.13Hz,1H),3.95(t,J=6.19Hz,2H),3.42-3.51(m,2H),3.37(t,J=6.25Hz, 2H),3.11(brs,2H),2.93-3.05(m,3H),2.80-2.89(m,2H),2.48-2.65(m,2H),2.30(s,3H) ),1.69(dt,J=8.35,3.46Hz,2H)1.34-1.41(m,2H),1.19(d,J=6.75Hz,3H),0.96(s,3H). LCMS[M+H] + :533.3.

[0491] Example 21 (EX21)

[0492] [ka]

[0493] Step 1: To a solution of EX04-2 (1.1 g, 3.84 mmol) and 6-((tert-butoxycarbonyl)amino)picolinic acid (1.1 g, 4.61 mmol) in DMF (24 mL) was added HATU (2.2 g, 5.76 mmol) and DIEA (1.27 mL, 7.68 mmol). The mixture was stirred at 30 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX21-1 (920 mg). LCMS [M+H] + :507.1.

[0494] Step 2: EX21 was prepared as described in Example 10 (EX10), step 3, except that EX21-1 was used instead of EX10-2. 1 H NMR(400MHz,Methanol-d4)δ8.35-8.26(m,1H),8.26-8.03(m,1H),7.92(dd,J=7.6 ,15.5Hz,1H),7.48-7.00(m,3H),4.61-4.51(m,1H),3.97(t,J=6.2Hz,2H),3.85-3 .65(m,1H),3.60-3.48(m,2H),3.39(t,J=6.2Hz,2H),3.29-3.23(m,1H),3.21-3.0 7(m,5H),3.05(brs,3H),2.87-2.47(m,2H),1.48-1.15(m,2H),1.07-0.96(m,3H). LCMS[M+H] + :532.2.

[0495] Example 22 (EX22)

[0496] [ka]

[0497] Step 1: EX22 (15.84 mg) was prepared as described in Example 21 (EX21), except that EX22-1 was used instead of EX04-2 in step 1. 1 H NMR(400MHz,DMSO-d6)δ13.19-10.76(m,1H),8.33-8.18(m,1H),8.14-7.71(m,2H), 7.38-7.28(m,1H),7.21-6.97(m,2H),4.45-3.83(m,1H),3.80(t,J=6.5Hz,2H),3.6 0(m,1H),3.37-3.31(m,3H),3.22-3.09(m,2H),3.08-2.82(m,8H),2.81-2.52(m,2H ),2.35(d,J=18.8Hz,1H),2.09-1.62(m,3H),1.33-1.09(m,2H),1.02-0.82(m,3H). LCMS[M+H] + :546.2.

[0498] Example 23 (EX23)

[0499] [ka]

[0500] Step 1: EX23 (14.37 mg) was prepared as described in Example 12 (EX12), except that EX09-1 was used instead of EX02-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.03(d,J=8.6Hz,1H),7.48(s,1H),7.31(d,J=2.2Hz,1H),7. 12(dd,J=8.6,2.2Hz,1H),3.95(t,J=6.2Hz,2H),3.68(t,J=5.5Hz,2H),3.64(t,J=5 .4Hz,2H),3.57(t,J=5.3Hz,2H),3.37(t,J=6.2Hz,2H),3.15-2.97(m,4H),2.40-2. 33(m,2H),2.33(s,3H),1.60(t,J=5.5Hz,2H),1.31(d,J=13.1Hz,2H),1.08(s,3H). LCMS[M+H] + :519.2.

[0501] Example 24 (EX24)

[0502] [ka]

[0503] Step 1: To a solution of EX02-1 (6 g, 22.27 mmol) in DCM (350 mL) was added NBS (7.93 g, 44.54 mmol) and triethylamine trihydrofluoride (4.31 g, 26.73 mmol) at 0° C. The reaction was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give EX24-1 (3.4 g). LCMS [M- t Bu+H] + :312.0.

[0504] Step 2: EX24-2 was prepared as described in Example 12 (EX12), step 2, except that EX24-1 was used instead of EX12-1. LCMS [M+H] + :425.3.

[0505] Step 3: EX24 (13.58 mg) was prepared as described in Example 12 (EX12), steps 3-6, except that EX24-2 was used instead of EX12-2 in step 3. 1 H NMR(400MHz,D2O+DMSO-d6)δ7.97(d,J=8.6Hz,1H),7.34(s,1H),7.21(s,1H),7.07(d,J=8.7 Hz,1H),4.53(d,J=46.7Hz,1H),4.18-4.03(m,2H),3.75(t,J=6.3Hz,2H),3.64-3.40(m,2H), 3.34(t,J=6.3Hz,2H),3.23(d,J=9.1Hz,1H),3.14(d,J=9.1Hz,1H),2.90(d,J=26.9Hz,4H), 2.41-2.24(m,2H),2.22(s,3H),1.22(d,J=11.6Hz,1H),1.13(d,J=13.2Hz,1H),0.87(s,3H). LCMS[M+H] + :537.3.

[0506] Example 25 (EX25-A)

[0507] [ka]

[0508] Step 1: EX25-1 (80 mg) was prepared as described in Steps 4-7 of Example 1 (EX01), except that EX12-3 was used instead of EX01-3 in Step 4 and EX07-3 was used instead of methyl 2-fluoro-4-iodobenzoate in Step 5. LCMS [M+H] + :651.5.

[0509] Step 2: To a solution of EX25-1 (60 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.21 mL, 2.77 mmol). The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, neutralized with saturated aqueous NaCO (pH = 8), and extracted with EtOAc (20 mL × 3). The combined organic layer was dried over MgSO and concentrated under reduced pressure. The residue was purified by preparative HPLC to give EX25 (16.03 mg) and EX25-A (7.31 mg).

[0510] EX25: 1 H NMR(400MHz,CD3OD)δ8.26(d,J=8.2Hz,1H),7.94(d,J=1.7Hz,1H),7.76(dd, J=8.2,1.8Hz,1H),7.49(s,1H),3.75(t,J=6.8Hz,2H),3.47(t,J=4.2Hz,2H) ,3.22(s,2H),3.14-3.06(m,4H),2.63(tt,J=12.4,5.5Hz,2H),2.34(s,3H), 1.78(p,J=6.7,6.1Hz,2H),1.28(d,J=13.8Hz,2H),1.23(s,9H),1.00(s,3H). LCMS[M+H] + :531.3.

[0511] EX25-A: 1 H NMR(400MHz,CD3OD)δ8.26(d,J=8.3Hz,1H),7.95(d,J=1.8Hz,1H),7.77(dd,J=8.3,1.8Hz,1H),7.49(s,1H),3.75(t,J=6.7Hz,2H),3.47(t,J=5. 6Hz,2H),3.22(s,2H),3.15-3.08(m,4H),2.62(td,J=12.7,5.9Hz,2H), 2.34(s,3H),1.78(p,J=6.1Hz,2H),1.28(d,J=13.4Hz,2H),1.00(s,3H). LCMS[M+H] + :475.2.

[0512] Example 26 (EX26)

[0513] [ka]

[0514] Step 1: EX26 (52.11 mg) was prepared as described in Example 1 (EX01) steps 5-8, except that EX26-1 was used instead of EX01-4 in step 5. 1 H NMR(400MHz,CD3OD)δ8.12(dd,J=8.7,1.4Hz,1H),7.58(s,1H),7.33(t,J=2.1Hz,1H),7.14(ddd, J=8.6,2.2,1.3Hz,1H),4.46(q,J=9.3Hz,2H),4.03(dd,J=9.1,6.3Hz,2H),3.95(t,J=6.2Hz,2H) ,3.46-3.43(m,2H),3.37(t,J=6.2Hz,2H),3.18(s,2H),3.02(dd,J=9.1,4.6Hz,4H),2.61(td,J= 12.6,5.9Hz,2H),2.35(s,3H),1.81(td,J=10.4,5.0Hz,2H),1.25(d,J=13.2Hz,2H),0.99(s,3H). LCMS[M+H] + :601.3.

[0515] Example 27 (EX27)

[0516] [ka]

[0517] Step 1: EX27 (43.76 mg) was prepared as described in Example 4 (EX04), except that EX17-3 was used instead of EX01-2 in step 1. 1H NMR(400MHz,CD3OD)δ8.09(d,J=8.7Hz,1H),7.44(s,1H),7.27(d,J=2.2Hz,1H),7.16(dd,J=8.7,2.1Hz,1H),3.98-3.86(m,4H),3.46(t,J=5.2 Hz,2H),3.41(s,2H),3.36(t,J=6.2Hz,2H),3.12-3.06(m,7H),2.71-2.59(m,2H),2.35(s,3H),1.91(d,J=14.6Hz,2H),1.83(p,J=6.0Hz,2H). LCMS[M+H] + :587.2.

[0518] Example 28 (EX28)

[0519] [ka]

[0520] Step 1: To a solution of 2-methylpropan-2-yl 4-(hydroxymethyl)-4-methylhexahydropyridine-1-carboxylate (15 g, 65.42 mmol) in THF (300 mL), NaH (7.8 g, 196.25 mmol, 60% in oil) was added portionwise at 0 °C under N protection. The mixture was stirred at 0 °C for 30 minutes. Then, 2,3-dibromoprop-1-ene (65.4 g, 327.08 mmol) was added at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. The mixture was poured into water (1 L) and extracted with EtOAc (1 L × 3). The combined organic layer was washed with brine, dried over MgSO , concentrated under reduced pressure, and purified by silica gel chromatography to give EX28-1 (5 g). LCMS [M- t Bu+H] + :292.0,294.0.

[0521] Step 2: To a solution of EX28-1 (4.5 g, 12.92 mmol) in DCM (15 mL) was added 1-[(acetoxyphenyl-λ 3[-iodanyl)]oxy]ethan-1-one (6.28 g, 19.38 mmol) and PyHF (64.02 g, 645.99 mmol) were added and the reaction was stirred at 25 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure to give crude product EX28-2 (3.7 g, crude). LCMS [M+H] + :286.0,288.0.

[0522] Step 3: To a solution of EX28-2 (3.7 g, 12.93 mmol) in THF (60 mL) was added aqueous Na2CO3 (2 M, 65 mL) and Boc2O (6 mL, 25.86 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography to give EX28-3 (1.5 g). LCMS [M- t Bu+H] + :330.0,332.0. 1 H NMR(400MHz,DMSO-d6)δ3.98-3.74(m,4H),3.49(td,J=4.9,13.5Hz,2H),3.29( s, 2H), 3.18-3.01 (m, 2H), 1.40-1.34 (m, 11H), 1.25-1.17 (m, 2H), 0.93 (s, 3H).

[0523] Step 4: To a solution of EX28-3 (1.5 g, 3.88 mmol) in DMF (4 mL), TMSN3 (1.342 g, 11.65 mmol) and K2CO3 (1.61 g, 11.65 mmol) were added under N2 protection. The resulting mixture was stirred at 120 °C for 1 h. The mixture was filtered, concentrated, and purified by silica gel chromatography to give EX28-4 (1.2 g). LCMS [M- t Bu+H] + :293.0.

[0524] Step 5: To a solution of EX28-4 (1.2 g, 3.44 mmol) in EtOAc (20 mL) was added Pd / C (1.83 g, 17.22 mmol, 10% purity). The mixture was purged and degassed with H2 three times. The mixture was stirred at 25 °C for 1 h. The mixture was filtered through Celite and concentrated to give EX28-5 (1.05 g). LCMS [M-Boc+H] + :223.1.

[0525] Step 6: EX28 (12.90 mg) was prepared as described in Example 20 (EX20), steps 5-8, except that EX28-5 was used instead of EX20-4 in step 5. 1 H NMR(400MHz,CD3OD)δ8.03(d,J=8.6Hz,1H),7.54(s,1H),7.25(d,J=2.1Hz,1H),7.11(dd,J=8.7,2.1Hz,1H),4.12(t,J=14.4Hz,2H),3.95(t,J=6.2Hz) ,2H),3.65(t,J=11.8Hz,2H),3.37(t,J=6.2Hz,2H),3.27(s,2H),3.07-2. 98(m,4H),2.61-2.48(m,2H),2.33(s,3H),1.27-1.20(m,2H),0.97(s,3H). LCMS[M+H] + :555.3.

[0526] Example 29 (EX29)

[0527] [ka]

[0528] Step 1: 2,6-Difluoropyridine-3-carboxylic acid (10.6 g, 66.63 mmol) was dissolved in SOCl (35 mL, 482.35 mmol) at 0 °C, and the resulting mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure, and toluene (100 mL) was added. The solvent was removed again, and the crude acid chloride was dissolved in DCM (50 mL) and cooled to 0 °C. Subsequently, a solution of TEA (25 mL, 180.34 mmol) and phenylmethanol (7.25 mL, 69.75 mmol) in DCM (50 mL) was added dropwise over 10 min. The resulting mixture was stirred at 25 °C for 30 min. The mixture was then concentrated under reduced pressure, diluted with water (200 mL), and extracted with DCM (3 × 200 mL). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX29-1 (5.2 g). LCMS[M+H] + :250.0.

[0529] Step 2: To a solution of 4,4-dimethyl-1,3-oxazolidin-2-one (0.8 g, 6.95 mmol) in THF (15 mL), t BuOK (0.75 g, 6.42 mmol) was added and the reaction was stirred at 25° C. for 5 minutes. A solution of EX29-1 (1.6 g, 6.42 mmol) in DMA (40 mL) was added and the resulting mixture was stirred at 25° C. for 25 minutes. The mixture was diluted with water (70 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure and purified by silica gel chromatography to give EX29-2 (1.4 g). LCMS [M+H] + :345.0.

[0530] Step 3: To a solution of EX29-2 (400 mg, 1.16 mmol) in EtOAc (9 mL) and EtOH (18 mL) was added Pd / C (400 mg, 3.76 mmol). The mixture was purged and degassed with H2 three times. The mixture was stirred under H2 (40 psi) at 25 °C for 3 h. The mixture was filtered through a Celite pad and the solid was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to give EX29-3 (270 mg). LCMS [M+H] + :255.0.

[0531] Step 4: EX29-4 (30.0 mg) was prepared as described in Example 1 (EX01) steps 5-7, except that EX29-3 was used instead of EX01-4 in step 5. LCMS [M+H] + :630.5.

[0532] Step 5: To a solution of EX29-4 (15 mg, 0.024 mmol) in MeOH (0.5 mL) was added NaOH (480 μL, 0.24 mmol). The resulting mixture was stirred at 70° C. for 1 hour. The mixture was concentrated under reduced pressure, neutralized with aqueous HCl, and extracted with DCM (3×5 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give compound EX29-5 (13 mg). LCMS [M+H] + :604.5.

[0533] Step 6: A solution of EX29-5 (13 mg, 0.019 mmol) in TFA (0.44 mL, 0.19 mmol) was stirred for 1 h at 50° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give EX29 (4.72 mg). 1H NMR(400MHz,DMSO-d6)δ7.86(d,J=8.7Hz,1H),7.24(s,1H),6.36(d,J=8.7Hz,1H),3.58(s,2H),3.52(t,J=6.9Hz,2H),3.36(t,J=5.1Hz,2H) ),3.12(s,2H),2.98(d,J=9.0Hz,4H),2.44-2.30(m,2H),2.17(s,3H),1.65-1.56(m,2H),1.33(s,6H),1.14(d,J=12.8Hz,2H),0.83(s,3H). LCMS[M+H] + :484.4.

[0534] Example 30 (EX30)

[0535] [ka]

[0536] Step 1: EX30 (19.37 mg) was prepared as described in Example 15 (EX15), except that EX17-3 was used instead of EX02-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.26(d,J=8.3Hz,1H),7.89(d,J=1.8Hz,1H),7.77(dd,J=8.2,1.7Hz,1H),7.45(s,1H),3.93(t,J=7.1Hz,2H),3.48(t,J=5.2Hz,2 H),3.43(s,2H),3.17(d,J=9.2Hz,4H),3.12(s,3H),2.68(dt,J=18.8,9.5H z, 2H), 2.37 (s, 3H), 1.96 (d, J=14.6Hz, 2H), 1.90-1.79 (m, 2H), 1.22 (s, 9H). LCMS[M+H] + :599.3

[0537] Example 31 (EX31)

[0538] [ka]

[0539] Step 1: To a solution of EX02-1 (5 g, 18.6 mmol) in DMSO (40 mL) and H2O (10 mL) was added NBS (3.63 g, 20.4 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over MgSO4, concentrated, and purified by silica gel chromatography to give EX31-1 (5 g). LCMS [M- t Bu+H] + :312.0.

[0540] Step 2: EX31-2 was prepared as described in Example 12 (EX12) Step 2, except that EX31-1 was used instead of EX12-1. LCMS [M+H] + :423.3.

[0541] Step 3: To a solution of EX31-2 (4.47 g, 10.6 mmol) in THF (80 mL) was added KHMDS (12 mL, 11.6 mmol) at −20° C. under a N atmosphere, and the resulting mixture was stirred for 30 min. Dimethyl sulfate (2.05 g, 16.3 mmol) was added to the mixture at −20° C. and stirred for an additional 1 h. The reaction was then warmed to 25° C. and stirred for an additional 2 h. The reaction was quenched with aqueous NaOH (1 M, 200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over MgSO, concentrated, and purified by silica gel chromatography to give EX31-3 (2.3 g). LCMS [M+H] + :437.3.

[0542] Step 4: EX31 (19.19 mg) was prepared as described in Example 12 (EX12), steps 3-6, except that EX31-3 was used instead of EX31-2 in step 3. 1H NMR(400MHz,DMSO-d6)δ8.00(dd,J=8.6,1.6Hz,1H),7.34(s,1H),7.24(d,J=2.2Hz,1H),7. 08(dt,J=8.7,1.9Hz,1H),4.16(dd,J=13.9,2.6Hz,1H),3.74(t,J=6.4Hz,2H),3.34(t,J=6. 4Hz,2H),3.31(s,3H),3.26-3.18(m,4H),3.11(d,J=9.0Hz,1H),3.00-2.87(m,4H),2.81(t, J=12.2Hz,1H),2.47-2.30(m,2H),2.21(s,3H),1.17(dd,J=43.6,12.9Hz,2H),0.89(s,3H). LCMS[M+H] + :549.5.

[0543] Example 32 (EX32, EX32-A, EX32-B)

[0544] [ka]

[0545] Step 1: To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (5 g, 21.81 mmol) in THF (5 mL) was added DBU (33.2 mg, 0.22 mmol) and 2-(trifluoromethyl)acrylonitrile (6.6 g, 54.51 mmol). The reaction mixture was stirred at 75 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX32-1 (2.3 g). LCMS [M- t Bu+H] + :295.0.

[0546] Step 2: To a solution of EX32-1 (2.8 g, 7.991 mmol) in MeOH (50 mL) was added CoCl (5.2 g, 39.95 mmol) and NaBH (0.95 g, 25.13 mmol) at 0 °C, and the reaction was stirred at 25 °C for 1 h. The reaction was quenched with saturated aqueous NH Cl (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over MgSO and concentrated under reduced pressure to give EX32-2. LCMS [M+H] + :355.1.

[0547] Step 3: EX32 (45.56 mg) was prepared as described in Example 20 (EX20), except that EX32-2 was used instead of EX20-4 in step 5. 1 H NMR(400MHz,CD3OD)δ8.12(d,J=8.8Hz,1H),7.54(s,1H),7.33(d,J=2.0Hz,1H),7.15(dd,J=2.1,8.7Hz ,1H),4.69-4.63(m,1H),3.95(t,J=6.2Hz,2H),3.67(dd,J=3.5,9.0Hz,1H),3.46(t,J=9.0Hz,1H),3.37 (t,J=6.3Hz,2H),3.27(brd,J=5.7Hz,1H),3.24(d,J=6.4Hz,2H),3.18-3.12(m,1H),3.08-3.02(m,1H) ,2.99-2.93(m,2H),2.71-2.52(m,3H),2.32(s,3H),1.39-1.33(m,1H),1.23-1.16(m,1H),1.01(s,3H). LCMS[M+H] + :587.3.

[0548] Step 4: EX32-A (15.56 mg) and EX32-B (12.95 mg) were separated from EX32 by SFC. SFC analysis conditions: Column: Chiralpak IE-3, 100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: isopropanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.8 mL / min; Column temperature: 35 °C.

[0549] EX32-A: 1 H NMR(400MHz,CD3OD)δ8.10(d,J=8.8Hz,1H),7.53(s,1H),7.31(s,1H),7.13(d,J=8.1Hz,1H),4.66 (d,J=14.3Hz,1H),3.99-3.89(m,2H),3.69-3.62(m,1H),3.45(t,J=8.8Hz,1H),3.36(d,J=6.1Hz,2 H),3.27(s,1H),3.23(d,J=3.5Hz,2H),3.15(d,J=12.5Hz,1H),3.07-3.01(m,1H),2.96(d,J=6.8Hz ,2H),2.70-2.51(m,3H),2.31(s,3H),1.31(d,J=14.5Hz,1H),1.19(d,J=13.1Hz,1H),1.01(s,3H). LCMS[M+H] + 587.4. Hold time @SFC: 1.496 minutes.

[0550] EX32-B: 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.1Hz,1H),7.53(s,1H),7.30(s,1H),7.12(d,J=9.1Hz,1H),4.66 (d,J=13.6Hz,1H),3.95(s,2H),3.66(d,J=8.0Hz,1H),3.44(t,J=8.6Hz,1H),3.38-3.34(m,2H),3 .26(d,J=3.8Hz,1H),3.23(s,2H),3.14(d,J=12.5Hz,1H),3.04(d,J=9.6Hz,1H),2.95(d,J=7.4Hz ,2H),2.70-2.51(m,3H),2.31(s,3H),1.31(d,J=14.9Hz,1H),1.19(d,J=12.9Hz,1H),1.01(s,3H). LCMS[M+H] + 587.1. Hold time @SFC: 1.870 minutes.

[0551] Example 33 (EX33-AおよびB)

[0552]

change

[0553] Step 1: EX33-A (12.66 mg) and EX33-B (12.43 mg) were prepared as described in Step 4 of Example 32 (EX32), except that EX33 was used instead of EX32. SFC analysis conditions: Column: Chiralpak AD-3, 50*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 5-40% Mobile phase B, 5 min; Flow rate: 4 mL / min; Column temperature: 35 °C.

[0554] EX33-A: 1 H NMR(400MHz,CD3OD)δ8.08(d,J=8.6Hz,1H),7.43(s,1H),7.29(d,J=2.2Hz,1H),7.12(dd,J =8.7,2.2Hz,1H),4.29(dd,J=13.5,7.1Hz,1H),3.94(t,J=6.2Hz,2H),3.46-3.34(m,4H),3 .26-3.20(m,2H),3.12(s,3H),3.09-3.02(m,3H),2.99-2.92(m,2H),2.71-2.52(m,2H),2. 34(s,3H),2.12-2.01(m,1H),1.31-1.26(m,1H),1.13(d,J=13.1Hz,1H),0.98-0.94(m,6H). LCMS[M+H] + :547.3. Retention time @SFC: 1.948 minutes.

