Inhibitors of KIF18A and uses thereof

Abstract

Described herein are inhibitors of KIF18A and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of diseases or conditions associated with KIF18A.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of PCT International Application No. PCT / CN2022 / 142885, filed on December 28, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor protein. KIF18A is believed to affect the dynamics of the plus end of kinetochore microtubules, thereby controlling the correct positioning of chromosomes and spindle tension. In HeLa cervical cancer cells, the depletion of human KIF18A can lead to spindle lengthening, increased metaphase chromosome oscillations, and activation of the mitotic spindle assembly checkpoint (MI Mayr et al., Current Biology 17,488-98,2007). KIF18A is a feasible target for treating cancer. 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. In addition, gene deletion or knockdown or inhibition of KIF18A can affect the mitotic spindle apparatus in cancer cell lines. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that promotes cell death in mitosis via apoptosis, mitotic catastrophe, or death following multipolarity-driven lethality or interphase mitotic slippage. Therefore, there has been significant interest in finding inhibitors of the KIF18A protein.

[0004] Therefore, inhibiting KIF18A ATPase activity is a promising approach for developing novel anticancer drugs. Summary of the Invention

[0005] Disclosed herein are compounds of formula (I), (II) or pharmaceutically acceptable salts thereof:

[0006] Each as disclosed herein.

[0007] In some embodiments, disclosed herein is a method of modulating kinase-like protein 18A (KIF18A) in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb') or (IIcc), 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 thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc), or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, disclosed herein is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from: (a) bladder cancer, endometrial cancer, squamous cell lung cancer, 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a solid tumor or hematogenic tumor selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt lymphoma; (c) a myeloid hematopoietic tumor selected from the group consisting of acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; € a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannoma; and (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xenoderomapigmentosum, a keratoctanthoma, a follicular thyroid carcinoma or a Kaposi's sarcoma.

[0009] Incorporation by reference

[0010] 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

[0011] definition

[0012] In the following description, certain specific details are set forth in order to provide a thorough understanding of each embodiment. However, it will be understood by those skilled in the art that the invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, in the specification and the claims below, the word "comprise" and its variations (e.g., "comprises" and "comprising") should be understood in an open, inclusive sense, that is, to mean "including but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0013] References throughout this specification to "some embodiments" or "an embodiment" mean that the particular features, structures, or characteristics described in conjunction with the embodiment are included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing everywhere throughout this specification do not necessarily all refer to the same embodiment. In addition, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Likewise, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" as used in this specification and the appended claims include the plural meaning. It should also be noted that the term "or" is generally used in its sense including "and / or," unless the context clearly indicates otherwise.

[0014] Unless otherwise indicated, the following terms used herein have the following meanings:

[0015] "Oxo" refers to =0.

[0016] "Carboxyl" refers to -COOH.

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent group having one to about ten carbon atoms, more preferably one to six 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups (e.g., heptyl, octyl, etc.). Whenever it appears in this document, a term such as "C1-C6 alkyl" or "C 1-6 The numerical range of "alkyl" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise expressly stated in this specification, alkyl may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0019] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans configuration around the double bond and is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a term such as "C2-C6 alkenyl" or "C 2-6The numerical range of "alkenyl" means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" without specifying a numerical range. Unless otherwise clearly stated in the present specification, the alkenyl group may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0020] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a group such as "C2-C6 alkynyl" or "C 2-6 The numerical range of "alkynyl" means that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless otherwise clearly stated in the present specification, the alkynyl group may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0021] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise expressly stated in this specification, alkylene may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0022] "Alkoxy" refers to a group of the formula -ORa Group, where R a is a defined alkyl group. Unless otherwise expressly stated in this specification, an alkoxy group may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy group is optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, an alkoxy group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, an alkoxy group is optionally substituted by halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl groups are 6 to 10 membered aryl groups. In some embodiments, aryl groups are 6 membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of the following groups: anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, , fluoranthene, fluorene, asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane, indene, naphthalene, phenanthren, phenanthren, pleiadene, pyrene and triphenylene. Unless otherwise expressly stated in this specification, aryl groups may be optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl groups are optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl groups are optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl groups are optionally substituted by halogen.