[0555] EX33-B: 1H NMR(400MHz,CD3OD)δ8.08(d,J=8.7Hz,1H),7.43(s,1H),7.29(d,J=2.2Hz,1H),7.12(dd, J=8.7,2.2Hz,1H),4.30(dd,J=13.6,7.2Hz,1H),3.94(t,J=6.2Hz,2H),3.46-3.34(m,4H) ,3.26-3.21(m,2H),3.13(s,3H),3.09-3.02(m,3H),3.00-2.91(m,2H),2.72-2.53(m,2H) ,2.34(s,3H),2.12-2.05(m,1H),1.35-1.29(m,1H),1.17-1.09(m,1H),0.99-0.95(m,6H). LCMS[M+H] + :547.3. Retention time @SFC: 2.953 minutes.

[0556] Example 34 (EX34)

[0557] [ka]

[0558] Step 1: To a solution of 2-methylpropan-2-yl 4-formylhexahydropyridine-1-carboxylate (35 g, 164.09 mmol) in DCM (200 mL) was added t-BuOK (23.9 g, 213.01 mmol) and CHCl (69.9 g, 492.6 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then at 25° C. for an additional 2 hours. The mixture was extracted with brine (400 mL) and DCM (3×200 mL). The combined organic layers were dried over MgSO, concentrated, and purified by flash silica gel chromatography to give EX34-1 (5 g). LCMS [M- t Bu+H] + :172.1.

[0559] Step 2: To a solution of [3-(benzyloxy)propyl]triphenylphosphanium bromide (9.08 g, 18.48 mmol) in THF (90 mL) was added NaHMDS in THF (19.8 mL, 1 M, 19.8 mmol) at −78° C. under a N atmosphere. The mixture was stirred at −78° C. for 1 h. Then, to the mixture was added EX34-1 (3 g, 13.2 mmol) in THF (90 mL) dropwise at −78° C. The mixture was stirred at 25° C. under a N atmosphere for an additional 4 h. The mixture was quenched with aqueous NH4Cl (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over MgSO4, concentrated, and purified by flash silica gel chromatography to give EX34-2 (3 g). LCMS [M-Boc+H] + :260.2.

[0560] Step 3: To a solution of EX34-2 (3 g, 8.35 mmol) in EtOH (500 mL) was added Pd / C (1.3 g, 12.5 mmol, 10% purity). The mixture was purged and degassed with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 6 h. The mixture was filtered through Celite and concentrated under reduced pressure to give EX34-3 (2.1 g). LCMS [M- t Bu+H] + :216.1.

[0561] Step 4: EX34 (29.07 mg) was prepared as described in Example 18 (EX18), steps 2-6, except that EX34-3 was used instead of EX34-1 in step 2. 1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),10.25(brs,1H),8.08(d,J=8.6Hz,1H),7.27-7.22( m,2H),7.14(dd,J=8.7,2.1Hz,1H),6.94(t,J=6.7Hz,1H),4.95(s,1H),3.75(t,J=6.5Hz, 2H),3.54-3.43(m,4H),3.38-3.36(m,2H),3.07(d,J=11.4Hz,2H),2.84(d,J=12.6Hz,2H) ,2.44-2.30(m,3H),2.20(s,3H),1.86(d,J=12.4Hz,2H),1.55-1.40(m,4H),1.27(s,3H). LCMS[M+H] + :517.3.

[0562] Example 35 (EX35)

[0563] [ka]

[0564] Step 1: EX35 (36 mg) was prepared as described in Example 4 (EX04), except that EX35-1 was used instead of EX01-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.45(s,1H),7.27(d,J=2.1Hz,1H),7.17(dd,J=8.7,2.1Hz ,1H),4.40(dd,J=13.6,7.9Hz,1H),3.96(t,J=6.2Hz,2H),3.56-3.45(m,2H),3.38(t,J=6.2Hz,2H),3.3 1-3.21(m,3H),3.21-3.16(m,2H),3.15(s,3H),3.07-2.98(m,2H),2.81-2.69(m,1H),2.63-2.51(m,1H) ,2.36(s,3H),2.16-2.07(m,1H),2.00(d,J=14.6Hz,1H),1.84(d,J=14.6Hz,1H),1.02(d,J=6.9Hz,3H). LCMS[M+H] + :601.3.

[0565] Example 36 (EX36-A and B)

[0566] [ka]

[0567] Step 1: EX36-1 (15 mg) was prepared as described in Example 19 (EX19), except that EX17-2 was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate in Step 1. LCMS [M+H] + :587.2.

[0568] Step 2: EX36-A (2.85 mg) and EX36-B (4.85 mg) were prepared as described in Step 4 of Example 32 (EX32-A and B), except that EX36-1 was used instead of EX32. SFC analysis conditions: Column: Chiralpak AD-3, 50*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 5 to 40% Mobile phase B, 5 min; Flow rate: 4 mL / min; Column temperature: 35 °C.

[0569] EX36-A: 1 H NMR(400MHz,DMSO-d6)δ8.00(d,J=8.6Hz,1H),7.28(s,1H),7.21(s,1H),7. 09(d,J=8.4Hz,1H),3.74(t,J=6.3Hz,2H),3.39-3.29(m,5H),3.13(t,J=9.1 Hz,1H),3.02(s,3H),2.90-2.71(m,3H),2.40-2.31(m,2H),2.20(s,3H),1.9 5-1.88(m,1H),1.85-1.77(m,1H),1.75-1.66(m,1H),0.85(d,J=6.8Hz,3H). LCMS[M+H] + :587.3. Retention time @SFC: 1.539 minutes.

[0570] EX36-B: 1 H NMR(400MHz,DMSO-d6)δ7.98(d,J=8.7Hz,1H),7.29(s,1H),7.16(s,1H),7.05(d,J=8.2Hz,1H),4 .03-3.96(m,1H),3.73(t,J=6.4Hz,2H),3.40-3.36(m,1H),3.36-3.31(m,2H),3.27(t,J=6.3Hz,2 H),3.13(t,J=9.0Hz,1H),3.04-2.94(m,3H),2.90-2.81(m,1H),2.77-2.67(m,2H),2.44-2.37(m, 1H),2.20(s,3H),1.94-1.88(m,1H),1.85-1.78(m,1H),1.74-1.65(m,1H),0.85(d,J=6.9Hz,3H). LCMS[M+H] + :587.2. Retention time @SFC: 2.291 minutes.

[0571] Example 37 (EX37)

[0572] [ka]

[0573] Step 1: EX37 (11.74 mg) was prepared as described in Example 12 (EX12), except that EX34-3 was used instead of EX02-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.11(d,J=8.6Hz,1H),7.51(s,1H),7.30(d,J=2.2Hz,1H),7 .14(dd,J=8.7,2.2Hz,1H),3.97(t,J=6.2Hz,2H),3.40(t,J=6.2Hz,2H),3.30-3.2 4(m,2H),3.10-3.04(m,4H),2.64-2.52(m,2H),2.34(s,3H),1.92-1.80(m,2H),1 .61(q,J=8.4,6.9Hz,2H),1.52-1.46(m,2H),1.32(d,J=12.9Hz,2H),1.09(s,3H). LCMS[M+H] + :587.2.

[0574] Example 38 (EX38)

[0575] [ka]

[0576] Step 1: EX38 (19.91 mg) was prepared as described in Example 12 (EX12), except that EX38-1 was used instead of EX02-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.15(d,J=8.7Hz,1H),7.47(s,1H),7.38(d,J=2.2Hz,1H),7.17(dd,J=8.7,2.2Hz,1H),3.9 5(t,J=6.2Hz,2H),3.84(ddd,J=14.1,10.4,4.2Hz,1H),3.61(ddd,J=13.4,9.8,6.4Hz,1H),3.52-3.43(m,2H),3 .38(t,J=6.2Hz,2H),3.17-3.09(m,1H),3.08-2.91(m,4H),2.76(td,J=12.4,5.9Hz,1H),2.56(td,J=13.4,4.6H z,1H),2.31(s,3H),1.92-1.81(m,1H),1.58-1.48(m,1H),1.32-1.20(m,2H),1.15(d,J=6.2Hz,3H),1.02(s,3H). LCMS[M+H] + :533.3.

[0577] Example 39 (EX39)

[0578] [ka]

[0579] Step 1: EX39 (30.72 mg) was prepared as described in steps 3-6 of Example 12 (EX12), except that in step 3, 2-chloro-6-methylpyrimidin-4-amine was used instead of 2-chloro-6-(trifluoromethyl)pyrimidin-4-amine.1 H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.02(d,J=8.7Hz,1H),7.76(s,1H),7.28(s,1H),7.11(d,J=8.7Hz,1H),3.75(t,J=6.3Hz,2H),3.6 3-3.55(m,2H),3.40-3.33(m,4H),3.15(s,2H),3.01-2.86(m,4H),2.45-2.34(m,2H),1.70-1.60(m,2H),1.24-1.17(m,2H),0.91(s,3H). LCMS[M+H] + :573.1.

[0580] Example 40 (EX40)

[0581] [ka]

[0582] Step 1: To a solution of EX31 (35 mg, 0.064 mmol) in ACN (1 mL) was added NaI (95.6 mg, 0.64 mmol) and TMSCl (81 μL, 0.64 mmol) at 0° C. under a N atmosphere. The reaction was stirred at 50° C. for 18 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over MgSO, concentrated, and purified by preparative HPLC to give EX40 (4.23 mg). 1H NMR(400MHz,CD3OD)δ8.11(d,J=8.7Hz,1H),7.51(s,1H),7.33(d,J=2.0Hz,1H),7.15(dd,J=8.6, 2.1Hz,1H),4.31(dd,J=14.1,2.8Hz,1H),3.97(t,J=6.2Hz,2H),3.78-3.68(m,1H),3.44(dd,J=8 .7,4.1Hz,1H),3.42-3.34(m,3H),3.31-3.27(m,1H),3.21-3.15(m,2H),3.15-3.09(m,1H),3.07 -2.91(m,3H),2.65-2.52(m,2H),2.33(s,3H),1.34-1.26(m,1H),1.26-1.17(m,1H),1.00(s,3H). LCMS[M+H] + :535.2.

[0583] Example 41 (EX41)

[0584] [ka]

[0585] Step 1: EX41-2 (1.2 g) was prepared as described in Steps 2-3 of Example 17 (EX17), except that EX41-1 was used instead of EX41-1 in Step 2. LCMS [M-Boc+H] + :214.2. Step 2: EX41 (37.18 mg) was prepared as described in Example 4 (EX04), except that EX41-2 was used instead of EX41-2 in step 1. 1H NMR(400MHz,CD3OD)δ8.08(d,J=8.6Hz,1H),7.42(s,1H),7.28(d,J=2.0Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),3.98-3.87(m,4H),3.44-3.35(m,4H) ,3.27-3.21(m,4H),3.09(s,3H),2.75(t,J=11.0Hz,2H),2.37(s,3H),2. 29-2.15(m,2H),1.93-1.79(m,4H),0.71-0.60(m,1H),0.49-0.36(m,4H). LCMS[M+H] + :559.3.

[0586] Example 42 (EX42)

[0587] [ka]

[0588] Step 1: EX42 (2.63 mg) was prepared as described in Example 19 (EX19), except that in step 1, tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate. 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=8.5Hz,1H),7.31(s,1H),7.22(s,1H),7.13(d,J=8.7Hz,1H) ,4.02-3.97(m,1H),3.85-3.78(m,3H),3.72-3.69(m,2H),3.63-3.57(m,1H),3.38-3.31(m,3H) ,3.25-3.11(m,3H),2.98(t,J=11.8Hz,1H),2.81(t,J=12.2Hz,1H),2.73-2.64(m,1H),2.21(s ,3H),1.92(d,J=12.8Hz,1H),1.82(d,J=12.3Hz,1H),1.76-1.68(m,1H),0.84(d,J=6.9Hz,3H). LCMS[M+H] + :544.3.

[0589] Example 43 (EX43)

[0590] [ka]

[0591] Step 1: NaOH (0.6 g, 15.88 mmol) was slowly dissolved in water (18 mL) and toluene (18 mL). The mixture was cooled to 20 °C. tert-Butyl 4-(hydroxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.8 g, 6.35 mmol), EX43-1 (201.1 mg, 0.882 mmol), and TBAB (2.0 g, 6.354 mmol) were added to the mixture under N2 atmosphere. The reaction was stirred at 70 °C under N2 atmosphere for 3 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography to give EX43-2 (1.8 g). LCMS [M- t Bu+H] + :307.0.

[0592] Step 2: EX43-3 (1.7 g, crude) was prepared as described in Example 32 (EX32), Step 2, except that EX43-2 was used instead of EX32-1. LCMS [M+H] + :367.1.

[0593] Step 3: EX43 (37.13 mg) was prepared as described in Example 20 (EX20), steps 5-8, except that EX43-3 was used instead of EX20-4 in step 5. 1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),7.95(d,J=8.6Hz,1H),7.28(s,1H),7.15(s ,1H),7.09(d,J=8.4Hz,1H),3.74(t,J=6.2Hz,2H),3.51-3.41(m,2H),3.38-3.31( m,4H),3.22-3.15(m,2H),3.11-3.00(m,2H),2.90(t,J=12.3Hz,2H),2.50-2.41( m,2H),2.21(s,3H),1.87(d,J=13.8Hz,2H),0.50-0.40(m,2H),0.34-0.24(m,2H). LCMS[M+H] + :599.3.

[0594] Example 44 (EX44)

[0595] [ka]

[0596] Step 1: EX44-1 (4.0 g) was prepared as described in Example 4 (EX04), step 1, except that EX17-3 was used instead of EX01-2.

[0597] Step 2: To a solution of EX44-1 (4 g, 9.54 mmol) and CDNH (HCl salt, 3.4 g, 47.68 mmol) in DMSO (40 mL) was added CsF (2.9 g, 19.07 mmol) and DIEA (12.64 mL, 76.28 mmol) under N atmosphere. The mixture was stirred at 80 °C for 12 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by flash silica gel chromatography to give EX44-2 (2.4 g). LCMS [M+H] + :358.2.

[0598] Step 3: EX44 (65.35 mg) was prepared as described in Example 4 (EX04), steps 3-4, except that EX44-2 was used instead of EX04-2 in step 3. 1 H NMR(400MHz,CD3OD)δ8.11(d,J=8.7Hz,1H),7.46(s,1H),7.29(d,J=2.1Hz,1H),7.18(dd,J=8.7,2.1Hz,1H),3.99-3.89(m,4H),3.52-3.46( m,2H),3.43(s,2H),3.38(t,J=6.2Hz,2H),3.11(d,J=8.8Hz,4H),2.74-2.61(m,2H),2.37(s,3H),1.94(d,J=15.1Hz,2H),1.89-1.80(m,2H). LCMS[M+H] + :590.3.

[0599] Example 45 (EX45)

[0600] [ka]

[0601] Step 1: To a solution of EX44-1 (1.9 g, 4.53 mmol) and cyclopropanamine (388 mg, 6.80 mmol) in DMSO (25 mL) was added DIEA (2.2 mL, 13.35 mmol), and the resulting reaction was stirred at 100° C. for 1 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO, concentrated, and purified by silica gel chromatography to give EX45-1 (2.2 g). LCMS [M+H] + :381.3.

[0602] Step 2: EX45 (23.04 mg) was prepared as described in Example 4 (EX04), steps 3-4, except that EX45-1 was used instead of EX04-2 in step 3. 1H NMR(400MHz,CD3OD)δ8.11(d,J=8.7Hz,1H),7.55(s,1H),7.29(d,J=2.0Hz,1H ),7.18(dd,J=8.7,2.1Hz,1H),3.99-3.88(m,4H),3.52-3.46(m,2H),3.43(s,2 H),3.38(t,J=6.2Hz,2H),3.11(d,J=8.6Hz,4H),2.74-2.58(m,3H),2.42(s,3H) ),1.99-1.91(m,2H),1.90-1.83(m,2H),0.96-0.88(m,2H),0.68-0.61(m,2H). LCMS[M+H] + :613.3.

[0603] Example 46 (EX46-A and EX46-B)

[0604] [ka]

[0605] Step 1: EX46-1 was prepared as described in Example 2 (EX02), step 1, except that EX17-2 was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate.

[0606] Step 2: EX46 was prepared as described in Example 31 (EX31), except that EX46-1 was used instead of EX02-1 in step 1.

[0607] Step 3: EX46-A (8.87 mg) and EX46-B (10.65 mg) were separated from EX46 by SFC. SFC analysis conditions: Column: Chiralpak AD-3, 150*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C. EX46-A: 1H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.48(s,1H),7.28(d,J=2.0Hz,1H) ,7.17(dd,J=2.0,8.6Hz,1H),4.16(dd,J=2.8,14.0Hz,1H),3.94(t,J=6.2Hz,2H ),3.63(dd,J=2.2,7.8Hz,1H),3.48(s,2H),3.44(s,3H),3.39-3.34(m,4H),3. 30-3.25(m,1H),3.21-3.01(m,4H),2.71-2.56(m,2H),2.31(s,3H),1.99-1.87. LCMS[M+H] + :603.3. Retention time @SFC: 1.202 minutes. EX46-B: 1 H NMR(400MHz,CD3OD)δ8.11(d,J=8.7Hz,1H),7.50(s,1H),7.30(d,J=2.1Hz,1H),7 .19(dd,J=8.6,2.1Hz,1H),4.18(dd,J=14.0,2.8Hz,1H),3.96(t,J=6.2Hz,2H),3 .64(dd,J=7.8,2.2Hz,1H),3.50(s,2H),3.46(s,3H),3.42-3.35(m,4H),3.32-3. 28(m,1H),3.25-3.01(m,4H),2.73-2.57(m,2H),2.33(s,3H),2.01-1.88(m,2H). LCMS[M+H] + :603.3. Retention time @SFC: 1.722 minutes.

[0608] Example 47 (EX-47)

[0609] [ka]

[0610] Step 1: EX47 (2.49 mg) was prepared as described in Example 4 (EX04), steps 3-4, except that EX47-1 was used instead of EX04-2 in step 3. 1H NMR(400MHz,CD3OD)δ8.04(d,J=8.2Hz,1H),7.44(s,1H),7.30(s,1H),7.13(d, J=7.8Hz,1H),4.04-3.88(m,2H),3.73-3.62(m,2H),3.59-3.52(m,2H),3.50(s ,2H),3.41-3.36(m,3H),3.28-3.25(m,1H),3.23-3.10(m,2H),2.52-2.39(m,2 H),2.36(s,3H),2.00(d,J=14.0Hz,2H),1.93-1.83(m,2H),1.68-1.59(m,2H). LCMS[M+H] + :604.3.

[0611] Example 48 (EX48)

[0612] [ka]

[0613] Step 1: To a solution of EX44-2 (950 mg, 2.39 mmol) and 2-chloro-6-nitropyridine (758 mg, 4.79 mmol) in NMP (8 mL) was added DIEA (1.19 mL, 7.178 mmol). The resulting mixture was stirred at 140 °C for 2 h. The mixture was cooled to room temperature, diluted with water (15 mL), and extracted with EtOAc (15 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by flash silica gel chromatography to give EX48-1 (710 mg). LCMS [M-Boc+H] + :380.2.

[0614] Step 2: To a solution of EX48-1 (560 mg, 1.17 mmol) in MeOH (5 mL) was added Pd / C (621.3 mg, 0.58 mmol, 10% purity) and TES (1.36 g, 11.68 mmol) under N2 atmosphere. The mixture was stirred at 40 °C for 0.5 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH (20 mL), and concentrated under reduced pressure to give EX48-2 (800 mg, crude). LCMS [M+H] + :450.3.

[0615] Step 3: EX48-3 was prepared as described in Example 1 (EX01) step 4, except that EX48-2 was used instead of EX01-3.

[0616] Step 4: EX48 (16.88 mg) was prepared as described in Example 1 (EX01) steps 5-8, except that EX48-3 was used instead of EX01-4 in step 5. 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.59(d,J=7.5Hz,1H),7.53(t,J=8 .0Hz,1H),7.26(d,J=2.1Hz,1H),7.16(dd,J=8.6,2.1Hz,1H),6.35(d,J=8.1Hz, 1H),4.01-3.91(m,4H),3.49-3.45(m,2H),3.41(s,2H),3.38(t,J=6.3Hz,2H),3 .19-3.05(m,4H),2.75-2.63(m,2H),1.93(d,J=14.8Hz,2H),1.85-1.77(m,2H). LCMS[M+H] + :575.3.

[0617] Example 49 (EX49)

[0618] [ka]

[0619] Step 1: EX49 (0.51 mg) was prepared as described in Example 21 (EX21), except that EX49-1 was used instead of EX04-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.60(d,J=8.6Hz,1H),8.25(d,J=8.7Hz,1H),8.02(d,J=7.9Hz,1H),7.83(d,J=7.6Hz,1H),7.44(s,1H),7.26-7.21( m,1H),3.97(t,J=6.2Hz,2H),3.72-3.66(m,4H),3.63(s,2H),3.41-3.39(m,2H),3.25-3.12(m,4H),2.70-2.61(m,2H),2.09-2.04(m,2H). LCMS[M+H] + :572.3.

[0620] Example 50 (EX50)

[0621] [ka]

[0622] Step 1: EX50 (4.36 mg) was prepared as described in Example 13 (EX13) steps 2-4, except that EX47-1 was used instead of EX13-1 in step 2. 1 H NMR(400MHz,CD3OD)δ8.36(d,J=9.8Hz,1H),8.12(d,J=8.5Hz,1H),7.32(s,1H), 7.22(d,J=8.2Hz,1H),7.07(d,J=9.6Hz,1H),4.29-4.17(m,2H),3.96(t,J=6.1Hz ,2H),3.57-3.51(m,2H),3.44(s,2H),3.38(t,J=6.3Hz,2H),3.19-3.05(m,4H), 2.71-2.57(m,2H),2.20-2.09(m,2H),1.98(d,J=14.4Hz,2H),1.59-1.47(m,2H). LCMS[M+H] + :574.3.

[0623] Example 51 (EX51)

[0624] [ka]

[0625] Step 1: To a solution of NaOH (1.1 g, 26.47 mmol) in HO (30 mL) was added EX17-2 (3.0 g, 10.59 mmol), (2Z)-1, 4-dichlorobut-2-ene (3.3 g, 26.47 mmol), and tetrabutylammonium bisulfate (0.2 g, 0.53 mmol) at 0 °C. The mixture was stirred at 70 °C for 6 h. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX51-1 (1.5 g). LCMS [M- t Bu+H] + :316.1.

[0626] Step 2: EX51 (18.83 mg) was prepared as described in Example 12 (EX12) steps 2-5, except that EX51-2 was used instead of EX12-2 in step 2. 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.02(d,J=8.7Hz,1H),7.30(s,1H),7.25(s,1 H),7.13(d,J=8.7Hz,1H),5.70-5.63(m,1H),5.48-5.40(m,1H),4.26-4.17(m,2H), 4.10-4.02(m,2H),3.74(t,J=6.3Hz,2H),3.45(s,2H),3.33(t,J=6.3Hz,2H),3.09- 3.01(m,2H),3.01-2.91(m,2H),2.22(s,3H),2.19-2.09(m,2H),2.07-2.01(m,2H). LCMS[M+H] + :585.3.

[0627] Example 52 (EX52)

[0628] [ka]

[0629] Step 1: EX52 (12.88 mg) was prepared as described in Example 51 (EX51), except that in step 1, (E)-1,4-dibromobut-2-ene was used instead of (Z)-1,4-dichlorobut-2-ene. 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),7.95(d,J=8.6Hz,1H),7.34(s,1H),7.23(d,J=1. 7Hz,1H),7.13(dd,J=8.6,1.9Hz,1H),6.43(s,1H),5.77-5.66(m,1H),5.64-5.54(m,1H) ,4.13(d,J=6.1Hz,2H),4.01(t,J=5.9Hz,2H),3.80(t,J=6.4Hz,2H),3.61(s,2H),3.35 (t,J=6.4Hz,2H),3.04-2.96(m,4H),2.28(s,3H),2.17-2.09(m,2H),2.00-1.88(m,2H). LCMS[M+H] + :585.4.

[0630] Example 53 (EX53)

[0631] [ka]

[0632] Step 1: EX53-1 (8 g, crude) was prepared as described in Example 1 (EX01), Step 4, except that EX17-2 was used instead of EX01-3. LCMS [M+H] + :184.1.

[0633] Step 2: To a solution of EX53-1 (7.37 g, 40.2 mmol) and CbzCl (6.24 mL, 44.25 mmol) in THF (85 mL) was added NaOH (5 M, 32 mL, 160.9 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX53-2 (9.6 g). LCMS [M+H] + :318.1.

[0634] Step 3: To a solution of EX53-2 (2.3 g, 7.25 mmol) and 2,6-lutidine (0.9 g, 8.7 mmol) in DCM (250 mL) was added TfO (2.5 g, 8.7 mmol) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated aqueous NH4Cl (150 mL) and extracted with DCM (200 mL×3). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure to give EX53-3 (3.1 g). LCMS [M+Na] + :472.0.

[0635] Step 4: To a solution of EX53-3 (3.1 g, 6.9 mmol) and tert-butyl trans-(3-hydroxycyclobutyl)carbamate (1.5 g, 8.28 mmol) in HO (70 mL) was added NaOH (2.2 g, 55.19 mmol) and TBAS (2.3 g, 6.9 mmol). The mixture was stirred at 70 °C for 3 h. The reaction mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over MgSO, concentrated in vacuo, and purified by silica gel chromatography to give EX53-4 (480 mg). LCMS [M- t Bu+H] + :431.1.

[0636] Step 5: EX53-5 (280 mg, crude) was prepared as described in Example 49 (EX49), Step 3, except that EX53-4 was used instead of EX49-3. LCMS [M+H] + :353.1.

[0637] Step 6: EX53-6 (330 mg) was prepared as described in Steps 5-6 of Example 1 (EX01), except that EX53-5 was used instead of EX01-4 in Step 5. LCMS [M+H] + :599.3.

[0638] Step 7: To a solution of EX53-6 (330 mg, 0.55 mmol) and 2-chloro-6-methylpyrimidin-4-amine (237.4 mg, 1.65 mmol) in dioxane (6 mL) was added T4P (3 mL, 11.02 mmol, 50% in EtOAc) and TEA (1.99 mL, 14.3 mmol). The mixture was stirred at 100° C. for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography to give EX53-7 (300 mg). LCMS [M+H] + :724.2.

[0639] Step 8: EX53-8 (210 mg) was prepared as described in Example 1 (EX01) Step 4, except that EX53-7 was used instead of EX01-3. LCMS [M+H] + :624.3.

[0640] Step 9: To a solution of EX53-8 (210 mg, 0.34 mmol) in i-PrOH (18 mL) was added DIEA (669 μL, 4.04 mmol) and CsF (511.4 mg, 3.37 mmol). The mixture was stirred at 120° C. for 24 hours. The reaction was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography to give EX53-9 (60 mg). LCMS [M+H] + :588.2.

[0641] Step 10: EX53 (13.4 mg) was prepared as described in Example 1 (EX01), step 8, except that EX53-9 was used instead of EX01-7. 1 H NMR(400MHz,DMSO-d6)δ8.08(d,J=8.1Hz,1H),7.33(s,1H),7.26(s,1H),7.15(d,J=8.9Hz,1H),3.78(t,J=6.4Hz,2H),3.50(s,2H), 3.33(t,J=6.4Hz,2H),3.17-3.09(m,2H),3.08-2.97(m,2H),2.46-2.37(m,4H),2.24(s,3H),2.21-2.11(m,4H),2.04-1.98(m,2H). LCMS[M+H] + :585.3.

[0642] Example 54 (EX54)

[0643] [ka]

[0644] Step 1: EX54 (37.69 mg) was prepared as described in steps 4-10 of Example 53 (EX53), except that in step 4, tert-butyl cis-(3-hydroxycyclobutyl)carbamate was used instead of tert-butyl trans-(3-hydroxycyclobutyl)carbamate. 1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.00(d,J=8.7Hz,1H),7.48(s,1H),7.12(s ,1H),7.08-7.03(m,1H),3.89-3.82(m,1H),3.74(t,J=6.4Hz,2H),3.51-3.45(m,1 H),3.34(t,J=6.4Hz,2H),3.27-3.18(m,4H),3.07-2.98(m,2H),2.84(t,J=13.0H z,2H),2.69-2.58(m,2H),2.38-2.32(m,2H),2.21(s,3H),1.89(d,J=14.8Hz,2H). LCMS[M+H] + :585.3.

[0645] Example 55 (EX55)

[0646] [ka]

[0647] Step 1: EX55-1 was prepared as described in Example 19 (EX19) steps 1-2, except that in step 1, EX17-2 was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate.

[0648] Step 2: EX55-2 was prepared as described in Example 12 (EX12) steps 1-3, except that EX55-1 was used instead of EX02-2 in step 1.

[0649] Step 3: EX55 (9.13 mg) was prepared as described in Example 29 (EX29), steps 4-6, except that EX55-2 was used instead of EX12-3 in step 4. 1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),7.93(d,J=8.8Hz,1H),7.27(s,1H),6.43 (d,J=8.7Hz,1H),4.06(d,J=10.9Hz,1H),3.56(s,2H),3.43-3.37(m,1H),3.36 -3.29(m,2H),3.23-3.10(m,2H),3.08-2.93(m,3H),2.70-2.55(m,2H),2.48-2 .40(m,1H),2.19(s,3H),1.94-1.67(m,3H),1.32(s,6H),0.85(d,J=6.8Hz,3H). LCMS[M+H] + :552.3.

[0650] Example 56 (EX56)

[0651] [ka]

[0652] Step 1: EX56-1 was prepared as described in Example 12 (EX12) steps 1-2, except that EX55-1 was used instead of EX02-2 in step 1.

[0653] Step 2: EX56-3 (350 mg) was prepared as described in Steps 3-4 of Example 48 (EX48), except that EX56-1 was used instead of EX48-2 in Step 3. LCMS [M+H] + :567.3.

[0654] Step 3: EX56 (3.96 mg) was prepared as described in Example 12 (EX12), steps 4-6, except that EX56-2 was used instead of EX12-3 in step 4. 1H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.47(d,J=7.7Hz,1H),7.36(t,J=7.9Hz, 1H),7.27(s,1H),7.16(d,J=8.7Hz,1H),6.25(d,J=8.0Hz,1H),4.19(dd,J=13.3,4.7H z,1H),3.96(t,J=6.2Hz,2H),3.47-3.41(m,3H),3.38(t,J=6.2Hz,2H),3.23-3.12(m ,4H),3.08-2.97(m,2H),2.85-2.61(m,2H),2.01-1.81(m,3H),0.99(d,J=6.9Hz,3H). LCMS[M+H] + :572.3.

[0655] Project 4: EX56-A (8.87mg) EX56-B (10.65mg), SFC EX56 separated. SFC analysis conditions: KARA: Phenomenex Lux Cellulose-4, 100*4.6mm, 3.0μm; mobile phase A: supercritical CO2, mobile phase B: MeOH (0.05% DEA), 40% mobile phase B, 5 minutes; flow rate: 2.8 mL / min; KARA temperature: 40°C.

[0656] EX56-A: 1 H NMR (400MHz, CD3OD) δ8.09(d,J=8.6Hz,1H),7.47(d,J=7.8Hz,1H),7.36(t,J=7.7Hz,1H),7.28(d,J=1. 7Hz,1H),7.16(d,J=8.6Hz,1H),6.25(d,J=8.1Hz,1H),4.19(dd,J=13.4,4.4Hz,1H),3.96(t,J=6.2Hz,2 H),3.43(t,J=6.6Hz,3H),3.38(t,J=6.3Hz,2H),3.17(dd,J=23.5,14.7Hz,4H),3.02(dd,J=13.3,7.2H z,2H),2.77(s,1H),2.68(s,1H),1.98(d,J=14.2Hz,1H),1.89(d,J=14.7Hz,2H),0.99(d,J=6.9Hz,3H). LCMS[M+H] + 572.3. Hold time @SFC: 2.399 minutes.

[0657] EX56-B: 1 H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.45(d,J=7.8Hz,1H),7.38-7.31(m,1H), 7.25(d,J=1.4Hz,1H),7.14(dd,J=1.2,8.6Hz,1H),6.23(d,J=8.1Hz,1H),4.17(dd,J=4 .6,13.4Hz,1H),3.94(t,J=6.2Hz,2H),3.45-3.39(m,3H),3.36(t,J=6.3Hz,2H),3.23- 3.09(m,5H),3.04-2.95(m,2H),2.83-2.60(m,2H),1.85(s,3H),0.97(d,J=7.0Hz,3H). LCMS[M+H] + :572.3. Retention time@SFC:3.210 minutes.

[0658] Example 57 (EX57)

[0659] [ka]

[0660] Step 1: EX57 was prepared as described in Example 56 (EX56), steps 2-3, except that in step 2, 2-fluoro-4-nitropyridine was used instead of 2-fluoro-6-nitropyridine. 1H NMR(400MHz,CD3OD)δ8.20(d,J=8.7Hz,1H),7.88(d,J=6.0Hz,1H),7.79(d,J=4.5Hz,1H),7.39(d, J=2.0Hz,1H),7.23(dd,J=8.7,2.0Hz,1H),6.41(s,1H),3.96(t,J=6.2Hz,2H),3.64-3.59(m,1H),3 .59-3.53(m,1H),3.48-3.43(m,2H),3.38(t,J=6.2Hz,2H),3.32-3.06(m,5H),2.94-2.85(m,1H), 2.71-2.57(m,2H),2.16-2.08(m,1H),2.05-1.98(m,1H),1.97-1.87(m,1H),1.03(d,J=6.9Hz,3H). LCMS[M+H] + :572.3.

[0661] Example 58 (EX58)

[0662] [ka]

[0663] Step 1: EX58 was prepared as described in Example 48 (EX48), except that in step 1, 2-fluoro-4-nitropyridine was used instead of 2-fluoro-6-nitropyridine. 1 H NMR(400MHz,CD3OD)δ8.18(d,J=8.5Hz,1H),7.98(d,J=5.9Hz,1H),7.78(d,J=5.3Hz,1H),7.37(s,1H),7.22(d,J=8.8Hz,1H),6.53(s,1H) ),4.02-3.90(m,2H),3.60-3.48(m,6H),3.41-3.36(m,2H),3.22-3.08(m,4H),2.69-2.55(m,2H),2.10-2.01(m,2H),1.98-1.86(m,2H). LCMS[M+H] + :575.3.

[0664] Example 59 (EX59)

[0665] [ka]

[0666] Step 1: To a solution of EX52 (50 mg, 0.071 mmol) in EtOAc (5 mL) was added Pd / C (200 mg, 1.88 mmol, 10% purity). The mixture was purged and degassed with H three times. The mixture was stirred under H (15 psi) at 25 °C for 2 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by preparative HPLC to give EX59 (15 mg). 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.95(d,J=8.6Hz,1H),7.26(s,1H),7.23(d,J =1.8Hz,1H),7.08(dd,J=8.7,1.9Hz,1H),3.74(t,J=6.3Hz,2H),3.47(t,J=5.0Hz, 2H),3.39(s,2H),3.35-3.29(m,4H),3.15-3.08(m,2H),3.02-2.93(m,2H),2.30-2 .23(m,2H),2.20(s,3H),1.95-1.87(m,2H),1.74-1.64(m,2H),1.57-1.49(m,2H). LCMS[M+H] + :572.3.

[0667] Example 60 (EX60)

[0668] [ka]

[0669] Step 1: To a mixture of EX17-1 (10.0 g, 33 mmol) in DCM (200 mL) was added DIBAL-H (66 mL, 66 mL) dropwise at −78° C. under a N atmosphere. The resulting mixture was stirred at −78° C. for 2 hours. The reaction was quenched with MeOH (80 mL) and neutralized with saturated potassium sodium tartrate. The mixture was extracted three times with DCM (300 mL), and the combined organic layers were concentrated in vacuo and purified by silica gel chromatography to give EX60-1 (5.9 g). LCMS [M+H] + :282.3.

[0670] Step 2: EX60-2 (2 g, crude) was prepared as described in Steps 2-3 of Example 34 (EX34), except that EX60-1 was used instead of EX34-1 in Step 2. LCMS [M- t Bu+H] + :284.1.

[0671] Step 3: EX60-3 was prepared as described in Example 44 (EX44) steps 1-2, except that EX60-2 was used instead of EX17-3 in step 1.

[0672] Step 4: EX60 was prepared as described in Example 48 (EX48), except that EX60-3 was used instead of EX44-2 in step 1. 1 H NMR(400MHz,DMSO-d6)δ7.88(d,J=8.4Hz,1H),7.53-7.43(m,2H),7.05-7.00 (m,2H),6.31(d,J=8.0Hz,1H),3.74(t,J=6.3Hz,2H),3.62(t,J=6.5Hz,2H),3 .31(t,J=6.3Hz,2H),3.05(d,J=8.9Hz,2H),2.82(t,J=11.6Hz,2H),2.09(s,2 H),1.87(d,J=14.7Hz,2H),1.57(d,J=26.1Hz,4H),1.40(s,2H),1.23(s,2H). LCMS[M+H] + :573.3.

[0673] Example 61 (EX61)

[0674] [ka]

[0675] Step 1: To a solution of EX44-2 (354 mg, 0.99 mmol) and 6-bromo-2,3-difluoropyridine (250 mg, 1.29 mmol) in NMP (5 mL) was added DIEA (493 μL, 2.97 mmol). The mixture was stirred at 120° C. for 1 hour. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX61-1 (200 mg). LCMS [M-Boc+H] + :431.2,433.1.

[0676] Step 2: To a solution of EX61-1 (200 mg, 0.38 mmol) and 2-methylpropan-2-ylaminomethanoate (44 mg, 0.38 mmol) in toluene (2 mL), CsCO (368 mg, 1.13 mmol), Xantphos (43.6 mg, 0.075 mmol), and Pd(dba) (35 mg, 0.038 mmol) were added under a N atmosphere. The reaction was stirred at 100 °C for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was dried over MgSO, concentrated, and purified by silica gel chromatography to give EX61-2 (170 mg). LCMS [M+H] + :568.5.

[0677] Step 3: EX61 was prepared as described in Example 1 (EX01) steps 4-8, except that EX61-2 was used instead of EX01-3 in step 4. 1H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.56(dd,J=8.4,2.1Hz,1H),7.3 4-7.27(m,1H),7.26(d,J=2.1Hz,1H),7.15(dd,J=8.6,2.1Hz,1H),3.99-3.89 (m,4H),3.54-3.47(m,2H),3.42(s,2H),3.38(t,J=6.3Hz,2H),3.18-3.05(m, 4H),2.64(dd,J=18.5,9.3Hz,2H),1.93(d,J=14.7Hz,2H),1.89-1.80(m,2H). LCMS[M+H] + :593.3.

[0678] Example 62 (EX62)

[0679] [ka]

[0680] Step 1: EX62-1 was prepared as described in Example 2 (EX02) steps 1-2, except that EX17-3 was used instead of EX01-2 in step 1.

[0681] Step 2: EX62 was prepared as described in Example 48 (EX48), except that EX62-1 was used instead of EX44-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.61-7.50(m,2H),7.26(d,J=2.1Hz,1 H),7.16(dd,J=8.6,2.1Hz,1H),6.36(d,J=8.1Hz,1H),3.96(td,J=6.6,3.6Hz,4H) ,3.50-3.44(m,2H),3.41(s,2H),3.38(t,J=6.2Hz,2H),3.20-3.05(m,4H),2.94(s ,3H),2.70(t,J=10.9Hz,2H),1.93(d,J=15.2Hz,2H),1.81(dd,J=11.9,6.3Hz,2H). LCMS[M+H] +:572.3.

[0682] Example 63 (EX63)

[0683] [ka]

[0684] Step 1: EX63 was prepared as described in Example 60 (EX60), steps 2-4, except that in step 2, (3-(benzyloxy)propyl)triphenylphosphonium bromide was used instead of (4-(benzyloxy)butyl)triphenylphosphonium bromide. 1 H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.57-7.50(m,2H),7.20(s,1H), 7.13(d,J=8.6Hz,1H),6.34(d,J=7.3Hz,1H),3.96(t,J=6.2Hz,2H),3.57(t, J=6.7Hz,2H),3.38(t,J=6.2Hz,2H),3.17(s,2H),3.08(t,J=11.7Hz,2H),2. 54(d,J=10.4Hz,2H),2.02(d,J=14.9Hz,2H),1.75(dt,J=20.5,10.6Hz,6H). LCMS[M+H] + :559.3.

[0685] Example 64 (EX64)

[0686] [ka]

[0687] Step 1: EX64-1 was prepared as described in Example 60 (EX60), Step 2, except that (5-(benzyloxy)pentyl)triphenylphosphonium bromide was used instead of (4-(benzyloxy)butyl)triphenylphosphonium bromide. LCMS [M- t Bu+H] + :298.1.

[0688] Step 2: EX64-2 was prepared as described in Example 4 (EX04), step 1, except that EX64-1 was used instead of EX01-2. LCMS [M- t Bu+H] + :376.1.

[0689] Step 3: EX64 was prepared as described in Example 13 (EX13) steps 2-4, except that EX64-2 was used instead of EX13-1 in step 2. 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=9.9Hz,1H),7.94(d,J=8.6Hz,1H),7.15(s ,1H),7.09(d,J=8.6Hz,1H),7.03(d,J=9.9Hz,1H),3.99(t,J=7.1Hz,2H),3. 74(t,J=6.3Hz,2H),3.32(t,J=6.4Hz,2H),3.03(s,2H),2.92(d,J=11.7Hz,2 H),2.12(s,2H),1.95(d,J=14.4Hz,2H),1.72(s,2H),1.44(d,J=30.1Hz,8H). LCMS[M+H] + :572.3.

[0690] Example 65 (EX65)

[0691] [ka]

[0692] Step 1: EX65 was prepared as described in Example 64 (EX64) steps 2-3, except that EX60-3 was used instead of EX64-1 in step 2. 1H NMR(400MHz,CD3OD)δ8.70(d,J=9.9Hz,1H),8.02(d,J=8.5Hz,1H),7.20(s,1H),7.16(d,J=8.6Hz,1H),7.11(d,J=9.9Hz,1H),4.27-4.22 (m,2H),3.96(t,J=6.2Hz,2H),3.39(t,J=6.2Hz,2H),3.11(d,J=15.1Hz,4H),2.25(s,2H),1.95-1.79(m,6H),1.71(s,2H),1.44(s,2H). LCMS[M+H] + :572.3.

[0693] Example 66 (EX66)

[0694] [ka]

[0695] Step 1: EX66-1 was prepared as described in Example 12 (EX12) step 2, except that EX51-1 was used instead of EX12-1.

[0696] Step 2: EX66 was prepared as described in Example 56 (EX56), steps 2-3, except that EX51-2 was used instead of EX56-1 in step 2. 1 H NMR(400MHz,CD3OD)δ8.16(d,J=8.7Hz,1H),7.47(d,J=7.6Hz,1H),7.40(dd,J=11.1,4.9Hz ,2H),7.19(dd,J=8.7,2.1Hz,1H),6.29(d,J=7.8Hz,1H),5.75(dd,J=11.5,5.8Hz,1H),5.53 (d,J=11.4Hz,1H),4.38(d,J=5.6Hz,2H),4.19(d,J=5.3Hz,2H),3.96(t,J=6.3Hz,2H),3.58 (s,2H),3.38(t,J=6.2Hz,2H),3.21(d,J=12.4Hz,4H),2.49(s,2H),2.12(d,J=14.1Hz,2H). LCMS[M+H] + :570.3.

[0697] Example 67 (EX67)

[0698] [ka]

[0699] Step 1: EX67 was prepared as described in Example 61 (EX61), except that in step 1, 2-bromo-6-fluoro-4-methylpyridine was used instead of 6-bromo-2,3-difluoropyridine. 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.49(s,1H),7.26(s,1H),7.15(dd,J=8.7,1.3Hz,1H),6.20(s,1H),3.99-3.91(m,4H),3.46(t ,J=5.1Hz,2H),3.38(dd,J=11.8,5.5Hz,4H),3.17-3.04(m,4H),2.75-2.63(m,2H),2.31(s,3H),1.92(d,J=14.6Hz,2H),1.83-1.76(m,2H). LCMS[M+H] + :589.4.

[0700] Example 68 (EX68)

[0701] [ka]

[0702] Step 1: EX68 was prepared as described in Example 58 (EX58), except that in step 1, EX43-3 was used instead of EX44-2 and 2-chloro-6-nitropyridine was used instead of 2-fluoro-4-nitropyridine. 1H NMR(400MHz,CD3OD)δ8.02(d,J=8.6Hz,1H),7.44(d,J=7.5Hz,1H),7.37(t,J=7.9Hz,1H),7. 21(d,J=2.0Hz,1H),7.14(dd,J=8.6,2.0Hz,1H),6.24(d,J=7.9Hz,1H),3.96(t,J=6.2Hz,2H ),3.64(s,2H),3.42(s,2H),3.38(t,J=6.2Hz,2H),3.28(s,2H),3.18(s,2H),3.08(t,J=12. 1Hz,2H),2.73(s,2H),1.93(d,J=14.5Hz,2H),0.51(d,J=4.6Hz,2H),0.42(d,J=4.3Hz,2H). LCMS[M+H] + :584.2.

[0703] Example 69 (EX69)

[0704] [ka]

[0705] Step 1: EX69 was prepared as described in Example 15 (EX15) step 2, except that EX48-3 was used instead of EX15-1. 1 H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.17(d,J=8.2Hz,1H),7.78(s,1H),7 .69(d,J=8.3Hz,1H),7.52(q,J=7.8Hz,2H),6.34(d,J=7.4Hz,1H),3.84(t, J=6.8Hz,2H),3.38(d,J=5.0Hz,2H),3.35(s,2H),3.11(s,2H),2.97(t,J=1 2.4Hz, 2H), 2.47 (s, 2H), 1.88 (d, J=14.4Hz, 2H), 1.70 (s, 2H), 1.08 (s, 9H). LCMS[M+H] + :587.4.