[0024] "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 bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (e.g., C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), three to ten carbon atoms (e.g. C3-C 10 Fully saturated cycloalkyl or C3-C10 In some embodiments, the cycloalkyl group is a 3-10 fully saturated cycloalkyl group or a 3-10 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3-6 fully saturated cycloalkyl group or a 3-6 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5-6 fully saturated cycloalkyl group or a 5-6 membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise expressly stated in this specification, cycloalkyl groups are optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 or -NO 2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0025] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0026] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0027] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxy groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0029] " assorted alkyl " refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof) other than carbon. Assorted alkyl is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. On the one hand, assorted alkyl is a C1-C6 assorted alkyl group (wherein assorted alkyl includes 1 to 6 carbon atoms and one or more atoms (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof) other than carbon), wherein assorted alkyl is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl is (e.g.) -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3 or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0030] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains one to three nitrogen atoms. In some embodiments, the heterocycloalkyl contains one or two nitrogen atoms. In some embodiments, the heterocycloalkyl contains one nitrogen atom. In some embodiments, the heterocycloalkyl contains one nitrogen atom and one oxygen atom. Unless otherwise specifically stated in the specification, the heterocycloalkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups having two to fifteen carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), two to ten carbon atoms (e.g. C2-C 10 Fully saturated heterocycloalkyl or C2-C 10The heterocycloalkyl radicals include heterocycloalkyl radicals having two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuran ... The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in the heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring, including heteroatoms) that make up the heterocycloalkyl group. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise expressly stated in the specification, heterocycloalkyl may be optionally substituted, for example, by the following groups, as described below: oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF , -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0031] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group contains one to three nitrogen atoms. In some embodiments, the heteroaryl group contains one or two nitrogen atoms. In some embodiments, the heteroaryl group contains one nitrogen atom. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aza benzo[b][1,4]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolane benzothiophenyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The heteroaryl radicals include, but are not limited to, 1-phenyl-1H-pyrrolyl ... In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF , -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0032] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted to any degree between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, the group is not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, any substituent described will generally be understood to have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0033] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses effective to produce the desired therapeutic effect.

[0034] "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention intended to alter a natural process in the individual or cell. In some embodiments, treatment comprises administering a pharmaceutical composition after the onset of a pathological event or contact with a pathogen and comprises stabilizing the condition (e.g., so that the condition does not worsen) or ameliorating the condition.

[0035] Compound

[0036] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc), or pharmaceutically acceptable salts thereof, as described herein, are KIF18A inhibitors and can be used to treat diseases or conditions associated with KIF18A. In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc), or pharmaceutically acceptable salts thereof, can be used to treat cancer. In some embodiments, the cancer is selected from: (a) a solid tumor or a hematopoietic tumor; (b) a lymphoid hematopoietic tumor; (c) a myeloid hematopoietic tumor; (d) a tumor of mesenchymal origin; (e) a central and peripheral nervous system tumor; and (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0037] In some embodiments, disclosed herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof:

[0038]

[0039] in:

[0040] R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three groups selected from R 9a The group substitution;

[0041] R 2 Selected from hydrogen and C 1-6 alkyl;

[0042] Ring B is selected from C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9b The group substitution;

[0043] R 3b and R 3c independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9c The group substitution;

[0044] R 3d Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)2R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11)-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d or R 2 With R 3d Combined to form C 2-9 Heterocycloalkyl or C 2-9 Heteroaryl, wherein C 2-9 Heterocycloalkyl and C 2-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d The group substitution;

[0045] R 4 Selected from hydrogen and C 1-6 alkyl;

[0046] Ring A is a pyridone ring, a pyridazinone ring, a bicyclic heterocycle or a tricyclic heterocycle, wherein the pyridone ring, the pyridazinone ring, the bicyclic heterocycle and the tricyclic heterocycle are optionally replaced by one or more R 6a group substitution;

[0047] Each R 6a are independently selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0048] Each R 9a 、R 9b 、R 9c 、R 9d and R 9e Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12)S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )-、N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2;

[0049] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group;

[0050] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl;

[0051] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0052] Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups in the heteroaryl group are substituted.