[0706] Example 70 (EX70)

[0707] [ka]

[0708] Step 1: EX70-1 was described similarly to Example 69, except that methyl 4-(N-(2-(benzyloxy)ethyl)sulfamoyl)-2-fluorobenzoate was used instead of methyl 4-(N-(tert-butyl)sulfamoyl)-2-fluorobenzoate. LCMS [M+H] + :665.4.

[0709] Step 2: To a solution of EX70-1 (17 mg, 0.026 mmol) in MeOH (3 mL) was added Pd / C (10%, 20 mg). The mixture was purged and degassed with H three times. The mixture was stirred at 25 °C for 5 h. The mixture was filtered through a Celite pad and the solid was washed with MeOH (20 mL). The combined filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC to give EX70. 1 H NMR(400MHz,CD3OD)δ8.25(d,J=8.2Hz,1H),7.81(s,1H),7.73(d,J=8.3Hz,1 H),7.62-7.53(m,2H),6.39(d,J=8.2Hz,1H),3.98(t,J=6.9Hz,2H),3.57(t,J =5.8Hz,2H),3.49-3.45(m,2H),3.42(s,2H),3.24(s,2H),3.17(d,J=13.0Hz, 2H), 3.02(t,J=5.9Hz,2H),2.70(s,2H),1.95(d,J=14.7Hz,2H),1.83(s,2H). LCMS[M+H] + :575.1.

[0710] Example 71 (EX71)

[0711] [ka]

[0712] Step 1: EX71 was prepared as described in Example 48 (EX48), except that EX45-1 was used instead of EX44-2 in step 1. 1 H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.64-7.61(m,1H),7.58-7.52(m,1H),7.26(d,J=2 .0Hz,1H),7.14(dd,J=2.0,8.6Hz,1H),6.82(d,J=8.1Hz,1H),3.94(q,J=5.9Hz,4H),3.45(t,J =5.0Hz,2H),3.39(s,2H),3.36(t,J=6.3Hz,2H),3.15-3.04(m,4H),2.71-2.59(m,2H),2.49-2 .43(m,1H),1.92(brd,J=15.0Hz,2H),1.85-1.78(m,2H),0.94-0.89(m,2H),0.64-0.59(m,2H). LCMS[M+H] + :598.3.

[0713] Example 72 (EX72)

[0714] [ka]

[0715] Step 1: EX72-1 was prepared as described in Steps 1-2 of Example 61 (EX61), except that EX62-1 was used instead of EX44-2 in Step 1 and 2-bromo-6-fluoropyridine was used instead of 6-bromo-2,3-difluoropyridine. LCMS [M+H] + :347.2.

[0716] Step 2: EX72 was prepared as described in Example 1 (EX01) steps 4-8, except that EX72-1 was used instead of EX01-3 in step 4 and methyl 6-bromo-2-fluoronicotinate was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1H NMR(400MHz,CD3OD)δ8.27(d,J=8.4Hz,1H),7.57-7.49(m,2H),6.74(d,J=8.4Hz,1H),6.39-6.32(m,1H),4.03-3.93(m,4H),3.80(t,J= 6.3Hz,2H),3.49-3.40(m,6H),3.24(t,J=12.9Hz,2H),2.93(s,3H),2.64(t,J=11.9Hz,2H),1.91(d,J=14.9Hz,2H),1.87-1.79(m,2H). LCMS[M+H] + :573.2.

[0717] Example 73 (EX73)

[0718] [ka]

[0719] Step 1: To a solution of EX62-1 (800 mg, 2.26 mmol) and 2-chloro-6-((4-methoxybenzyl)amino)nicotinonitrile in NMP (10 mL) was added DIEA (1.12 mL, 6.77 mmol). The reaction was stirred at 140° C. for 12 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX73-1. LCMS [M+H] + :592.4.

[0720] Step 2: A solution of EX73-1 (1.1 g, 1.86 mmol) in TFA (10 mL) was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with DIEA (pH=7) to give EX73-2. LCMS [M+H] + :372.3.

[0721] Step 3: EX73 was prepared as described in Example 1 (EX01) steps 5-8, except that EX73-2 was used instead of EX01-4 in step 5. 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),7.99-7.94(m,1H),7.89-7.85(m,1H),7.61(d,J= 8.6Hz,1H),7.19-7.15(m,1H),7.11-7.06(m,1H),3.91(brt,J=7.2Hz,2H),3.73(t,J=6. 3Hz,2H),3.43-3.37(m,2H),3.35-3.30(m,4H),3.29-3.26(m,3H),3.03(brd,J=9.7Hz, 2H), 2.94-2.83 (m, 2H), 2.43-2.29 (m, 2H), 1.85 (brd, J=14.7Hz, 2H), 1.78-1.70 (m, 2H). LCMS[M+H] + :597.2.

[0722] Example 74 (EX74)

[0723] [ka]

[0724] Step 1: To a solution of EX62-1 (401.9 mg, 3.1 mmol) and 2-chloropyrimidin-4-amine in NMP (10 mL) was added DIEA (771 μL, 4.66 mmol) under N atmosphere. The mixture was stirred at 140 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX74-1. LCMS [M+H] + :448.3.

[0725] Step 2: EX74 was prepared as described in Example 1 (EX01) steps 4-8, except that EX74-1 was used instead of EX01-3 in step 4. 1H NMR(400MHz,CD3OD)δ8.23(d,J=5.7Hz,1H),8.13(dd,J=8.7,1.7Hz,1H),7.56(d,J=5.7Hz,1H),7.31(t,J=2.0Hz,1H),7.22-7.14(m,1H),3. 99-3.89(m,4H),3.52-3.47(m,2H),3.44(s,2H),3.38(t,J=6.2Hz,2H) ,3.17-3.05(m,7H),2.67(s,2H),1.96(d,J=14.7Hz,2H),1.86(s,2H). LCMS[M+H] + :573.2.

[0726] Example 75 (EX75)

[0727] [ka]

[0728] Step 1: EX75 was prepared as described in Example 74, except that in step 1, 6-chloropyrazin-2-amine was used instead of 2-chloropyrimidin-4-amine. 1 H NMR(400MHz,CD3OD)δ12.21(s,1H),8.80(s,1H),8.16(d,J=8.7Hz,1H),7.74(s,1H),7.32(d,J=2.0Hz,1H),7.20(dd,J=8.7,2.0Hz,1H),3.99-3.89( m,4H),3.52-3.46(m,2H),3.44(s,2H),3.39(t,J=6.2Hz,2H),3.13(d,J=8 .0Hz,4H),3.07(s,3H),2.66(s,2H),1.96(d,J=14.8Hz,2H),1.85(s,2H). LCMS[M+H] + :573.3.

[0729] Example 76 (EX76-A and B)

[0730] [ka]

[0731] Step 1: EX76-1 was prepared as described in Example 20 (EX20) steps 3-4, except that EX35-1 was used instead of EX20-2 in step 3. LCMS [M+H] + :355.3.

[0732] Step 2: To a solution of EX76-1 (3 g, 8.47 mmol) and 6-bromo-2,3-difluoropyridine (1.0 g, 5.08 mmol) in NMP (60 mL) was added DIEA (7.0 mL, 42.3 mmol). The mixture was stirred at 140° C. under N atmosphere for 2 hours. The mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL×3). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give EX76-2. LCMS [M+H] + :428.2,430.2.

[0733] Step 3: EX76 was prepared as described in Example 61 (EX61) steps 2-3, except that EX76-2 was used instead of EX61-1 in step 2.

[0734] Step 4: EX76-A (51.12 mg) and EX76-B (52.57 mg) were separated from EX76 by SFC. SFC analysis conditions: Column: (S,S) Whelk-01, 100*4.6 mm, 5.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C.

[0735] EX76-A: 1H NMR(400MHz,CD3OD)δ8.10(d,J=8.6Hz,1H),7.48(dd,J=2.7,8.4Hz,1H),7.28(d,J= 2.0Hz,1H),7.25-7.15(m,2H),4.27(dd,J=5.0,13.5Hz,1H),3.96(t,J=6.3Hz,2H),3 .50-3.45(m,2H),3.42-3.36(m,3H),3.26-3.15(m,3H),3.12-2.98(m,3H),2.85-2. 60(m,2H),2.00(brdd,J=1.7,14.8Hz,1H),1.92-1.84(m,2H),1.01(d,J=7.0Hz,3H). LCMS[M+H] + 590.2. Hold time @SFC: 2.637 minutes.

[0736] EX76-B: 1 H NMR(400MHz,CD3OD)δ8.10(d,J=8.6Hz,1H),7.48(dd,J=2.5,8.3Hz,1H),7.29(s,1 H),7.25-7.14(m,2H),4.27(brdd,J=5.0,13.4Hz,1H),3.96(t,J=6.1Hz,2H),3.50- 3.44(m,2H),3.41-3.36(m,3H),3.26-3.15(m,3H),3.11-2.99(m,3H),2.83-2.60(m ,2H),2.00(brd,J=14.0Hz,1H),1.88(brd,J=13.0Hz,2H),1.01(brd,J=6.9Hz,3H). LCMS[M+H] + 590.3. Hold time @SFC: 3.151 minutes.

[0737] Example 77 (EX77)

[0738]

change

[0739] Project 1: To a mixture of EX17-2 (2 g, 7.06 mmol) in HO (60 mL) was added (E)-((4-bromo-3-methylbut-2-en-1-yl)oxy)(tert-butyl)diphenylsilane (4.3 g, 10.59 mmol) and NaOH (2.8 g, 70.6 mmol). The mixture was stirred at 25 °C for 10 min, and then TBAS (0.5 g, 1.41 mmol) was added. The mixture was stirred at 70 °C for 3 h. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over MgSO, concentrated, and purified by silica gel chromatography to give EX77-1. LCMS [M+Na] + :628.3.

[0740] Step 2: To a solution of EX77-1 (2.7 g, 4.46 mmol) in THF (10 mL) was added TBAF (22.28 mL, 22.28 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with brine (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX77-2.

[0741] Step 3: To a solution of EX77-2 (1.5 g, 4.08 mmol) in THF (20 mL) was added PBr3 (460 μL, 4.9 mmol) at −10° C. The solution was stirred at −10° C. for 1 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography to give EX77-3. LCMS [M- t Bu+H] + :374.1,376.1.

[0742] Step 4: EX77 was prepared as described in Example 66 (EX66), except that EX77-3 was used instead of EX51-1 in step 1. 1H NMR(400MHz,CD3OD)δ7.91(d,J=8.6Hz,1H),7.48(d,J=7.7Hz,1H),7.39(t,J=7.9Hz,1H) ,7.19(d,J=2.0Hz,1H),7.09(dd,J=8.5,2.0Hz,1H),6.28(d,J=8.0Hz,1H),5.80(s,1H),3 .96(t,J=6.2Hz,4H),3.80(s,2H),3.49(s,2H),3.37(t,J=6.3Hz,2H),3.28(d,J=12.1Hz, 2H), 3.08(t,J=11.7Hz,2H),2.10(d,J=14.6Hz,2H),1.93(t,J=10.6Hz,2H),1.74(s,3H). LCMS[M+H] + :584.3.

[0743] Example 78 (EX78-A and B)

[0744] [ka]

[0745] Step 1: EX78-1 was prepared as described in Example 31 (EX31) steps 1-3, except that EX48-1 was used instead of EX02-1 in step 1.

[0746] Step 2: EX78 was prepared as described in Example 66, Step 2, except that EX78-1 was used instead of EX66-1. LCMS [M+H] + :588.3.

[0747] Step 3: EX78-A and EX78-B were separated from EX78 by SFC. SFC analysis conditions: column: Cellulose-2, 100*4.6 mm, 3.0 μm; mobile phase A: supercritical CO2, mobile phase B: ethanol (0.05% DEA), 40% mobile phase B, 5 min; flow rate: 2.8 mL / min; column temperature: 35 °C.

[0748] EX78-A:1 H NMR (400MHz, CD3OD) δ8.08(d,J=8.6Hz,1H),7.50(d,J=7.6Hz,1H),7.38(t,J=7.9Hz,1H),7.26( d,J=2.0Hz,1H),7.16(dd,J=8.6,2.1Hz,1H),6.28(d,J=8.0Hz,1H),4.22(d,J=12.1Hz,1H),3.96 (t,J=6.2Hz,2H),3.62(d,J=5.2Hz,1H),3.48(t,J=5.6Hz,2H),3.45(s,3H),3.38(t,J=6.2Hz,5 H),3.15(d,J=8.9Hz,3H),3.07(d,J=13.0Hz,1H),2.67(d,J=9.4Hz,2H),1.93(t,J=15.3Hz,2H). LCMS[M+H] + 588.3. Hold time @SFC: 1.793 minutes.

[0749] EX78-B: 1 H NMR(400MHz,CD3OD)δ8.08(d,J=8.6Hz,1H),7.50(d,J=7.4Hz,1H),7.38(t,J=7.9Hz,1H),7.26( d,J=2.1Hz,1H),7.16(dd,J=8.6,2.1Hz,1H),6.28(d,J=8.0Hz,1H),4.22(d,J=11.2Hz,1H),3.96 (t,J=6.2Hz,2H),3.62(d,J=5.4Hz,1H),3.48(t,J=5.7Hz,2H),3.45(s,3H),3.38(t,J=6.2Hz,5H ),3.15(d,J=8.8Hz,3H),3.06(t,J=12.7Hz,1H),2.67(d,J=10.4Hz,2H),1.93(t,J=15.1Hz,2H). LCMS[M+H] + 588.3. Duration @SFC: 2.350 minutes.

[0750] Example 79 (EX79-AおよびB)

[0751]

change

[0752] Step 1: EX79-1 was prepared as described in Example 34 (EX34) Step 2, except that EX70-1 was used instead of EX34-1 and (4-methoxy-3-methyl-4-oxobutyl)triphenylphosphonium bromide was used instead of (4-(benzyloxy)butyl)triphenylphosphonium bromide. LCMS [M- t Bu+H] + :296.1.

[0753] Step 2: To a solution of EX79-1 (6.9 g, 18.2 mmol) in THF (200 mL) was added LiBHEt (1 M, 55 mL, 55 mmol) at 0 °C under N atmosphere. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with MeOH (300 mL) and concentrated under reduced pressure. The residue was diluted with saturated aqueous NH Cl (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX79-2. LCMS [M- t Bu+H] + :296.1

[0754] Step 3: EX79-3 was prepared as described in Steps 1-3 of Example 76 (EX76), except that EX79-1 was used instead of EX35-1 in Step 1 and 6-bromo-2-fluoropyridine was used instead of 6-bromo-2,3-difluoropyridine in Step 2. LCMS [M+H] + :568.2.

[0755] Step 4: EX79 was prepared as described in Example 59 (EX59), except that EX79-3 was used instead of EX52. LCMS [M+H] + :570.3.

[0756] Step 5: EX79-A (12.03mg) EX79-B (12.10mg), SFC EX79 separated. SFC analysis conditions: カラム: Chiralpak AD-3, 150*4.6mm, 3.0μm; mobile phase A: supercritical CO2, mobile phase B: エタノール (0.05%DEA), 40% mobile phase B, 5 minutes; flow rate: 2.5mL / min; カラム temperature: 35°C.

[0757] EX79-A: 1 H NMR (400MHz, CD3OD) δ7.86(d,J=8.5Hz,1H),7.38(d,J=7.7Hz,1H),7.24(t,J=8.0Hz,1H),7.03-6. 96(m,2H),6.16(d,J=8.0Hz,1H),3.84(t,J=6.2Hz,2H),3.38(d,J=5.0Hz,2H),3.26(t,J=6.2Hz,2H ),3.10-3.01(m,2H),2.97-2.80(m,2H),2.25-2.09(m,2H),1.89-1.78(m,2H),1.78-1.67(m,1H), 1.67-1.58(m,1H),1.54-1.43(m,2H),1.36-1.25(m,2H),1.16-1.09(m,1H),0.92(d,J=6.9Hz,3H). LCMS[M+H] + 570.1. Hold time @SFC: 1.300 minutes.

[0758] EX79-B: 1 H NMR (400MHz, CD3OD) δ7.98(d,J=8.5Hz,1H),7.50(d,J=7.6Hz,1H),7.36(t,J=8.0Hz,1H),7.15-7. 08(m,2H),6.28(d,J=8.1Hz,1H),3.96(t,J=6.2Hz,2H),3.50(d,J=4.9Hz,2H),3.38(t,J=6.3Hz,2H ),3.23-3.14(m,2H),3.09-2.94(m,2H),2.37-2.21(m,2H),2.02-1.90(m,2H),1.89-1.70(m,2H), 1.68-1.54(m,2H),1.50-1.42(m,1H),1.40-1.32(m,1H),1.29-1.18(m,1H),1.04(d,J=6.9Hz,3H). LCMS[M+H]+ :570.5. Retention time @SFC: 1.446 minutes.

[0759] Example 80 (EX80)

[0760] [ka]

[0761] Step 1: EX80 was prepared as described in Example 76 (EX76) steps 2-3, except that in step 2, EX80-1 was used instead of EX76-2 and 6-bromo-2-fluoropyridine was used instead of 6-bromo-2,3-difluoropyridine. 1 H NMR(400MHz,CD3OD)δ8.20(d,J=8.7Hz,1H),7.49-7.43(m,2H),7.32(d,J=2.1 Hz,1H),7.22(dd,J=8.7,2.2Hz,1H),6.38(dd,J=7.2,1.6Hz,1H),4.44(s,2H), 3.96(t,J=6.2Hz,2H),3.74-3.67(m,2H),3.38(t,J=6.2Hz,2H),3.14(d,J=12. 9Hz, 4H), 2.98 (s, 3H), 2.51 (s, 2H), 2.27 (d, J=14.5Hz, 2H), 2.10-2.01 (m, 2H). LCMS[M+H] + :585.3.

[0762] Example 81 (EX81-A and B)

[0763] [ka]

[0764] Step 1: EX81-1 was prepared as described in Example 31 (EX31) steps 1-2, except that EX46-1 was used instead of EX02-1 in step 1.

[0765] Step 2: To a mixture of EX81-1 (5 g, 10.49 mmol) and TEA (2.9 mL, 20.99 mmol) in DCM (85 mL) was added chloroacetyl chloride (1.8 g, 15.74 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was dried over MgSO4 and concentrated to give EX81-2. LCMS [M-Boc+H] + :453.2.

[0766] Step 3: To a solution of EX81-2 (5 g, 9.04 mmol) in MeOH (85 mL) and H2O (8.5 mL) was added K2CO3 (1.9 g, 13.56 mmol). The mixture was stirred at 80 °C for 18 h. The resulting mixture was concentrated, quenched with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over MgSO4, concentrated, and purified by silica gel chromatography to give EX81-3. LCMS [M-Boc+H] + :417.3.

[0767] Step 4: To a solution of EX81-3 (2.9 g, 5.61 mmol) in THF (145 mL) was added borane tetrahydrofuran (11 mL, 11.23 mmol) under N2 atmosphere at 0 °C, and the reaction was stirred at 70 °C for 18 h. The reaction was quenched with MeOH (50 mL), and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM (50 mL x 3). The combined organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography to give EX81-4. LCMS [M+H] + :503.4.

[0768] Step 5: To a solution of EX81-4 (2.65 g, 5.27 mmol) in EtOAc (30 mL) was added Pd / C (10%, 2.8 g, 2.64 mmol). The mixture was purged with H2 three times. The mixture was stirred under an atmosphere of H2 (15 Psi) at 25 °C for 18 h. The reaction mixture was filtered, washed with EtOAc (50 mL), and the filtrate was concentrated to give EX81-5. LCMS [M+H] + :383.2.

[0769] Step 6: EX81 was prepared as described in Example 62, Step 2, except that EX81-5 was used instead of EX62-1. LCMS [M+H] + :600.3.

[0770] Step 7: EX81-A (18.72 mg) and EX81-B (19.56 mg) were separated from EX81 by SFC. SFC analysis conditions: Column: Cellulose-4, 100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (0.05% DEA), 60% Mobile phase B, 5 min; Flow rate: 2.8 mL / min; Column temperature: 40 °C.

[0771] EX81-A: 1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.64-7.53(m,2H),7.27(d,J=2.1Hz,1H),7.1 6(dd,J=8.6,2.1Hz,1H),6.52(d,J=7.5Hz,1H),4.16(d,J=13.2Hz,1H),3.99-3.91(m,3H) ,3.88-3.76(m,2H),3.73-3.65(m,2H),3.57(dd,J=12.3,7.0Hz,3H),3.52-3.44(m,2H),3 .38(t,J=6.2Hz,2H),3.24-3.05(m,4H),2.67-2.53(m,2H),1.97(dd,J=26.4,13.8Hz,2H). LCMS[M+H] + :600.3. Retention time @SFC: 1.675 minutes.

[0772] EX81-B:1 H NMR(400MHz,CD3OD)δ8.09(d,J=8.6Hz,1H),7.64-7.53(m,2H),7.27(d,J=2.1Hz,1H),7.1 6(dd,J=8.6,2.1Hz,1H),6.52(d,J=7.6Hz,1H),4.17(d,J=10.7Hz,1H),3.99-3.91(m,3H) ,3.88-3.77(m,2H),3.74-3.64(m,2H),3.57(dd,J=12.2,7.0Hz,3H),3.51-3.45(m,2H),3 .38(t,J=6.2Hz,2H),3.24-3.05(m,4H),2.67-2.51(m,2H),1.97(dd,J=25.7,14.5Hz,2H). LCMS[M+H] + :600.3. Retention time @SFC: 1.810 minutes.

[0773] Example 82 (EX82)

[0774] [ka]

[0775] Step 1: EX82 was prepared as described in Example 1 (EX01) steps 4-8, except that EX72-1 was used instead of EX01-3 in step 4 and 6-bromo-4-chloropyridine-3-carboxylate was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1 H NMR(400MHz,CD3OD)δ8.25(s,1H),7.41-7.58(m,2H),6.76(s,1H),6.36(d,J=8.14Hz,1H),3.87-4.03 (m,4H)3.35-3.48(m,8H),3.08(t,J=12.21Hz,2H),2.90(s,3H),2.42-2.62(m,2H),1.75-1.95(m,4H). LCMS[M+H] + :573.3.

[0776] Example 83 (EX83)

[0777] [ka]

[0778] Step 1: EX83 was prepared as described in Example 79 (EX79) steps 1-3, except that in step 1, (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide was used instead of (4-methoxy-3-methyl-4-oxobutyl)triphenylphosphonium bromide. 1 H NMR(400MHz,CD3OD)δ7.99(d,J=8.5Hz,1H),7.46(d,J=7.7Hz,1H),7.37(t,J=7.9Hz,1H), 7.26(d,J=1.8Hz,1H),7.14(dd,J=8.6,1.9Hz,1H),6.24(d,J=8.0Hz,1H),5.59-5.44(m,2 H),3.96(t,J=6.2Hz,2H),3.48(t,J=6.1Hz,2H),3.38(t,J=6.2Hz,2H),3.19(s,2H),3.08 (t,J=12.1Hz,2H),2.59(t,J=12.1Hz,4H),2.19(d,J=14.8Hz,2H),1.64(d,J=8.1Hz,2H). LCMS[M+H] + :554.3.

[0779] Example 84 (EX84-A and B)

[0780] [ka]

[0781] Step 1: To a solution of EX17-2 (2 g, 7.06 mmol) in DMF (20 mL) was added NaH (1.4 g, 35.3 mmol) under N2 at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. Then, 4-methyl-1,3,2-dioxathiolane 2,2-dioxide (2.9 g, 21.18 mmol) was added to the reaction mixture. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water (10 mL) at 0°C, and the reaction mixture was concentrated under reduced pressure to give EX84-1. LCMS [M- t Bu+H] + :366.1.

[0782] Step 2: To a solution of EX84-1 (2.7 g, 6.41 mmol) in MeOH (30 mL) was added HCl / dioxane (4 M, 32 mL, 128.14 mmol). The reaction was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give EX84-2. LCMS [M+H] + :242.1.

[0783] Step 3: To a solution of EX84-2 (1.4 g, 5.8 mmol) and BocO (4 mL, 17.41 mmol) in THF (20 mL) was added NaCO (20.61 mL, 40.61 mmol). The resulting mixture was stirred at 25 °C for 3 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX84-3. LCMS [M- t Bu+H] + :286.1.

[0784] Step 4: To a solution of EX84-3 (1.3 g, 3.81 mmol) in DMF (20 mL) was added NaH (0.5 g, 11.42 mmol) under N at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. Then, 2-bromo-6-(chloromethyl)pyridine (0.9 g, 4.569 mmol) was added to the reaction mixture. The resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with water (50 mL) at 0° C. and then extracted with EtOAc (50 mL×3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX84-4. LCMS [M-Boc+H] + :411.2,413.2.

[0785] Step 5: EX84 was prepared as described in Example 61 (EX61) steps 2-3, except that EX84-4 was used instead of EX61-1 in step 2. LCMS [M+H] + :573.1.

[0786] Step 6: EX84-A (34.58 mg) and EX84-B (34.99 mg) were separated from EX84 by SFC. SFC analysis conditions: Column: Cellulose 2,100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 60% Mobile phase B, 5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C.

[0787] EX84-A: 1H NMR(400MHz,CD3OD)δ8.30(d,J=7.9Hz,1H),8.08(d,J=8.6Hz,1H),7.85-7.78(m,1H),7.26(d ,J=2.0Hz,1H),7.18(dd,J=8.6,2.1Hz,1H),7.14(d,J=7.2Hz,1H),4.72(d,J=12.2Hz,1H),4. 52(d,J=12.2Hz,1H),3.97(t,J=6.2Hz,2H),3.77(s,1H),3.57-3.36(m,6H),3.13(dd,J=28.7 ,15.0Hz,4H),2.78(s,1H),2.55(s,1H),1.94(dd,J=29.3,14.3Hz,2H),1.17(d,J=6.3Hz,3H). LCMS[M+H] + 573.2. Hold time @SFC: 1.012 minutes.

[0788] EX84-2: 1 H NMR(400MHz,CD3OD)δ8.30(d,J=8.1Hz,1H),8.09(d,J=8.6Hz,1H),7.82(dd,J=7 .4,8.3Hz,1H),7.26(d,J=2.0Hz,1H),7.21-7.12(m,2H),4.72(d,J=12.3Hz,1H) ,4.52(d,J=12.1Hz,1H),3.96(t,J=6.3Hz,2H),3.77(s,1H),3.55-3.35(m,6H), 3.20-3.05(m,4H),2.83-2.47(m,2H),2.02-1.85(m,2H),1.17(d,J=6.4Hz,3H). LCMS[M+H] + 573.2. Hold time @SFC: 1.708 minutes.

[0789] Example 85 (EX85-AおよびB)

[0790]

change

[0791] Project 1: EX85-A (13.17mg) EX85-B (13.50mg), SFC EX79-3 separated. SFC analysis conditions: カラム: (S, S) Whelk-01, 100*4.6mm, 5.0μm; mobile phase A: supercritical CO2, mobile phase B: エタノール (0.05% DEA), 40% mobile phase B, 5 minutes; flow rate: 2.5mL / min; カラム temperature: 40°C.

[0792] EX85-A: 1 H NMR(400MHz,CD3OD)δ7.96(d,J=8.7Hz,1H),7.29-7.52(m,2H),7.23(s,1H ),7.12(d,J=8.4Hz,1H),6.23(d,J=8.1Hz,1H),5.55(s,2H),3.94(t,J=5.7 Hz,2H),3.32-3.46(m,4H),2.92-3.23(m,4H),2.59-2.73(m,2H),2.34-2. 55(m,2H),2.04-2.25(m,2H),1.78(d,J=1.9Hz,1H),0.96(d,J=6.1Hz,3H). LCMS[M+H] + 568.3. Duration @SFC: 2.722 minutes.

[0793] EX85-B: 1 H NMR (400MHz, CD3OD) δ7.98(d,J=8.6Hz,1H),7.46(d,J=7.6Hz,1H),7.37(t,J=7.9Hz,1H),7.25(d,J=2 .0Hz,1H),7.14(dd,J=8.6,2.0Hz,1H),6.25(d,J=8.0Hz,1H),5.62-5.52(m,2H),3.96(t,J=6.2Hz,2H ),3.41(dt,J=12.6,6.9Hz,3H),3.31-3.08(m,4H),3.01(t,J=12.6Hz,1H),2.75-2.60(m,2H),2.56-2 .36(m,2H),2.22(d,J=13.6Hz,1H),2.11(d,J=14.8Hz,1H),1.86-1.75(m,1H),0.98(d,J=6.7Hz,3H). LCMS[M+H] + 568.3. Duration @SFC: 3.150 minutes.

[0794] Example 86 (EX86)

[0795] [ka]

[0796] Step 1: EX86 was prepared as described in Example 1 (EX01) steps 4-8, except that EX72-1 was used instead of EX01-3 in step 4 and methyl 5-bromo-3-fluoropyridine-2-carboxylate was used instead of methyl 2-fluoro-4-iodobenzoate in step 5. 1 H NMR(400MHz,CD3OD)δ8.54-8.14(m,1H),7.70(s,1H),7.62(d,J=7.5Hz,1H ),7.57-7.50(m,1H),6.37(d,J=8.3Hz,1H),3.96(t,J=5.9Hz,4H),3.45(t, J=5.2Hz,2H),3.42-3.37(m,4H),3.24-3.17(m,2H),3.15-3.05(m,2H),2. 92(s,3H),2.72-2.62(m,2H),1.92(brd,J=14.8Hz,2H),1.85-1.78(m,2H). LCMS[M+H] + :573.3.

[0797] Example 87 (EX87)

[0798] [ka]

[0799] Step 1: To a solution of EX62-1 (1 g, 1.69 mmol) and 4-chloropyrimidin-2-amine (439 mg, 3.39 mmol) in NMP (15 mL) was added DIEA (0.84 mL, 5.08 mmol) and CsF (514 mg, 3.39 mmol) under N2 atmosphere. The mixture was stirred at 140 °C for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by flash silica gel chromatography to give EX87-1. LCMS [M+H] + :448.3.

[0800] Step 2: EX87 was prepared as described in Example 1 (EX01) steps 4-8, except that EX87-1 was used instead of EX01-3. 1 H NMR(400MHz,CD3OD)δ8.16(d,J=8.5Hz,1H),8.07(d,J=6.0Hz,1H),7.30(d,J=1.5Hz,1 H),7.20-7.14(m,1H),6.46(d,J=6.3Hz,1H),4.60(s,1H),3.98(t,J=7.2Hz,2H),3.94( t,J=6.1Hz,2H),3.48(t,J=5.0Hz,2H),3.43(s,2H),3.36(t,J=6.1Hz,2H),3.12(d,J= 9.3Hz, 4H), 3.06 (s, 3H), 2.73-2.61 (m, 2H), 1.95 (d, J=15.1Hz, 2H), 1.90-1.82 (m, 2H). LCMS[M+H] + :573.2.

[0801] Example 88 (EX88-A and B)

[0802] [ka]

[0803] Step 1: EX88-1 was prepared as described in Steps 1-2 of Example 61 (EX61), except that EX76-1 was used instead of EX44-2 in Step 1, and 6-bromo-2-fluoropyridine was used instead of 6-bromo-2,3-difluoropyridine. LCMS [M+H] + :347.2.

[0804] Step 2: EX88-2 was prepared as described in Example 1 (EX01) steps 4-7, except that EX88-1 was used instead of EX01-3 in step 4. LCMS [M+H] + :575.2.

[0805] Step 3: To a solution of EX88-2 (170 mg, 0.30 mmol) and ethanesulfonamide (161 mg, 1.48 mmol) in DMF (5 mL) was added CuI (56 mg, 0.30 mmol), KPO (189 mg, 0.89 mmol), and DMDACH (41 mg, 0.30 mmol). The reaction was stirred at 145 °C for 2 h. The reaction was quenched with saturated aqueous NHCl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by preparative HPLC to give EX88. LCMS [M+H] + :556.3

[0806] Step 4: EX88-A (48.23 mg) and EX88-B (47.04 mg) were separated from EX88 by SFC. SFC analysis conditions: Column: Chiralpak IC-3, 100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: isopropanol (0.05% DEA), 50% Mobile phase B, 5 min; Flow rate: 2.8 mL / min; Column temperature: 35 °C.

[0807] EX88-A: 1H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.44(d,J=7.6Hz,1H),7.37-7.30( m,1H),7.25(s,1H),7.13(d,J=8.5Hz,1H),6.23(d,J=8.0Hz,1H),4.17(dd,J=4 .5,13.4Hz,1H),3.44-3.36(m,3H),3.22-3.08(m,6H),3.06-2.95(m,2H),2.82 -2.59(m,2H),1.99-1.78(m,3H),1.32(t,J=7.3Hz,3H),0.96(d,J=6.9Hz,3H). LCMS[M+H] + 556.3. Hold time @SFC: 1.395 minutes.

[0808] EX88-B: 1 H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.44(d,J=7.6Hz,1H),7.38-7.31( m,1H),7.26(s,1H),7.13(d,J=8.5Hz,1H),6.23(d,J=8.0Hz,1H),4.17(dd,J=4 .5,13.4Hz,1H),3.46-3.37(m,3H),3.21-3.10(m,6H),3.07-2.97(m,2H),2.83 -2.58(m,2H),1.99-1.79(m,3H),1.32(t,J=7.3Hz,3H),0.96(d,J=6.9Hz,3H). LCMS[M+H] + 556.2. Hold time @SFC: 1.792 minutes.

[0809] Example 89 (EX89)

[0810]

change

[0811] Project 1: EX89-1 was prepared as described in Steps 1-2 of Example 79 (EX79), except that (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide was used instead of (4-methoxy-3-methyl-4-oxobutyl)triphenylphosphonium bromide in Step 1. LCMS [M- t Bu+H] + :282.1.

[0812] Step 2: EX89-2 was prepared as described in Example 4 (EX04) steps 1-2, except that EX89-1 was used instead of EX01-2 in step 1. LCMS [M+H] + :351.1.

[0813] Step 3: EX89-3 was prepared as described in Example 72, steps 1-2, except that EX89-2 was used instead of EX62-1 in step 1 and 6-bromo-4-chloropyridine-3-carboxylate was used instead of methyl 6-bromo-2-fluoronicotinate in step 2. LCMS [M+H] + :569.3.

[0814] Step 4: EX89 was prepared as described in Example 59 (EX59), except that EX89-3 was used instead of EX89. 1 H NMR(400MHz,CD3OD)δ8.06(s,1H),7.60(d,J=7.7Hz,1H),7.54(t,J=8.0Hz, 1H),6.67(s,1H),6.38(d,J=8.1Hz,1H),4.00(t,J=6.4Hz,2H),3.86(t,J=6 .0Hz,2H),3.55-3.45(m,2H),3.38(s,2H),3.13-3.03(m,2H),2.90(s,3H), 2.20-2.04(m,2H),1.85-1.61(m,6H),1.45-1.38(m,2H),1.30-1.18(m,2H). LCMS[M+H] + :571.3.

[0815] Example 90 (EX90) and Example 91 (EX91)

[0816] [ka]

[0817] Step 1: EX91 was prepared as described in Example 74 (EX74) steps 1-2, except that EX89-2 was used instead of EX62-1 in step 1. 1 H NMR(400MHz,CD3OD)δ8.25(d,J=5.7Hz,1H),7.98(d,J=8.6Hz,1H),7.54(d,J=5.7 Hz,1H),7.27(d,J=2.1Hz,1H),7.20-7.12(m,1H),5.62-5.48(m,2H),3.96(t,J=6. 2Hz,2H),3.75(t,J=6.1Hz,2H),3.38(t,J=6.2Hz,2H),3.24-3.15(m,5H),3.13-3. 04(m,2H),2.55(d,J=11.6,7.1Hz,4H),2.20(d,J=14.9Hz,2H),1.81-1.70(m,2H). LCMS[M+H] + :569.3.

[0818] Step 2: EX90 was prepared as described in Example 59 (EX59), except that EX91 was used instead of EX52. 1 H NMR(400MHz,CD3OD)δ8.24(d,J=5.7Hz,1H),7.97(d,J=8.5Hz,1H),7.60(d,J=5.7H z,1H),7.16-7.08(m,2H),3.96(t,J=6.2Hz,2H),3.80(t,J=6.6Hz,2H),3.38(t,J= 6.2Hz,2H),3.22-3.12(m,2H),3.08-3.00(m,5H),2.28-2.15(m,2H),2.02-1.92(m ,2H),1.83-1.74(m,2H),1.74-1.67(m,2H),1.57-1.48(m,2H),1.42-1.31(m,2H). LCMS[M+H] + :571.3.

[0819] Example 92 (EX92-A and B)

[0820] [ka]

[0821] Step 1: EX92-1 was prepared as described in Example 48 (EX48) steps 1-2, except that EX81-5 was used instead of EX44-2 in step 1.

[0822] Step 2: EX92 was prepared as described in Example 82 (EX82), except that EX92-1 was used instead of EX72-1. LCMS [M+H] + :601.3.

[0823] Step 4: EX92-A (8.65 mg) and EX92-B (9.60 mg) were separated from EX92 by SFC. SFC analysis conditions: Column: Chiralcel OD-3, 50*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 4 mL / min; Column temperature: 35 °C.

[0824] EX92-A: 1 H NMR(400MHz,CD3OD)δ8.32(s,1H),7.58(t,J=8.0Hz,1H),7.46(d,J=7.8Hz,1 H),6.80(s,1H),6.54(d,J=8.3Hz,1H),4.21-4.14(m,1H),4.06-3.96(m,3H) ,3.88-3.78(m,2H),3.76-3.67(m,2H),3.65-3.58(m,2H),3.56-3.38(m,7H) ,3.19-3.09(m,2H),2.57-2.44(m,2H),2.07-1.98(m,1H),1.95-1.86(m,1H). LCMS[M+H] + :601.2. Retention time @SFC: 0.939 minutes.

[0825] EX92-B: 1 H NMR(400MHz,CD3OD)δ8.32(s,1H),7.58(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H) ,6.79(s,1H),6.53(d,J=8.3Hz,1H),4.21-4.12(m,1H),4.04-3.95(m,3H),3.8 7-3.78(m,2H),3.76-3.66(m,2H),3.65-3.57(m,2H),3.56-3.36(m,7H),3.19- 3.07(m,2H),2.58-2.44(m,2H),2.01(d,J=15.0Hz,1H),1.91(d,J=14.7Hz,1H). LCMS[M+H] + :601.2. Retention time @SFC: 1.240 minutes.

[0826] Example 93 (EX93-A and B)

[0827] [ka]

[0828] Step 1: EX93 was prepared as described in Example 74 (EX74) steps 1-2, except that EX81-5 was used instead of EX62-1 in step 1. LCMS [M+H] + :601.1.

[0829] Step 2: EX93-A (8.65 mg) and EX93-B (9.60 mg) were separated from EX93 by SFC. SFC analysis conditions: Column: Cellulose 2,100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.8 mL / min; Column temperature: 35 °C.

[0830] EX93-A: 1H NMR(400MHz,CD3OD)δ8.27(d,J=5.6Hz,1H),8.08(d,J=8.6Hz,1H),7.54(d,J=5.6Hz,1H ),7.28(d,J=2.1Hz,1H),7.20-7.14(m,1H),4.18-4.10(m,1H),4.00-3.94(m,3H),3.92 -3.81(m,3H),3.81-3.74(m,1H),3.73-3.63(m,2H),3.59(d,J=9.1Hz,1H),3.51-3.45( m,2H),3.39(t,J=6.3Hz,2H),3.20-3.08(m,4H),2.64-2.44(m,2H),2.05-1.90(m,2H). LCMS[M+H] + :601.3. Hold time @SFC:2.993 minutes.

[0831] EX93-B: 1 H NMR(400MHz,CD3OD)δ8.27(d,J=5.6Hz,1H),8.07(d,J=8.6Hz,1H),7.54(d,J=5.6Hz,1H) ,7.27(d,J=2.1Hz,1H),7.17(dd,J=8.6,2.1Hz,1H),4.19-4.11(m,1H),4.00-3.93(m,3H ),3.91-3.82(m,3H),3.80-3.74(m,1H),3.73-3.63(m,2H),3.62-3.56(m,1H),3.51-3.4 5(m,2H),3.38(t,J=6.3Hz,2H),3.18-3.08(m,4H),2.65-2.42(m,2H),2.05-1.90(m,2H). LCMS[M+H] + :601.2. Hold time @SFC:3.599 minutes.

[0832] Example 94 (EX94)

[0833]

change

[0834] Project 1: To a solution of EX62-1 (2 g, 5.64 mmol) and 2,6-dichloropyrimidin-4-amine (1.85 g, 11.29 mmol) in n-BuOH (100 mL) was added DIEA (2.8 mL, 16.93 mmol) under N2 atmosphere. The mixture was stirred at 120 °C for 2 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX94-1. LCMS [M+H] + :482.2,484.1.

[0835] Step 2: EX94 was prepared as described in Example 74 (EX74) step 2, except that EX94-1 was used instead of EX74-1. 1 H NMR(400MHz,CD3OD)δ8.12(dd,J=8.7,1.7Hz,1H),7.56(s,1H),7.31(t,J=2.1Hz,1H),7.22-7.15(m,1H),3.96(t,J=6.2Hz,2H),3.90(t,J=7.3 Hz,2H), 3.49(t,J=5.2Hz,2H),3.44(s,2H),3.39(t,J=6.2Hz,2H),3.10(s,7H),2.72-2.58(m,2H),1.95(d,J=14.6Hz,2H),1.90-1.80(m,2H). LCMS[M+H] + :607.2.

[0836] Example 95 (EX95)

[0837] [ka]

[0838] Step 1: To a solution of 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate (50 g, 205.51 mmol) in THF (800 mL) was added LDA (123.3 mL, 246.61 mmol) under N protection at −78° C. The mixture was stirred at −78° C. for 1 h. Then, formaldehyde (11.3 mL, 411 mmol) was added at −78° C. The mixture was stirred at 25° C. for 3 h. The mixture was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX95-1.

[0839] Step 2: To a solution of DMSO (26.0 mL, 365.9 mmol) in DCM (170 mL) was added (COCl) (15.5 mL, 182.9 mmol) in DCM (170 mL) at −78° C. over 20 min, and the reaction was warmed to −60° C. over 25 min. EX95-1 (25 g, 91.5 mmol) in DCM (300 mL) was then added slowly, and the resulting mixture was warmed to −45° C. After stirring at −45° C. for 1 h, TEA (101.4 mL, 731.8 mmol) was added, and the reaction was warmed to 0° C. over 1 h. The reaction was quenched with saturated aqueous NaHCO (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX95-2. LCMS [M-Boc+H] + :172.1.

[0840] Step 3: To a solution of EX95-2 (18 g, 66.34 mmol) in DCM (400 mL) was added DAST (21.4 g, 132.7 mmol) at 0 °C, and the reaction was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO (200 mL) and extracted with DCM (200 mL × 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX95-3.

[0841] Step 4: EX95-4 was prepared as described in Example 17 (EX17) steps 2-3, except that EX95-3 was used instead of EX17-1 in step 2. LCMS [M- t Bu+H] + :268.1.

[0842] Step 5: EX95-5 was prepared as described in Example 4 (EX04) steps 1-2, except that EX95-4 was used instead of EX01-2 in step 1. LCMS [M+H] + :337.1.

[0843] Step 6: EX95 was prepared as described in Example 74 (EX74), except that EX95-5 was used instead of EX62-1 in step 1. 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.22(d,J=5.6Hz,1H),8.03-7.96(m,1H),7.41(d,J=5.6Hz,1H),7.20(s,1H),7.13-7.06(m,1H),6 .31(t,J=55.1Hz,1H),3.82-3.72(m,4H),3.39-3.33(m,4H),3.30-3.26(m,2H),3.00-2.97(m,7H),2.43-2.33(m,2H),1.74-1.68(m,4H). LCMS[M+H] + :555.3.

[0844] Example 96 (EX96-A and B)

[0845] [ka]

[0846] Step 1: To a solution of EX81-5 (1.8 g, 4.71 mmol) and 2-chloro-6-methylpyrimidin-4-amine (1.0 g, 7.06 mmol) in NMP (18 mL) was added DIEA (2.3 mL, 14.1 mmol) under N2 atmosphere. The mixture was stirred at 140 °C for 2 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX96-1. LCMS [M+H] + :490.3.

[0847] Step 2: EX96-2 was prepared as described in Example 1 (EX01) step 4, except that EX96-1 was used instead of EX01-3.

[0848] Step 3: To a solution of EX96-2 (1.4 g, 3.60 mmol) and methyl 2-fluoro-4-iodobenzoate (1.5 g, 5.39 mmol) in DMF (15 mL) was added K2CO3 (1.5 g, 10.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 120 °C for 18 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX96-3. LCMS [M+H] + :650.2.

[0849] Step 4: To a solution of EX96-3 (640 mg, 0.99 mmol) in MeOH (20 mL) was added NaOH (1 M, 9.9 mL, 9.85 mmol). The resulting mixture was stirred at 50 °C for 3 h. The reaction was concentrated under reduced pressure and then neutralized (pH = 7) with aqueous HCl (1 M). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give EX96-4. LCMS [M+H] + :636.2.

[0850] Step 5: To a solution of EX96-4 (260 mg, 0.41 mmol) in DCM (30 mL) was added POCl (114 μL, 1.23 mmol) and pyridine (1981 μL, 24.5 mmol), and the reaction was stirred at 40° C. for 3 h. The reaction was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX96-5. LCMS [M+H] + :618.2.