[0053] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, Ring A is a pyridone ring or a pyridazinone ring, wherein the pyridone ring and the pyridazinone ring are optionally substituted by one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, or a pharmaceutically acceptable salt thereof, Ring A is optionally substituted with one or more R 6a In some embodiments, each R 6a independently selected from halogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e The group is substituted.

[0054] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, Ring A is a bicyclic heterocycle or a tricyclic heterocycle, wherein the bicyclic heterocycle and the tricyclic heterocycle are optionally replaced by one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e substituted by a group.

[0055] In some embodiments, disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Ring A is a bicyclic heteroaryl ring or a tricyclic heteroaryl ring, wherein the bicyclic heteroaryl ring and the tricyclic heteroaryl ring are optionally substituted by one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, Ring A is a bicyclic heteroaryl ring optionally substituted with one or more R 6a In some embodiments, Ring A is an 11-15 membered bicyclic heterocyclic ring or an 11-17 membered tricyclic heterocyclic ring, wherein the 11-15 membered bicyclic heterocyclic ring and the 11-17 membered tricyclic heterocyclic ring are optionally substituted with one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, each R6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6a In some embodiments, each R 6a Independently selected from optionally one, two or three selected from R 9e C 1-6 In some embodiments, each R 6a are independently optionally selected from one, two or three R 9e C 1-6 In some embodiments, each R 6a is optionally selected from one, two or three R 9e C 3-6 In some embodiments, each R 6a is optionally selected from one, two or three R 9e C 2-9 Heterocycloalkyl.

[0056] In some embodiments, disclosed herein is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] in:

[0059] Each R 6 and R 6b are independently hydrogen or independently selected from R 6a ;and

[0060] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6a has the same meaning as herein.

[0061] In some embodiments, disclosed herein is a compound of Formula (Iaa) or a pharmaceutically acceptable salt thereof:

[0062]

[0063] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6b has the same meaning as herein.

[0064] In some embodiments, disclosed herein is a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof:

[0065]

[0066] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6b has the same meaning as herein.

[0067] In some embodiments, disclosed herein is a compound of Formula (Ibb) or a pharmaceutically acceptable salt thereof:

[0068]

[0069] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6b has the same meaning as herein.

[0070] In some embodiments, disclosed herein is a compound of Formula (Ic) or a pharmaceutically acceptable salt thereof:

[0071]

[0072] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 、R 6 and R 6b has the same meaning as herein.

[0073] In some embodiments, disclosed herein is a compound of Formula (Icc) or a pharmaceutically acceptable salt thereof:

[0074]

[0075] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6b has the same meaning as herein.

[0076] In some embodiments of the compound of Formula (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc), or a pharmaceutically acceptable salt thereof, R 6b In some embodiments, R 6b R 6a In some embodiments, R 6b R 6a , and R 6a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, or a pharmaceutically acceptable salt thereof, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 1-6 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 1-6In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 3-6 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 2-9 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e A tetrahydropyranyl group substituted with a group.

[0077] In some embodiments, disclosed herein is a compound of Formula (Id) or a pharmaceutically acceptable salt thereof:

[0078]

[0079] in:

[0080] X is selected from -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )- and -N(R 8c )-;

[0081] R 8a and R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0082] R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0083] R 9e Selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2;

[0084] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group;

[0085] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl;

[0086] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0087] Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9One, two or three groups are substituted in the heteroaryl group;

[0088] n is 1, 2, or 3; and

[0089] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 4 and R 6 has the same meaning as herein.

[0090] In some embodiments, disclosed herein is a compound of formula (Idd) or a pharmaceutically acceptable salt thereof:

[0091]

[0092] Each of X, R 1 、R 2 , Ring B, R 4 and R 6 has the same meaning as herein.

[0093] In some embodiments, disclosed herein is a compound of Formula (Ie) or a pharmaceutically acceptable salt thereof:

[0094]

[0095] Each of X, R 1 、R 2 , Ring B, R 4 and R 6 has the same meaning as herein.