[0851] Step 6: To a solution of EX96-5 (165 mg, 0.27 mmol) and 2-hydroxyethane-1-sulfonamide (167 mg, 1.34 mmol) in DMF (5 mL) was added CsCO (435 mg, 1.34 mmol), DMEDA (18 mg, 0.13 mmol), and CuI (10.2 mg, 0.053 mmol) under a N atmosphere. The reaction was stirred at 100 °C for 18 h. The reaction was quenched with saturated aqueous NHCl (30 mL). The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by preparative HPLC to give EX96. LCMS [M+H] + :615.4.

[0852] Step 7: EX96-A (8.59 mg) and EX96-B (10.09 mg) were separated from EX96 by SFC. SFC analysis conditions: Column: Cellulose-4, 100*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.8 mL / min; Column temperature: 40 °C.

[0853] EX96-A: 1H NMR(400MHz,CD3OD)δ8.07(d,J=8.7Hz,1H),7.44(s,1H),7.27(d,J=2.2Hz,1H),7.17 (dd,J=8.6,2.1Hz,1H),4.18-4.10(m,1H),3.98-3.90(m,5H),3.87-3.80(m,1H),3.7 9-3.69(m,2H),3.68-3.61(m,1H),3.59(d,J=9.1Hz,1H),3.50-3.44(m,2H),3.38(t, J=6.2Hz,2H),3.19-3.08(m,4H),2.63-2.46(m,2H),2.37(s,3H),2.03-1.90(m,2H). LCMS[M+H] + :615.3. Holding time @SFC:2.252 minutes.

[0854] EX96-B: 1 H NMR(400MHz,CD3OD)δ8.07(d,J=8.6Hz,1H),7.44(s,1H),7.26(d,J=2.2Hz,1H),7.16(dd, J=8.6,2.2Hz,1H),4.14(d,J=12.2Hz,1H),4.00-3.89(m,5H),3.87-3.80(m,1H),3.79-3. 73(m,1H),3.73-3.69(m,1H),3.68-3.62(m,1H),3.59(d,J=9.1Hz,1H),3.51-3.45(m,2H) ,3.40-3.37(m,2H),3.21-3.08(m,4H),2.62-2.47(m,2H),2.37(s,3H),2.06-1.88(m,2H). LCMS[M+H] + :615.3. Holding time @SFC:2.480 minutes.

[0855] Example 97 (EX97)

[0856]

change

[0857] Project 1: EX97 was prepared as described in Example 1 (EX01) steps 4-8, except that EX82-1 was used instead of EX01-3 in step 4 and ethanesulfonamide was used instead of 2-hydroxyethane-1-sulfonamide in step 8. 1 H NMR(400MHz,DMSO-d6)δ8.29(s,1H)7.47-7.56(m,1H)7.37(d,J=7.92Hz,1H)6.63(s,1H)6.32(d,J=8.14Hz,1H)3.80-3.86(m,2H)3.2 0-3.37(m,8H)2.90(t,J=11.66Hz,2H)2.81(s,3H)2.31-2.41(m,2H)1.81(d,J=14.09Hz,2H)1.65-1.74(m,2H)1.20(t,J=7.37Hz,3H). LCMS[M+H] + :557.3.

[0858] Example 98 (EX98)

[0859] [ka]

[0860] Step 1: EX98-1 was prepared as described in Example 89, Step 3, except that ethanesulfonamide was used instead of 2-hydroxyethane-1-sulfonamide. LCMS [M+H] + :553.1.

[0861] Step 2: EX98 was prepared as described in Example 59 (EX59), except that EX98-1 was used instead of EX52. 1H NMR(400MHz,CD3OD)δ8.18-8.00(m,1H),7.61(d,J=7.8Hz,1H),7.54(t,J=8.0Hz,1H),6.64(s,1H),6.38(d,J=8.2Hz,1H),3. 89-3.83(m,2H),3.52-3.43(m,2H),3.10-3.03(m,2H),2.89(s,3H),2.15-2.07(m,2H),1.79-1.62(m,6H),1.42-1.30(m,9H). LCMS[M+H] + :555.1.

[0862] Example 99 (EX99)

[0863] [ka]

[0864] Step 1: To a solution of EX62-1 (1.6 g, 4.5 mmol) and 4,6-dichloro-2-fluoropyridine (0.8 g, 5 mmol) in NMP (20 mL) was added DIEA (3.7 mL, 22.6 mmol) under N2 atmosphere. The reaction mixture was stirred at 140 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX99-1. LCMS [M+H] + :500.2,502.1.

[0865] Step 2: EX99 was prepared as described in Example 61 (EX61) steps 2-3, except that EX99-1 was used instead of EX61-1 in step 2. 1H NMR(400MHz,CD3OD)δ8.10(d,J=8.7Hz,1H),7.68(d,J=1.5Hz,1H),7.27(d,J=2.2Hz,1H),7.16(dd,J=8.6,2.2Hz,1H),6.36(d,J=1.4Hz,1H),3. 99-3.93(m,4H),3.49-3.45(m,2H),3.43-3.36(m,4H),3.16-3.06(m,4H ),2.93(s,3H),2.72-2.61(m,2H),1.98-1.90(m,2H),1.87-1.77(m,2H). LCMS[M+H] + :606.3.

[0866] Example 100 (EX100-A and B)

[0867] [ka]

[0868] Step 1: EX100-1 was prepared as described in Example 34 (EX34), step 3, except that EX79-2 was used instead of EX34-2. LCMS [M- t Bu+H] + :298.0.

[0869] Step 2: EX100-2 was prepared as described in Example 20 (EX20) steps 3-4, except that EX100-1 was used instead of EX20-2 in step 3. LCMS [M+H] + :353.1.

[0870] Step 3: EX100 was prepared as described in Example 92 (EX92) steps 1-2, except that EX100-2 was used instead of EX81-5. LCMS [M+H] + :571.4.

[0871] Step 4: EX100-A (25.53mg) EX100-B (24.54mg), SFC EX100 separated. SFC analysis conditions: カラム: Chiralcel OD-3, 150*4.6mm, 3.0μm; mobile phase A: supercritical CO2, mobile phase B: メタノール (0.05%DEA), 40% mobile phase B, 5 minutes; flow rate: 2.5mL / min; カラム temperature: 35°C.

[0872] EX100-A: 1 H NMR(400MHz,CD3OD)δ8.07(s,1H),7.48(d,J=7.7Hz,1H),7.36(t,J=8.0Hz,1H ),6.68(s,1H),6.27(d,J=8.1Hz,1H),4.00(t,J=6.4Hz,2H),3.74-3.66(m,1H ),3.50-3.38(m,5H),3.12-3.02(m,2H),2.20-2.07(m,2H),1.89-1.70(m,4H) ,1.56-1.46(m,2H),1.36-1.28(m,2H),1.25-1.16(m,1H),1.06-1.00(m,3H). LCMS[M+H] + 571.3. Duration @SFC: 2.980 minutes.

[0873] EX100-B: 1 H NMR(400MHz,CD3OD)δ8.07(s,1H),7.48(d,J=7.7Hz,1H),7.36(t,J=8.0Hz,1H), 6.68(s,1H),6.27(d,J=8.2Hz,1H),4.00(t,J=6.4Hz,2H),3.77-3.65(m,1H),3.5 0-3.38(m,5H),3.07(t,J=12.7Hz,2H),2.14(t,J=14.6Hz,2H),1.92-1.69(m,4H) ,1.57-1.45(m,2H),1.35-1.28(m,2H),1.26-1.16(m,1H),1.02(d,J=6.9Hz,3H). LCMS[M+H] + 571.3. Duration @SFC: 4.530 minutes.

[0874] Example 101 (EX101-AおよびB)

[0875] [ka]

[0876] Step 1: EX101 was prepared as described in Example 100 (EX100), Step 3, except that ethanesulfonamide was used instead of 2-hydroxyethane-1-sulfonamide. LCMS [M+H] + :555.3.

[0877] Step 2: EX101-A (14.34 mg) and EX101-B (15.39 mg) were separated from EX101 by SFC. SFC analysis conditions: Column: Chiralcel OD-3, 150*4.6 mm, 3.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (0.05% DEA), 40% Mobile phase B, 5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C.

[0878] EX101-A: 1 H NMR(400MHz,CD3OD)δ8.07(s,1H),7.39-7.30(m,2H),6.50(s,1H),6.25(dd,J=7.7,1.2Hz,1H),3.33-3.21(m,6H),2.94-2.83 (m,2H),2.05-1.95(m,2H),1.76-1.59(m,4H),1.44-1.33(m,2H),1.25-1.16(m,5H),1.11-1.00(m,1H),0.91(d,J=6.9Hz,3H). LCMS[M+H] + :555.3. Retention time @SFC: 2.448 minutes.

[0879] EX101-B: 1H NMR(400MHz,CD3OD)δ8.15-7.95(m,1H),7.40-7.30(m,2H),6.50(s,1H),6.25(d,J=7.8Hz,1H),3.35-3.20(m,6H),2.94-2.84 (m,2H),2.04-1.95(m,2H),1.75-1.61(m,4H),1.46-1.33(m,2H),1.25-1.18(m,5H),1.11-1.03(m,1H),0.92(d,J=6.9Hz,3H). LCMS[M+H] + :555.3. Retention time @SFC: 3.717 minutes.

[0880] Example 102 (EX102-A and B)

[0881] [ka]

[0882] Step 1: To a solution of EX95-3 (3 g, 10.23 mmol) in DCM (150 mL) was added DIBAL-H (1 M, 20.5 mL, 20.46 mmol) under a N atmosphere at −78° C. The mixture was stirred at −78° C. for 3 h. MeOH (80 mL) was added to the mixture at −78° C., followed by saturated aqueous potassium sodium tartrate solution. The resulting mixture was stirred until the mixture became a clear solution. The mixture was extracted with DCM (300 mL × 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by flash silica gel chromatography to give EX102-1.

[0883] Step 2: EX102 was prepared as described in Example 79 (EX79) steps 1-4, except that EX102-1 was used instead of EX60-1 in step 1. LCMS [M+H] + :552.4.

[0884] Step 3: EX102-A (40.79mg) EX102-B (40.40mg), SFC EX102 separated. SFC analysis conditions: カラム: ChiralCel OJ-H, 150*4.6mm, 5.0μm; mobile phase A: supercritical CO2, mobile phase B: メタノール (0.05%DEA), 5%~40% mobile phase B, 8 minutes; flow rate: 2.5mL / min; カラム temperature: 40°C.

[0885] EX102-A: 1 H NMR (400MHz, CD3OD) δ7.98(d,J=8.6Hz,1H),7.50(d,J=7.7Hz,1H),7.36(t,J=8.0Hz,1H),7.14(d,J=2 .1Hz,1H),7.09(dd,J=8.6,2.2Hz,1H),6.28(d,J=8.1Hz,1H),5.94(t,J=56.4Hz,1H),3.96(t,J=6.3H z,2H),3.51-3.47(m,2H),3.39-3.36(m,2H),3.19-3.12(m,2H),3.09-2.97(m,2H),2.33-2.14(m,2H) ,1.86-1.70(m,4H),1.64-1.53​​(m,1H),1.49-1.42(m,1H),1.38-1.24(m,3H),1.03(d,J=6.9Hz,3H). LCMS[M+H] + 552.4. Hold time @SFC: 4.678 minutes.

[0886] EX102-B: 1H NMR(400MHz,CD3OD)δ7.98(d,J=8.6Hz,1H),7.50(dd,J=7.8,0.8Hz,1H),7.36(t,J=8.0Hz,1H),7.14(d,J =2.2Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),6.28(dd,J=8.2,0.8Hz,1H),5.94(t,J=56.5Hz,1H),3.96(t,J=6 .3Hz,2H),3.49(t,J=4.5Hz,2H),3.38(t,J=6.3Hz,2H),3.19-3.10(m,2H),3.10-2.95(m,2H),2.32-2.13( m,2H),1.87-1.71(m,4H),1.64-1.53(m,1H),1.50-1.40(m,1H),1.37-1.21(m,3H),1.03(d,J=6.9Hz,3H). LCMS[M+H] + :552.3. Retention time@SFC:5.011 minutes.

[0887] Example 103 (EX103)

[0888] [ka]

[0889] Step 1: EX103 was prepared as described in Example 56 (EX56), steps 1-3, except that EX60-3 was used instead of EX55-1 in step 1. 1H NMR(400MHz,CD3OD)δ7.98(d,J=8.5Hz,1H),7.46(d,J=7.7Hz,1H),7.36(t,J=7.9Hz,1H),7. 16-7.08(m,2H),6.22(d,J=8.1Hz,1H),3.96(t,J=6.2Hz,2H),3.59(t,J=6.5Hz,2H),3.38(t ,J=6.2Hz,2H),3.17(d,J=7.9Hz,2H),3.02(t,J=12.2Hz,2H),2.35-2.21(m,2H),1.98(d,J= 15.1Hz,2H),1.75-1.59(m,4H),1.53(dd,J=10.7,5.4Hz,2H),1.44(dd,J=12.7,5.9Hz,2H). LCMS[M+H] + :556.3.

[0890] Example 104. (EX104)

[0891] [ka]

[0892] Step 1: EX104-1 was prepared as described in Example 4 (EX04) steps 1-2, except that EX60-3 was used instead of EX01-2 in step 1.

[0893] Step 2: EX104-2 was prepared as described in Example 48 (EX48) steps 1-2, except that EX104-1 was used instead of EX44-2 in step 1.

[0894] Step 3: EX104-2 was prepared as described in Example 1 (EX01) step 4, except that EX104-2 was used instead of EX01-3.

[0895] Step 4: To a solution of EX104-3 (500 mg, 1.45 mmol) and methyl 4-bromo-2,5-difluorobenzoate (547 mg, 2.18 mmol) in CAN (5 mL) was added DIEA (3.6 mL, 21.8 mmol). The reaction was stirred at 90 °C for 48 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel chromatography to give EX104-4. LCMS [M+H] + :575.2,577.2.

[0896] Step 5: EX104 was prepared as described in Example 1 (EX01) steps 6-8, except that EX104-4 was used instead of EX01-5. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),7.76(d,J=11.7Hz,1H),7.57-7.47(m ,2H),7.36(d,J=7.1Hz,1H),6.35(d,J=8.0Hz,1H),3.81-3.75(m,4H),3.35 (t,J=6.3Hz,2H),3.09-3.00(m,2H),2.90-2.79(m,5H),2.21-2.10(m,2H), 1.98-1.89(m,2H),1.69-1.51(m,4H),1.47-1.38(m,2H),1.32-1.23(m,2H). LCMS[M+H] + :588.3.

[0897] Example 105. (EX105-A and B)

[0898] [ka]

[0899] Step 1: EX105-1 was prepared as described in Example 48 (EX48) steps 1-2, except that EX100-2 was used instead of EX44-2 in step 1.

[0900] Step 2: EX105 was prepared as described in Example 104 (EX104, steps 3-5), except that EX105-1 was used instead of EX104-2 in step 3.

[0901] Step 3: EX105-A (13.67 mg) and EX105-B (24.45 mg) were separated from EX105 by SFC. SFC analysis conditions: Column: ChiralPak AY-3 100 × 4.6 mm ID, 3 μm; Mobile phase A: supercritical CO2, Mobile phase B: IPA (0.05% DEA), 40% Mobile phase B, 8 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C.

[0902] EX105-A: 1 H NMR(400MHz,CD3OD)δ7.84(d,J=11.8Hz,1H),7.54(d,J=7.2Hz,1H),7.48(d,J=7.7Hz,1H),7. 37(t,J=8.0Hz,1H),6.30(d,J=8.1Hz,1H),3.98(t,J=6.2Hz,2H),3.60-3.52(m,1H),3.41(t,J =6.3Hz,2H),3.17-3.10(m,2H),3.09-2.97(m,2H),2.42-2.22(m,2H),2.06-1.94(m,2H),1.84 -1.71(m,2H),1.71-1.56(m,2H),1.54-1.43(m,1H),1.43-1.23(m,3H),1.04(d,J=6.8Hz,3H). LCMS[M+H] + :588.3. Retention time @SFC: 1.877 minutes.

[0903] EX105-B: 1H NMR(400MHz,CD3OD)δ7.84(d,J=11.8Hz,1H),7.54(d,J=7.1Hz,1H),7.48(d,J=7.7Hz,1H), 7.37(t,J=8.0Hz,1H),6.30(d,J=8.1Hz,1H),4.00-3.97(m,2H),3.59-3.53(m,1H),3.42-3. 40(m,2H),3.16-3.11(m,2H),3.08-2.97(m,2H),2.41-2.23(m,2H),2.04-1.98(m,2H),1.8 3-1.73(m,2H),1.67-1.57(m,2H),1.55-1.47(m,1H),1.41-1.36(m,3H),1.06-1.03(m,3H). LCMS[M+H] + :588.3. Retention time @SFC:5.983.

[0904] Example 106 (EX106)

[0905] [ka]

[0906] Step 1: To a solution of cis-cyclohexane-1,3-dicarboxylic acid (15 g, 87.1 mmol) in THF (45 mL) was added BH (1 M in THF, 192 mL, 191.6 mmol) at 0 °C under a N atmosphere, and the reaction was stirred at 25 °C for 18 h. The reaction was quenched with water (60 mL) and MeOH (210 mL). The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (200 mL × 3). The combined organic layers were dried over MgSO, concentrated in vacuo, and purified by silica gel chromatography to give EX106-1.

[0907] Step 2: To a solution of EX106-1 (8.4 g, 58.25 mmol) in DMF (80 mL) was added imidazole (7.9 g, 116.5 mmol) and TBDPSCl (15.11 mL, 58.25 mmol). The reaction was stirred at 25° C. for 2 hours. The reaction was extracted with brine and EtOAc. The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography to give EX106-2. LCMS [M+H] + :383.2.

[0908] Step 3: To a solution of EX106-2 (90 mg, 0.235 mmol) in DMF was added NaH (8.5 mg, 0.353 mmol) at 0° C., and the resulting mixture was stirred for 1 h, followed by the addition of 2-methylpropan-2-yl 2,2-dioxo-2λ6-1,2,3-oxathiazolidine-3-carboxylate (78.8 mg, 0.353 mmol). The reaction was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The organic layer was washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give EX106-3. LCMS [M+H] + :526.5.

[0909] Step 4: To a solution of EX106-3 (3500 mg, 6.657 mmol) in DMF (30 mL) was added NaH (239.6 mg, 9.985 mmol) at 0° C., and the resulting mixture was stirred for 1 h, followed by the addition of 4-(chloromethyl)-1-methoxybenzene (2084.8 mg, 13.313 mmol). The reaction was stirred at 25° C. for 2 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel chromatography to give EX106-4. LCMS [M+H] + :646.7.

[0910] Step 5: To a solution of EX106-4 (2700 mg, 4.180 mmol) in THF (30 mL) was added TBAF (3278.9 mg, 12.539 mmol). The reaction was stirred at 25° C. for 2 h, quenched with aqueous NH4Cl, and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel chromatography to give EX106-5. LCMS [M+H] + :246.9.

[0911] Step 6: To a solution of EX106-5 (1300 mg, 3.189 mmol) and PPh3 (1673.2 mg, 6.379 mmol) in THF (2 mL) was added methyl 2-hydroxy-4-iodobenzoate (34.2 mg, 0.123 mmol) and DIAD (1289.8 mg, 6.379 mmol). The reaction was stirred at 25 °C overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give EX106-6. LCMS [M+H] + :668.2.

[0912] Step 7: To a solution of EX106-6 (1100 mg, 1.648 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at 25° C. for 2 hours. The reaction mixture was evaporated under reduced pressure to give EX106-7. LCMS [M+H] + :568.2.

[0913] Step 8: To a solution of EX106-7 (800 mg, 1.41 mmol) in DMSO (10 mL) was added DIEA (0.70 mL, 4.229 mmol) and 2-chloro-6-methylpyrimidin-4-amine (404.9 mg, 2.81 mmol). The reaction was stirred at 120° C. for 48 hours. The reaction was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give EX106-8. LCMS [M+H]+ :675.3.

[0914] Step 9: EX106-9 was prepared as described in Example 1 (EX01) steps 6-7, except that EX106-8 was used instead of EX01-5 in step 6.

[0915] Step 10: EX106 was prepared as described in Example 12 (EX12), steps 5-6, except that EX106-9 was used instead of EX12-4 in step 5. 1 H NMR(400MHz,CD3OD)δ7.88(d,J=8.6Hz,1H),7.42(s,1H),7.06(d,J=1.9Hz,1H),6.96(dd,J=8.5,1.9Hz, 1H),4.05-3.92(m,4H),3.70(dt,J=12.1,5.3Hz,2H),3.51(dd,J=10.4,4.1Hz,1H),3.40(t,J=6.2Hz,3H) ,3.24(t,J=10.1Hz,1H),2.63(d,J=12.6Hz,1H),2.33(s,3H),1.86(d,J=12.8Hz,3H),1.72(d,J=13.5Hz ,1H),1.57(d,J=13.1Hz,1H),1.49-1.40(m,1H),1.31(s,1H),1.17-1.05(m,1H),0.91(q,J=12.0Hz,2H). LCMS[M+H] + :520.3.

[0916] Example 107. (EX107-A and B)

[0917] [ka]

[0918] Step 1: EX107-2 was prepared as described in Example 61 (EX61) steps 1-2, except that in step 1, EX107-1 was used instead of EX44-2 and 2-bromo-6-fluoropyridine was used instead of 2-bromo-3,6-difluoropyridine.

[0919] Step 2: EX107 was prepared as described in Example 20 (EX20), steps 6-8, except that EX107-2 was used instead of EX20-5 in step 6.

[0920] Step 3: EX107-A (16.89 mg) and EX107-B (23.56 mg) were separated from EX105 by SFC. SFC analysis conditions: Column: (S,S) Whelk-01 100 × 4.6 mm ID, 5.0 μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (0.05% DEA), 50% Mobile phase B, 8 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C.

[0921] EX107-A: 1 H NMR(400MHz,CD3OD)δ8.05(d,J=8.6Hz,1H),7.46(d,J=7.7Hz,1H),7.36(t,J=7.9Hz,1H),7.24(d,J=2.2Hz,1H),7.15( dd,J=8.6,2.1Hz,1H),6.22(d,J=8.0Hz,1H),4.84-4.73(m,2H),3.96(t,J=6.2Hz,2H),3.63-3.53(m,2H),3.49-3.41( m,1H),3.38(t,J=6.3Hz,2H),3.29-3.18(m,3H),3.10(d,J=11.9Hz,1H),2.91(t,J=12.8Hz,1H),2.85-2.74(m,1H),2. 61-2.49(m,1H),2.05(dd,J=14.7,2.6Hz,1H),1.77(dd,J=14.6,2.6Hz,1H),1.72-1.62(m,2H),1.17(d,J=6.8Hz,3H). LCMS[M+H] + :572.1. Retention time @SFC: 1.665 minutes.

[0922] EX107-B: 1 H NMR(400MHz,CD3OD)δ8.03(d,J=8.5Hz,1H),7.47-7.41(m,1H),7.38-7.31(m,1H),7.22(d,J=1.4Hz,1H),7.13( d,J=8.6Hz,1H),6.20(d,J=8.0Hz,1H),4.81-4.73(m,2H),3.94(t,J=6.2Hz,2H),3.54(d,J=8.5Hz,2H),3.46-3 .40(m,1H),3.36(t,J=6.2Hz,2H),3.27-3.18(m,3H),3.08(d,J=10.4Hz,1H),2.89(t,J=12.8Hz,1H),2.82-2.7 2(m,1H),2.60-2.47(m,1H),2.03(d,J=14.6Hz,1H),1.75(d,J=14.5Hz,1H),1.66(s,2H),1.15(d,J=6.8Hz,3H). LCMS[M+H] + :572.3. Retention time @SFC: 1.970 minutes.

[0923] Example 108 (EX108)

[0924] [ka]

[0925] Step 1: EX108-1 was prepared as described in Example 28 (EX28) steps 1-5, except that in step 1, EX17-2 was used instead of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate.

[0926] Step 2: EX108-2 was prepared as described in Example 61 (EX61) step 1, except that EX108-1 was used instead of EX44-2 and 2-bromo-6-fluoropyridine was used instead of 2-bromo-3,6-difluoropyridine.

[0927] Step 3: To a solution of EX108-2 (700 mg, 1.32 mmol) in THF (20 mL) was added NaH (263.0 mg, 6.57 mmol) under N protection. The mixture was stirred at 25° C. for 0.5 h, followed by the addition of iodomethane (559.7 mg, 3.94 mmol). The resulting mixture was stirred at 60° C. for 1.5 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over MgSO, concentrated in vacuo, and purified by silica gel chromatography to give EX108-3. LCMS [M+H] + :546.0.

[0928] Step 4: EX108 was prepared as described in Example 61 (EX61) steps 2-3, except that EX108-3 was used instead of EX61-1 in step 2. 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.00(d,J=8.6Hz,1H),7.67-7.55(m,2H ),7.19(s,1H),7.13-7.06(m,1H),6.43(d,J=7.9Hz,1H),4.35(t,J=15.7Hz,2 H),3.73(dd,J=12.5,6.1Hz,4H),3.49(s,2H),3.33(t,J=6.4Hz,2H),3.07(s, 2H),2.99(s,3H),2.93(d,J=12.7Hz,2H),2.44(s,2H),1.89(d,J=14.0Hz,2H). LCMS[M+H] + :608.2.

[0929] Example 109. (EX109)

[0930] [ka]

[0931] Step 1: EX109 was prepared as described in Example 61 (EX61) steps 2-3, except that EX108-2 was used instead of EX61-1 in step 2. 1H NMR(400MHz,CD3OD)δ8.02(d,J=8.6Hz,1H),7.56(d,J=7.7Hz,1H),7.44(t,J=8.0Hz,1H),7 .21(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),6.33(d,J=8.1Hz,1H),4.11(t,J=14.0Hz ,2H),3.96(t,J=6.2Hz,2H),3.71(t,J=11.7Hz,2H),3.53(s,2H),3.39(t,J=6.2Hz,2H),3. 18(t,J=8.2Hz,2H),3.09(t,J=12.7Hz,2H),2.64(t,J=12.8Hz,2H),1.93(d,J=14.6Hz,2H). LCMS[M+H] + :594.2.

[0932] Example 110 (EX110)

[0933] [ka]

[0934] Step 1: EX110 was prepared as described in Example 72 (EX72), except that EX95-5 was used instead of EX62-1 in step 1. 1 H NMR(400MHz,CD3OD)δ8.08(d,J=8.6Hz,1H),7.59(d,J=7.7Hz,1H),7.52(t,J=8.0Hz, 1H),7.26(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.2Hz,1H),6.34(d,J=8.1Hz,1H),6.15( t,J=55.6Hz,1H),4.01-3.90(m,4H),3.48-3.42(m,2H),3.42-3.37(m,2H),3.36-3.3 4(m,2H),3.14-3.05(m,4H),2.96-2.89(m,3H),2.68-2.55(m,2H),1.83-1.74(m,4H). LCMS[M+H] + :554.3.

[0935] Example 111 (EX111-A and B)

[0936] [ka]

[0937] Step 1: To a solution of methyl 2-(morpholin-2-yl)acetate (HCl salt, 50 g, 255.62 mmol) in DCM (500 mL) was added TEA (177.2 mL, 1278.12 mmol) and CbzCl (43.2 mL, 306.75 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction was diluted with water (300 mL) and extracted with DCM (300 mL × 3). The combined organic layer was dried over MgSO4 and purified by silica gel chromatography to give EX111-1. LCMS [M-44+H] + :250.1.

[0938] Step 2: To a solution of EX111-1 (20 g, 68.19 mmol) in THF (600 mL) was added Super-H (1 M, 200 mL, 200 mmol) under N2 atmosphere at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with MeOH (500 mL) and concentrated under reduced pressure. Saturated NH4Cl (500 mL) was added, and the mixture was extracted with EtOAc (500 mL x 3). The combined organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX111-2. LCMS [M-44+H] + :222.2.

[0939] Step 3: To a solution of EX111-2 (40 g, 150.77 mmol) and PPh3 (47.5 g, 180.93 mmol) in DCM (800 mL) was added a solution of CBr4 (75 g, 226.16 mmol) in DCM (400 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to give EX111-3. LCMS [M-44+H] + :284.0,286.0.

[0940] Step 4: A solution of EX111-3 (43 g, 131.02 mmol) and PPh3 (34.4 g, 131.02 mmol) in toluene (600 mL) was stirred at 120 °C for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to give EX111-4. LCMS [M+H] + :510.3.

[0941] Step 5: To a solution of EX111-4 (12 g, 23.5 mmol) in THF (125 mL) was added NaHMDS (1 M, 32 mL, 32.05 mmol) under N2 atmosphere at -78 °C. The mixture was stirred at -78 °C for 1 h, followed by the dropwise addition of a solution of EX60-1 (6 g, 21.37 mmol) in THF (25 mL) at -78 °C. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX111-5. LCMS [M-Boc+H] + :413.1.

[0942] Step 6: To a solution of EX111-5 (8.5 g, 16.58 mmol) in EtOAc (150 mL) was added Pd / C (6 g, 10% purity) under N atmosphere. The mixture was stirred at 25 °C for 12 h under H atmosphere. The reaction mixture was filtered through Celite, washed with EtOAc (200 mL), and concentrated under reduced pressure to give EX111-6. LCMS [M+H] + :381.1.

[0943] Step 7: EX111 was prepared as described in Example 81 (EX81) step 6, except that EX111-6 was used instead of EX81-5.

[0944] Step 8: EX111-A (16.44mg) EX111-B (18.05mg), SFC EX111 separated. SFC analysis conditions: カラム:Column:Column:(S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase A: supercritical CO2, mobile phase B: エタノール (0.05%DEA), 50% mobile phase B, 8 minutes; flow rate: 2.5mL / min; KLA temperature: 40°C.

[0945] EX111-A: 1 H NMR(400MHz,CD3OD)δ8.16(d,J=8.7Hz,1H),7.42(s,1H),7.27(d,J=2.2Hz,1H),7.20 (dd,J=8.7,2.1Hz,1H),4.74-4.69(m,1H),4.46-4.39(m,1H),3.96(t,J=6.2Hz,2H), 3.93-3.88(m,1H),3.64-3.54(m,2H),3.38(t,J=6.1Hz,3H),3.18-3.00(m,5H),2.47 -2.39(m,1H),2.36(s,3H),2.32-2.20(m,2H),2.16-2.07(m,1H),1.78-1.55(m,6H). LCMS[M+H] + :613.2. Hold time @SFC:2.713 minutes.

[0946] EX111-B: 1 H NMR(400MHz,CD3OD)δ8.16(d,J=8.7Hz,1H),7.42(s,1H),7.27(d,J=2.2Hz,1H),7.20 (dd,J=8.7,2.2Hz,1H),4.75-4.68(m,1H),4.46-4.39(m,1H),3.96(t,J=6.2Hz,2H), 3.93-3.88(m,1H),3.64-3.55(m,2H),3.38(t,J=6.2Hz,3H),3.18-2.99(m,5H),2.47 -2.38(m,1H),2.36(s,3H),2.33-2.19(m,2H),2.14-2.05(m,1H),1.77-1.58(m,6H). LCMS[M+H] + :613.2. Hold time @SFC: 3.279 minutes:

[0947] Example 112 (EX112)

[0948] [ka]

[0949] Step 1: EX112 was prepared as described in Example 104 (EX104, steps 2-5), except that EX81-5 was used instead of EX104-1 in step 2. 1 H NMR(400MHz,CD3OD)δ7.90(d,J=11.8Hz,1H),7.70(d,J=7.2Hz,1H),7.43(s, 1H),4.32-4.23(m,1H),4.03-3.95(m,3H),3.88-3.81(m,2H),3.79-3.70(m,2 H),3.69-3.62(m,2H),3.59-3.50(m,2H),3.49-3.45(m,1H),3.42(t,J=6.2H z,2H),3.15-3.08(m,4H),2.60-2.48(m,2H),2.37(s,3H),2.03-1.93(m,2H). LCMS[M+H] + :633.2.

[0950] Example 113 (EX113-A and B)

[0951] [ka]

[0952] Step 1: EX113-1 was prepared as described in Example 17 (EX17), step 2, except that EX95-3 was used instead of EX17-1.

[0953] Step 2: To a solution of EX113-1 (8 g, 30.16 mmol) in THF (150 mL) was added NaH (60% in oil, 2.4 g, 60.31 mmol) under a N atmosphere at 0 °C, followed by the addition of 2-(chloromethyl)oxirane (3.1 g, 33.17 mmol). The mixture was stirred at 80 °C for 6 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was dried over MgSO and purified by silica gel chromatography to give EX113-2. LCMS [M- t Bu+H] + :266.0.

[0954] Step 3: To a solution of EX113-2 (5 g, 15.56 mmol) in EtOH (100 mL) was added PMBNH (4.27 g, 31.1 mmol) and DIEA (21.74 mL, 124 mmol) under N atmosphere. The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure, diluted with saturated NH Cl (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layer was dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX113-3. LCMS [M+H] + :459.2.

[0955] Step 4: EX113-4 was prepared as described in Example 81 (EX81) steps 2-5, except that EX113-3 was used instead of EX81-1 in step 2.

[0956] Step 5: EX113 was prepared as described in Example 96 (EX96), step 1, except that EX113-4 was used instead of EX81-5.

[0957] Step 6: EX113-A (30.49mg) EX113-B (14.28mg), SFC EX111 separated. SFC analysis conditions: カラム:Column:Column:Cellulose-2 100×4.6mm ID, 3μm; mobile phase A: supercritical CO2, mobile phase B: メタノール (0.05%DEA), 40% mobile phase B, 8 minutes; flow rate: 2.8mL / min; カラム temperature: 35℃.

[0958] EX113-A: 1 H NMR (400MHz, CD3OD) δ8.06(d,J=8.6Hz,1H),7.45(s,1H),7.27(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),6.23(t,J=55.3Hz,1H),4.25-4 .17(m,1H),4.01-3.79(m,6H),3.75-3.59(m,3H),3.55-3.36(m,6H), 3.20-3.05(m,4H),2.56-2.40(m,2H),2.37(s,3H),1.90-1.73(m,2H). LCMS[M+H] + 597.3. Hold time @SFC: 2.916 minutes.

[0959] EX113-B: 1 H NMR (400MHz, CD3OD) δ8.07(d,J=8.6Hz,1H),7.45(s,1H),7.27(d,J=2.2Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),6.23(t,J=55.3Hz,1H),4.25-4 .17(m,1H),3.98-3.81(m,6H),3.75-3.61(m,3H),3.54-3.37(m,6H), 3.18-3.08(m,4H),2.57-2.40(m,2H),2.37(s,3H),1.88-1.77(m,2H). LCMS[M+H] + 597.3. Hold time @SFC: 3.213 minutes.

[0960] Example 114 (EX114-AおよびB)

[0961]

change

[0962] Step 1: EX114 was prepared as described in Example 112 (EX112), except that EX113-4 was used instead of EX81-5.

[0963] Step 2: EX114-A (24.71 mg) and EX114-B (9.74 mg) were separated from EX111 by SFC. SFC analysis conditions: Column: Cellulose-2 100 × 4.6 mm ID, 3 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (0.05% DEA), 40% Mobile phase B, 8 min; Flow rate: 2.8 mL / min; Column temperature: 35 °C.

[0964] EX114-A: 1 H NMR(400MHz,DMSO-d6)δ12.07(s,1H),7.77(d,J=11.5Hz,1H),7.51(d,J=7.2Hz,1H),7.32(s,1H),6.44(t,J=54.9Hz,1H),4.23-4.14(m,1H) ),3.96-3.87(m,1H),3.78(t,J=6.3Hz,2H),3.70-3.46(m,6H),3.43-3.33(m,5H),3.10-2.90(m,4H),2.31-2.18(m,5H),1.76-1.66(m,2H). LCMS[M+H] + :615.3. Retention time @SFC: 2.419 minutes.

[0965] EX114-B: 1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),7.77(d,J=11.5Hz,1H),7.50(d,J=7.1Hz,1H),7.31(s,1H),6.40(t,J=54.9Hz,1H),4.18(d,J=10.9Hz, 1H),3.94-3.89(m,1H),3.78(t,J=6.2Hz,2H),3.72-3.48(m,6H),3.42 -3.34(m,5H),3.09-2.88(m,4H),2.30-2.18(m,5H),1.76-1.64(m,2H). LCMS[M+H] + :615.3. Retention time @SFC: 2.778 minutes.

[0966] Example 115 (EX115-A and B)

[0967] [ka]

[0968] Step 1: To a solution of 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (80 g, 311 mmol) in DMF (500 mL) was added NaH (14.92 g, 373 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, followed by the addition of ethyl 2-bromoacetate (51.9 g, 311 mmol). The resulting mixture was stirred at 25 °C for an additional 5 h. The mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to give EX115-1. LCMS [M-Boc+H] + :244.1.

[0969] Step 2: A solution of EX115-1 (210 g, 612 mmol) in concentrated HCl (510 mL, 6116 mmol) was stirred at 95° C. for 6 hours and concentrated in vacuo to give EX115-2. LCMS [M+H] + :158.0.

[0970] Step 3: A solution of EX115-2 (210 g, 534 mmol) in EtOH (2100 mL) was stirred at 75° C. for 12 hours. The reaction was concentrated under reduced pressure, and the resulting residue was neutralized with DIEA (pH=7) to give EX115-3. LCMS [M+H] + :186.1.

[0971] Step 4: To a solution of EX115-3 (200 g, 432 mmol) in DCM (3000 mL) was added TEA (181 mL, 1296 mmol) and CbzCl (81 g, 475 mmol) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction was diluted with water (2000 mL) and extracted with DCM (1500 mL×2). The combined organic layer was dried over MgSO4 and purified by silica gel chromatography to give EX115-4. LCMS [M+H] + :320.1.

[0972] Step 5: To a solution of EX115-4 (48 g, 150 mmol) in DCM (1000 mL) was added DAST (119 mL, 902 mmol) at 0 °C. The reaction was stirred at 25 °C for 12 h. The reaction was quenched with saturated NaHCO (1500 mL) and extracted with DCM (1000 mL x 3). The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by silica gel chromatography to give EX115-5. LCMS [M+H] + :342.1.

[0973] Step 6: EX115 was prepared as described in Example 111 (EX111) steps 2-7, except that EX115-5 was used instead of EX111-1 in step 2 and EX34-1 was used instead of EX60-1 in step 5.

[0974] Step 7: EX115-A (24.71mg) EX115-B (9.74mg), SFC EX111 separated. SFC analysis conditions: カラム:Column:Column:(S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase A: supercritical CO2, mobile phase B: エタノール (0.05%DEA), 40% mobile phase B, 8 minutes; flow rate: 2.5mL / min; KLA temperature: 40°C.

[0975] EX115-A: 1 H NMR (400MHz, CD3OD) δ8.02(d,J=8.6Hz,1H),7.49(s,1H),7.18(s,1H),7.11-7.04(m,1H),4.11-3.79(m,6H),3.40-3.34(m,2H),3.10- 2.85(m,4H),2.34(s,3H),2.31-2.23(m,1H),2.09-1.98(m,2H),1.96-1.79(m,2H),1.64-1.26(m,7H),1.20-1.11(m,1H),1.05(s,3H). LCMS[M+H] + 593.3. Hold time @SFC: 2.727 minutes.

[0976] EX115-B: 1 H NMR(400MHz,CD3OD)δ8.04(d,J=8.6Hz,1H),7.51(s,1H),7.21(d,J=2.2Hz,1H ),7.10(dd,J=8.6,2.1Hz,1H),4.10-3.83(m,6H),3.39(t,J=6.3Hz,2H),3.12 -2.98(m,3H),2.96-2.87(m,1H),2.36(s,3H),2.34-2.26(m,1H),2.16-2.06( m,2H),1.95-1.83(m,2H),1.66-1.29(m,7H),1.22-1.14(m,1H),1.07(s,3H). LCMS[M+H] + 593.4. Duration @SFC: 3.243 minutes.

[0977] II. Biological Evaluation Example B1:KIF18Aアッセイ

[0978] The KIF18A assay was performed as follows. 1.1. Preparation of 1x kinase buffer 1.2. Compound Screening: a) 40 μL of test compound was added to a 384-well dilution plate b) For each column, compounds were serially diluted 1:3 in DMSO to 10 μl c) 0.1 μL of diluted compound solution was transferred to a 384 assay plate using an Echo, each column containing two replicates d) 5 μL of enzyme working solution was added to a 384-well assay plate and centrifuged at 1000 RPM for 1 minute. e) Incubated at 25°C for 15 minutes f) The reaction was initiated by adding 5 μL of ATP working solution. g) Incubated at 25°C for 60 minutes h) 10 μL of ADP Glo reagent was added and centrifuged at 1000 RPM for 1 minute. i) Incubated at 25°C for 60 minutes j) 20 μL of kinase detection reagent was added and centrifuged at 1000 RPM for 1 minute. k) Incubated at 25°C for 60 minutes l) Luminescence signals were read on an Envisio N2104 plate reader. 1.3. Data Analysis – Compound IC 50 and plot dose-response curves were calculated: IC was calculated by fitting % inhibition values ​​and the logarithm of compound concentration to a nonlinear regression (dose response - variable slope) using GraphPad 6.0. 50 was calculated. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) X: logarithm of inhibitor concentration; Y: % inhibition

[0979] Data for selected compounds disclosed herein are presented in Table 3.

[0980] [Table 3]

[0981] Example B2: OVCAR3 CTG assay

[0982] Assay conditions

[0983] [Table 4]

[0984] method 1) Cell seeding: a) Preparation of complete medium: Add FBS and appropriate additives according to the information sheet provided by the vendor. Mix gently. b) Check the cell name and complete medium marked on the flask and the passage number. For adherent cell lines, see c-k. For suspension cell lines, see g-k. c) The medium was removed using a vacuum pump and discarded. d) Briefly, the cell layer was rinsed with a 0.25% (w / v) trypsin-0.038% (w / v) EDTA solution to remove all traces of serum containing trypsin inhibitors. e) 3.0 ml of trypsin-EDTA solution was added to the flask, and the cells were observed under an inverted microscope until the cell layer was dispersed. f) 9.0 ml of complete growth medium was added and the cells were aspirated by gentle pipetting. g) The cell suspension was transferred to a centrifuge tube and centrifuged at 1000 rpm for 4 minutes. h) The supernatant was discarded using a vacuum pump. i) An appropriate volume of complete medium was added. The cell pellet was suspended by gently pipetting. j) The cell number was counted using Vi-cell XR, and the cells were adjusted to an appropriate density. k) 190 μL of cell suspension was added to a 96-well opaque-walled, clear-bottom plate according to the planned plate layout, and the plate was placed in a CO 2 incubator overnight. 2) Preparation of compound stocks: a) Preparation of test article plates: Compounds were dissolved in DMSO to prepare 10 mM stock solutions. Starting working concentrations (2 mM) were prepared in DMSO. b) Preparation of staurosporine plates: A working concentration of 0.4 mM staurosporine was prepared in DMSO. c) Addition of compounds: 20x compound-containing medium was prepared according to the plate map. 10 μL of 20x compound-containing medium was added to each well of the assay plate. Centrifuge at 1000 rpm for 1 minute. The total dilution was 200-fold. 3) Cells were incubated with compounds at 37°C in 5% CO2 for 6 days.

[0985] Assay measurement of CTG assay 1) Preparation of reagents a) CellTiter-Glo buffer was thawed and equilibrated to room temperature before use. b) Lyophilized CellTiter-Glo substrate was equilibrated to room temperature before use. c) The appropriate volume of CellTiter-Glo buffer was transferred to the amber bottle containing the CellTiter-Glo substrate to reconstitute the lyophilized enzyme / substrate mixture, thereby forming the CellTiter-Glo reagent. d) Mix by gently vortexing, swirling, or inverting the contents to obtain a homogenous solution. The CellTiter-Glo substrate went into solution easily in less than 1 minute. 2) Assay measurement a) Cell morphology was observed under an inverted microscope after the corresponding treatments. b) The plate and its contents were allowed to equilibrate to room temperature for approximately 30 minutes. c) 100 μL of CellTiter-Glo reagent was added to the assay plate using the Multidrop Combi instrument. d) The contents were mixed on an orbital shaker for 10 minutes to induce cell lysis. e) The plate was incubated at room temperature for 10 minutes to allow the luminescent signal to stabilize. f) The transparent bottom was attached with a white backing sticker, and the luminescence was recorded with Envision. The settings were as follows: luminescence, measurement time 0.1 seconds.

[0986] Assay Results: Data for selected compounds disclosed herein are presented in Table 5.

[0987] [Table 5-1]

[0988] [Table 5-2]

Claims

1. Formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is C ３ -C ７ cycloalkyl, 4- to 12-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl, each of which may be selected from one or more R ａ optionally substituted with Ring B is phenyl, 5- to 10-membered heteroaryl, C ３ -C １２ cycloalkyl, or 5- to 12-membered heterocycloalkyl, each of which may be one or more R ｂ optionally substituted with L １ is a bond or linker moiety connecting ring A and ring B, said linker moiety comprising a linear sequence ranging from 1 to 20 non-hydrogen atoms, and one or more R ｃ optionally substituted with L ２ represents a bond, —O—, —S—, —N(R ８ ) -, -N(R ８ )CO-,-CON(R ８ ) -, C １ -C ６ Alkylene, or C １ -C ６ heteroalkylene, wherein alkylene and heteroalkylene are optionally substituted with one or more R; L ３ represents a bond, —O—, —S—, —N(R ８ )CO-,-CON(R ８ ) -, -N(R ８ ) -, C １ -C ６ Alkylene, or C １ -C ６ heteroalkylene, wherein alkylene and heteroalkylene are optionally substituted with one or more R; X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and X ４ is N or CR ４ and R １ , R ２ , and R ４ are each independently hydrogen, —CN, —OH, —SH, halogen, amino, C １ -C ６ Alkyl, C １ -C ６ Alkoxyl, C １ -C ６ Heteroalkyl, C ２ -C ６ alkenyl, and C ２ -C ６ alkynyl, wherein alkyl, alkoxyl, heteroalkyl, alkenyl, and alkynyl are each selected from one or more R ６ optionally substituted with Each R ６ are independently halogen, —CN, —NO ２ , —OH, oxo, —OR ７ , -OC(=O)R ７ , -OC(=O)OR ７ , -OC(=O)NR ８ R ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ NR ８ R ８ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -NR ８ C(=O)NR ８ R ８ , -NR ８ C(=O)R ８ , -NR ８ C(=O)OR ７ , -NR ８ S (= O) ２ R ７ , -N=S(=O)(R ７ ) ２ , -C(=O)R ７ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ alkenyl, and C ２ -C ６ alkynyl, R ３ is —CN or a group —Z—R ５ and or R ４ and R ３ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -Z-R ５ and one or more R ｄ optionally substituted with or R ３ and R ２ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is -Z-R ５ and one or more R ｄ optionally substituted with or R ２ and R １ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be selected from one or more R ｄ optionally substituted with Z is a bond, C １ -C ８ Alkylene, C １ -C ８ Heteroalkylene, —NR ８ -, -S(=O)C ０ -C ６ Alkylene-, -NR ８ SO ２ -(C ０ -C ６ (alkylene)-, -SO ２ NR ８ -(C ０ -C ６ alkylene)-, -NR ８ SO ２ NR ８ -, -NR ８ SO ２ NR ８ C(=O)O-,-(C ０ -C ６ alkylene)-S(=O)(=NH)-, -(C ０ -C ６ alkylene)-NR ８ -S(=O)(=NH)-,-(C ０ -C ６ alkylene)-S-, -(C ０ -C ６ alkylene)-S(=O)-, -(C ０ -C ６ (alkylene)-SO ２ -, -O-, -P(=O)-, -P(=O) ２－ , -P(=O)(OR ８ )-, -(C=O)-, -(C=O)NR ８ - or -NR ８ (C═O)—, wherein the alkylene or heteroalkylene is optionally substituted with one or more R; R ５ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ is selected from the group consisting of alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R ｅ optionally substituted with The group -Z-R ５ is -N=S(=O)-(R ５ ) ２ and two R ５ may alternatively be combined with the sulfur atom to which they are attached to form one or more R ｅ can form a heterocycloalkyl optionally substituted with R ａ , R ｂ , R ｃ , and R ｄ are each independently a halogen, oxo, —CN, or —NO ２ , —OH, —OR ７ , -OC(=O)R ７ , -OC(=O)OR ７ , -OC(=O)NR ８ R ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ NR ８ R ８ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -NR ８ C(=O)NR ８ R ８ , -NR ８ C(=O)R ７ , -NR ８ C(=O)OR ７ , -NR ８ S (= O) ２ R ７ , -N=S(=O)(R ７ ) ２ , -C(=O)R ７ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ selected from alkynyl, cycloalkyl, and heterocycloalkyl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or two R's ｃ together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two R's ｃ together with the intervening atoms form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; or two Rs bonded to adjacent atoms ｃ come together to form a bond, Each R ｅ are independently halogen, oxo, —CN, —NO ２ , O.H., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, -OR ７ , -OC １ -C ４ Haloalkyl, —CN, —C(═O)R ７ , -C(=O)OR ８ , -C(=O)N(R ８ ) ２ , -C(=NR ８ ) N (R ８ ) ２ , -OC(=O)R ７ , -OC(=O)N(R ８ ) ２ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -OC ２ -C ６ alkylene)N(R ８ ) ２ , -OC ２ -C ６ Alkylene OR ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ N (R ８ ) 2, -N(R ８ ) C(=O)R ７ , -NR ８ C(=O)OR ７ , -N(R ８ )C(=O)N(R ８ ) ２ , -N(R ８ ) C(=NR ８ ) N (R ８ ) ２ , -N=S(=O)(R ７ ) ２ , -N(R ８ ) S(=O) ２ R ７ , -N(R ８ ) S(=O) ２ N (R ８ ) ２ , -NR ８ C ２ -C ６ Alkylene N(R ８ ) ２ , -NR ８ C ２ -C ６ Alkylene OR ８ , -C １ -C ６ Alkylene N(R ８ ) ２ , -C １ -C ６ Alkylene OR ８ , -C １ -C ６ Alkylene N(R ８ ) C(=O)R ７ , -C １ -C ６ Alkylene OC(=O)R ８ , -C １ -C ６ Alkylene C(=O)N(R ８ ) ２ , and -C １ -C ６ Alkylene C(=O)OR ７ wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R ７ is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R ８ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), or C １ -C ６ alkylene (heterocycloalkyl), where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R; or Two R on the same atom ８ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, —CN, —OH, oxo, or —SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, —S(═O) ２ C １ -C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ３ Alkyl, —S(═O) ２ N (C １ -C ３ alkyl) ２ , -S(=O)(=NC １ -C ３ alkyl) (C １ -C ３ alkyl), -NH ２ , -NHC １ -C ３ Alkyl, —N(C １ -C ３ alkyl) ２ , -N=S(=O)(C １ -C ３ alkyl) ２ , -C(=O)C １ -C ３ Alkyl, —C(═O)OH, —C(═O)OC １ -C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, —C(═O)N(C １ -C ３ alkyl) ２ , -P(=O)(C １ -C ３ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ heteroalkyl, or C ３ -C ６ cycloalkyl, or a pharmaceutically acceptable salt thereof.

2. L １ But C １ -C ６ Alkylene or C １ -C ６ heteroalkylene, each of which is one or more R ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with:

3. L １ is -heterocycloalkyl-C １ -C ６ Alkylene-, -heterocycloalkyl-C １ -C ６ Heteroalkylene-, -cycloalkyl-C １ -C ６ Alkylene-, -cycloalkyl-C １ -C ６ Heteroalkylene, -C １ -C ６ Alkylene-heterocycloalkyl-, -C １ -C ６ Heteroalkylene-heterocycloalkyl-, -C １ -C ６ Alkylene-cycloalkyl-, -C １ -C ６ Heteroalkylene-cycloalkyl-, -C １ -C ６ Heteroalkylene-cycloalkyl-C １ -C ６ Heteroalkylene, -C １ -C ６ Alkylene-cycloalkyl-C １ -C ６ Alkylene, C １ -C ６ Heteroalkylene-cycloalkyl-C １ -C ６ Alkylene, C １ -C ６ Alkylene-cycloalkyl-C １ -C ６ Heteroalkylene, -C １ -C ６ Heteroalkylene-heterocycloalkyl-C １ -C ６ Heteroalkylene, -C １ -C ６ Heteroalkylene-heterocycloalkyl-C １ -C ６ Alkylene, -C １ -C ６ Alkylene-heterocycloalkyl-C １ -C ６ heteroalkylene, or —C １ -C ６ Alkylene-heterocycloalkyl-C １ -C ６ Alkylene, —O—, —S—, —N(R ８ )-, and each of the cycloalkyl, heterocycloalkyl, alkylene, and heteroalkylene is selected from one or more R ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with:

4. Each R ｃ are independently halogen, oxo, —OH, —OR ７ , C １ -C ６ Haloalkyl, C １ -C ６ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from alkyl, and cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more R.

5. L １ Yes, -OCH ２ CH ２ OCH ２ -、-OCH ２ CH ２ CH ２ OCH ２ -、-OCH ２ CH ２ CH ２ CH ２ CH ２ -、-OCH(CH ３ )CH ２ CH ２ OCH ２ -、-OCH ２ HH(H) ３ )CH ２ OCH ２ -、-OCH ２ HH(H) ３ )OCH ２ CH ２ -、-OCH(CH ３ )CH ２ OCH ２ CH ２ -、-CH ２ OCH ２ -、-CH ２ CH ２ OCH ２ -、-CH ２ CH ２ CH ２ CH ２ OCH ２ -、-CH ２ OCH(CH) ３ )CH ２ OCH ２ -、-CH ２ OCH ２ CH ２ -、-N(CH ３ )CH ２ CH ２ OCH ２ -、-N(シクロローピル)CH ２ CH ２ CH ２ OCH ２ -、-N(CH ３ )CH ２ CH ２ CH ２ OCH ２ -、-NHCH ２ CH ２ OCH ２ -、-NHCH ２ CH ２ CH ２ OCH ２ -、-NHCH ２ CH(CH ３ )CH ２ OCH ２ -、-N(CH ３ )CH ２ CH ２ OCH ２ CH ２ -、-NHCH ２ CH ２ OCH ２ CH ２ -、-NH(CH ２ ) ４ -、-NH(CH ２ ) ５ -、-NHCH ２ CH(CH ３ (CH) ２ ) ３ -、-N(CH ３ (CH) ２ ) ４ -、-N(CH ３ (CH) ２ ) ５ -、-NHCH ２ CH ２ CH ２ CH ２ O-NHCH ２ C(=0)N(CH) ３ )CH ２ CH ２ -、-NHCH ２ CH ２ CH ２ NHCH ２ -、-NHCH(CH ３ )CH ２ OCH ２ CH ２ -、-NHCH ２ CH(CH ３ )OCH ２ CH ２ -、-N(CH ３ )CH ２ CH(CH ３ )OCH ２ CH ２ -、-NHCH ２ CF ２ CH ２ OCH ２ -、-N(CH ３ )CH ２ CF ２ CH ２ OCH ２ -、-NHCH ２ HH(H) ３ )CH ２ OCH ２ -、-N(CH ３ )CH ２ HH(H) ３ )CH ２ OCH ２ -、-NHCH(CH ３ )CH ２ CH ２ OCH ２ -、-NHCH ２ CH ２ HH(H) ３ )OCH ２ -、-NHCH ２ HH(H) ３ )CH ２ OCH ２ -、-NHCH ２ CHFCH ２ OCH ２ -、-NHCH ２ CH(OCH) ３ )CH ２ OCH ２ -、-NHCH ２ CH(CF) ３ )CH ２ OCH ２ -、-NHCH ２ CF ２ CH ２ OCH ２ -、-NHCH ２ CH(OH)CH ２ OCH ２ -、-N(CH ３ )CH ２ HH(H) ３ )CH ２ OCH ２ -、-N(CH ３ )CH ２ CHFCH ２ OCH ２ -、-N(CH ３ ) CH ２ CH (OCH ３ ) CH ２ OCH ２ -, -N(CH ３ ) CH ２ CH (CF ３ ) CH ２ OCH ２ -, -N(CH ３ ) CH ２ CF ２ CH ２ OCH ２ -, -N(CH ３ ) CH ２ CH(OH)CH ２ OCH ２ -, -C(=O)N(CH ３ ) CH ２ CH ２ OCH ２ -, -C(=O)N(CH ３ ) CH ２ CH ２ CH ２ OCH ２ -, and -C(=O)N(CH ３ ) CH ２ CH ２ CH ２ CH ２ 4. The compound of claim 1, wherein the compound is selected from the group consisting of:

6. Two R's ｃ together with the atoms to which they are attached, optionally substituted with one or more R ３ -C ６ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

7. Two R's ｃ are optionally substituted, together with the atoms to which they are attached, with one or more R 【Chemistry 2】 7. The compound of claim 6, wherein the compound forms:

8. L １ but, 【Transformation 3】 4. The compound according to any one of claims 1 to 3, wherein:

9. Two R's ｃ together with the intervening atoms, optionally substituted with one or more R ３ -C ６ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

10. Two R's ｃ But together with the intervening atom, 【Chemistry 4】 10. The compound of claim 9, wherein the compound forms: each of which is optionally substituted with one or more R, or a pharmaceutically acceptable salt thereof.

11. L １ but, 【Transformation 5】 11. The compound of claim 10, wherein:

12. Two R's ｃ or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein R is substituted with R, ...

13. Two R's ｃ But together with the intervening atom, 【Transformation 6】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein each of said compounds is optionally substituted with one or more R.

14. L １ but, 【Transformation 7】 14. The compound of claim 13, wherein:

15. Two Rs bonded to adjacent atoms ｃ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

16. L １ but, 【Transformation 8】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. L １ is represented by formula (II) 【Chemistry 9】 The structure of During the ceremony, L １１ , L １２ , L １３ , L １４ , and L １５ each independently represents a substituted or unsubstituted C １ -C ２０ Alkylene, substituted or unsubstituted C １ -C １９ Heteroalkylene, substituted or unsubstituted C ２ -C ２０ Alkenylene, substituted or unsubstituted C ２ -C ２０ Alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -(CH ２ CH ２ O) ｐ -, -(OCH ２ CH ２ ) ｐ -, -O-, -S-, -S(=O)-, -S(=O) ２ -, -S(=O)(=NR ＬＫ )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR ＬＫ -, -NR ＬＫ C(=O)-, -OC(=O)NR ＬＫ -, -NR ＬＫ C(=O)O-, -NR ＬＫ C(=O)NR ＬＫ -, -C(=O)NR ＬＫ C(=O)-, -S(=O) ２ NR ＬＫ -, -NR ＬＫ S (= O) ２ -, -NR ＬＫ -, -N(OR ＬＫ )—, and a bond; Each R ＬＫ are independently hydrogen or substituted or unsubstituted C １ -C ６ is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is an integer selected from 1 to 6.

18. L ２ is a bond, -OCH ２ - or -CH ２ O-, L ３ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is -NHC(=O)-.

19. Ring A is C ４ -C ７ cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, or bicyclic 6- to 10-membered heterocycloalkyl, each of which is selected from the group consisting of one or more R ａ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, optionally substituted with:

20. Ring A is 【Chemistry 10】 wherein * is selected from the group consisting of L ２ indicates the point of attachment to L １ indicates the point of attachment to R ａ１ , R ａ２ , and R ａ３ are each independently hydrogen, halogen, oxo, —CN, or —NO ２ , —OH, —OR ７ , -OC(=O)R ７ , -OC(=O)OR ７ , -OC(=O)NR ８ R ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ NR ８ R ８ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -NR ８ C(=O)NR ８ R ８ , -NR ８ C(=O)R ７ , -NR ８ C(=O)OR ７ , -NR ８ S (= O) ２ R ７ , -N=S(=O)(R ７ ) ２ , -C(=O)R ７ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from alkynyl, 3- to 9-membered cycloalkyl, and 3- to 9-membered heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.

21. R ａ１ , R ａ２ , and R ａ３ are each independently hydrogen, halogen, oxo, —CN, or —NO ２ , -OH, C １ -C ３ Alkyl, C １ -C ３ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the alkyl is selected from haloalkyl, 3- to 6-membered cycloalkyl, and 5- to 6-membered heterocycloalkyl.

22. Ring A is 【Chemistry 11】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

23. Ring B is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heterocycloalkyl, each of which is selected from the group consisting of one or more R ｂ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, optionally substituted with:

24. Ring B is 【Chemistry 12】 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

25. The group -Z-R ５ But -NHSO ２ -R ５ 25. The compound according to any one of claims 1 to 24, wherein:

26. Z is a bond, C １ -C ８ Alkylene, —NR ８ -, -NR ８ SO ２ -(C ０ -C ６ (alkylene)-, -SO ２ NR ８ -(C ０ -C ６ alkylene)-, -NR ８ SO ２ NR ８ -, and -(C ０ -C ６ (alkylene)-SO ２ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

27. R ５ But hydrogen, C １ -C ６ Alkyl, C １ -C ４ Haloalkyl, and C １ -C ６ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, selected from the group consisting of hydroxyalkyl.

28. -Z-R ５ But -NHSO ２ CH ２ CH ２ OH, -NHSO ２ CH ２ CH ３ , -NHSO ２ CH ３ , -NHC(CH ３ ) ２ CH ２ OH, and 【Chemistry 13】 or -Z-R ５ But, -SO ２ NHCH ２ CH ２ OH, -SO ２ NHC (CH ３ ) ３ , -SO ２ NHCH ３ , and -SO ２ NH ２ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

29. Formula (IV) 【Chemistry 14】 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is C ３ -C ７ cycloalkyl, 4- to 12-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl, each of which may be selected from one or more R ａ optionally substituted with Ring B is phenyl, 5- to 10-membered heteroaryl, C ３ -C １２ cycloalkyl, or 5- to 12-membered heterocycloalkyl, each of which may be one or more R ｂ optionally substituted with Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L １ is a bond or linker moiety connecting ring A and ring B, said linker moiety comprising a linear sequence ranging from 1 to 20 non-hydrogen atoms, and one or more R ｃ optionally substituted with L ２ represents a bond, —O—, —S—, —N(R ８ ) -, -N(R ８ )CO-,-CON(R ８ ) -, C １ -C ６ Alkylene, or C １ -C ６ heteroalkylene, wherein alkylene and heteroalkylene are optionally substituted with one or more R; L ３ represents a bond, —O—, —S—, —N(R ８ )CO-,-CON(R ８ ) -, -N(R ８ ) -, C １ -C ６ Alkylene, or C １ -C ６ heteroalkylene, wherein said alkylene and heteroalkylene are optionally substituted with one or more R; Each R ２ are independently hydrogen, —CN, —OH, —SH, halogen, amino, C １ -C ６ Alkyl, C １ -C ６ Alkoxyl, C １ -C ６ Heteroalkyl, C ２ -C ６ alkenyl, and C ２ -C ６ alkynyl, wherein alkyl, alkoxyl, heteroalkyl, alkenyl, and alkynyl are each selected from one or more R ６ optionally substituted with Each R ６ are independently halogen, —CN, —NO ２ , —OH, oxo, —OR ７ , -OC(=O)R ７ , -OC(=O)OR ７ , -OC(=O)NR ８ R ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ NR ８ R ８ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -NR ８ C(=O)NR ８ R ８ , -NR ８ C(=O)R ８ , -NR ８ C(=O)OR ７ , -NR ８ S (= O) ２ R ７ , -N=S(=O)(R ７ ) ２ , -C(=O)R ７ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ alkenyl, and C ２ -C ６ alkynyl, k2 is 0, 1, 2, or 3; R ３ is —CN or a group —Z—R ５ and k1 is 0, 1, 2, or 3; Z is a bond, C １ -C ８ Alkylene, C １ -C ８ Heteroalkylene, —NR ８ -, -S(=O)C ０ -C ６ Alkylene-, -NR ８ SO ２ -(C ０ -C ６ (alkylene)-, -SO ２ NR ８ -(C ０ -C ６ alkylene)-, -NR ８ SO ２ NR ８ -, -NR ８ SO ２ NR ８ C(=O)O-,-(C ０ -C ６ alkylene)-S(=O)(=NH)-, -(C ０ -C ６ alkylene)-NR ８ -S(=O)(=NH)-,-(C ０ -C ６ alkylene)-S-, -(C ０ -C ６ alkylene)-S(=O)-, -(C ０ -C ６ (alkylene)-SO ２ -, -O-, -P(=O)-, -P(=O) ２－ , -P(=O)(OR ８ )-, -(C=O)-, -(C=O)NR ８ - or -NR ８ (C═O)—, wherein the alkylene or heteroalkylene is optionally substituted with one or more R; R ５ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ is selected from the group consisting of alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R ｅ optionally substituted with The group -Z-R ５ is -N=S(=O)-(R ５ ) ２ and two R ５ may alternatively be combined with the sulfur atom to which they are attached to form one or more R ｅ can form a heterocycloalkyl optionally substituted with R ａ , R ｂ , R ｃ , R ｄ , and R ｆ are each independently a halogen, oxo, —CN, or —NO ２ , —OH, —OR ７ , -OC(=O)R ７ , -OC(=O)OR ７ , -OC(=O)NR ８ R ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ NR ８ R ８ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -NR ８ C(=O)NR ８ R ８ , -NR ８ C(=O)R ７ , -NR ８ C(=O)OR ７ , -NR ８ S (= O) ２ R ７ , -N=S(=O)(R ７ ) ２ , -C(=O)R ７ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; or two R's ｃ together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R ｅ are independently halogen, oxo, —CN, —NO ２ , O.H., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, -OR ７ , -OC １ -C ４ Haloalkyl, —CN, —C(═O)R ７ , -C(=O)OR ８ , -C(=O)N(R ８ ) ２ , -C(=NR ８ ) N (R ８ ) ２ , -OC(=O)R ７ , -OC(=O)N(R ８ ) ２ , -S(=O)(=NR ８ ) R ７ , -NR ８ R ８ , -OC ２ -C ６ alkylene)N(R ８ ) ２ , -OC ２ -C ６ Alkylene OR ８ , -SH, -SR ７ , -S(=O)R ７ , -S(=O) ２ R ７ , -S(=O) ２ N (R ８ ) 2, -N(R ８ ) C(=O)R ７ , -NR ８ C(=O)OR ７ , -N(R ８ )C(=O)N(R ８ ) ２ , -N(R ８ ) C(=NR ８ ) N (R ８ ) ２ , -N=S(=O)(R ７ ) ２ , -N(R ８ ) S(=O) ２ R ７ , -N(R ８ ) S(=O) ２ N (R ８ ) ２ , -NR ８ C ２ -C ６ Alkylene N(R ８ ) ２ , -NR ８ C ２ -C ６ Alkylene OR ８ , -C １ -C ６ Alkylene N(R ８ ) ２ , -C １ -C ６ Alkylene OR ８ , -C １ -C ６ Alkylene N(R ８ ) C(=O)R ７ , -C １ -C ６ Alkylene OC(=O)R ８ , -C １ -C ６ Alkylene C(=O)N(R ８ ) ２ , and -C １ -C ６ Alkylene C(=O)OR ７ wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R ７ is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R ８ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), or C １ -C ６ alkylene (heterocycloalkyl), where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylene is optionally substituted with one or more R; or Two R on the same atom ８ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, —CN, —OH, oxo, or —SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, —S(═O) ２ C １ -C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ３ Alkyl, —S(═O) ２ N (C １ -C ３ alkyl) ２ , -S(=O)(=NC １ -C ３ alkyl) (C １ -C ３ alkyl), -NH ２ , -NHC １ -C ３ Alkyl, —N(C １ -C ３ alkyl) ２ , -N=S(=O)(C １ -C ３ alkyl) ２ , -C(=O)C １ -C ３ Alkyl, —C(═O)OH, —C(═O)OC １ -C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, —C(═O)N(C １ -C ３ alkyl) ２ , -P(=O)(C １ -C ３ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ heteroalkyl, or C ３ -C ６ cycloalkyl, or a pharmaceutically acceptable salt thereof.

30. 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring D is a 9- to 10-membered fused bicyclic ring.

31. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is selected from the compounds disclosed in Table 1 or Table 2.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

33. 32. A method of modulating or inhibiting kinase-like protein 18A (KIF18A) in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32.

34. 33. A method of treating cancer in a mammal in need thereof, comprising administering to said mammal a compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32.

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