[0096] In some embodiments of the compound of Formula (Id) or (Ie), or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0097] In some embodiments, disclosed herein is a compound of Formula (Iee) or a pharmaceutically acceptable salt thereof:

[0098]

[0099] Each of X, R 1 、R 2 , Ring B, R 4 and R 6 has the same meaning as herein.

[0100] In some embodiments of the compound of Formula (Id), (Idd), (Ie), or (Iee), or a pharmaceutically acceptable salt thereof, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -S(O)2-. In some embodiments, X is -C(R 8a )(R 8b )-. In some embodiments, X is -CH2-. In some embodiments, X is -N(R 8c In some embodiments, X is -N(H)-.

[0101] In some embodiments of the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), or (Iee), or a pharmaceutically acceptable salt thereof, each R 6 are independently selected from hydrogen and R 6a In some embodiments, R 6 R 6a In some embodiments, one or more R 6 R 6a In some embodiments, one or more R 6 In some embodiments, each R 6 are independently selected from hydrogen and R 6a , where each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6 are independently selected from hydrogen and R 6a , where each R 6a independently selected from halogen and optionally substituted by one, two or three selected from R 9e C 1-6 In some embodiments, each R 6 are independently selected from hydrogen and R 6a , where each R 6a In some embodiments, each R 6 are independently selected from hydrogen and R 6a , where each R 6aIndependently selected from optionally one, two or three selected from R 9e C 1-6 In some embodiments, each R 6 are independently selected from hydrogen and R 6a , where each R 6a are independently optionally selected from one, two or three R 9e C 1-6 In some embodiments, each R 6 For hydrogen.

[0102] In some embodiments, disclosed herein is a compound of formula (If) or a pharmaceutically acceptable salt thereof:

[0103]

[0104] in:

[0105] Ring C is a 5-7 membered heterocycloalkyl group;

[0106] X 1 Selected from -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )- and -N(R 8c )-;

[0107] Each R 8a and each R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e and

[0108] Each R 8c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0109] k is 0, 1, 2, 3, 4, 5, or 6; and

[0110] Each R 1 、R 2 , Ring B, R 3b 、R 3c 、R 3d 、R 9e 、R 4 and R 6a has the same meaning as herein.

[0111] In some embodiments, disclosed herein is a compound of formula (Iff) or a pharmaceutically acceptable salt thereof:

[0112]

[0113] in:

[0114] X 1 and X 2 Each independently selected from -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )- and -N(R 8c )-;

[0115] Each R 8a and each R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0116] Each R 8c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0117] Each R 1 、R 2 、R 9e , Ring B and R 4 has the same meaning as herein.

[0118] In some embodiments, disclosed herein is a compound of Formula (Ig) or a pharmaceutically acceptable salt thereof:

[0119]

[0120] Each X 1 ,k,R 1 、R 2 , Ring B, Ring C, R 3b 、R 3c 、R 3d 、R 4 and R 6a has the same meaning as herein.

[0121] In some embodiments of the compound of Formula (If) or (Ig), or a pharmaceutically acceptable salt thereof, Ring C is a 5-membered heterocycloalkyl. In some embodiments, Ring C is a 6-membered heterocycloalkyl. In some embodiments, Ring C is a 7-membered heterocycloalkyl.

[0122] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, R 3b is selected from hydrogen, halogen, -CN and optionally substituted by one, two or three selected from R 9c C 1-6 In some embodiments, R 3b In some embodiments, R 3b In some embodiments, R 3b is optionally selected from one, two or three R 9c C 1-6 alkyl.

[0123] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, R 3c is selected from hydrogen, halogen, -CN and optionally substituted by one, two or three selected from R 9c C 1-6 In some embodiments, R 3c In some embodiments, R 3c In some embodiments, R 3c is optionally selected from one, two or three R 9c C 1-6 alkyl.

[0124] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, R 3d is selected from hydrogen, halogen, -CN and optionally substituted by one, two or three selected from R 9d C 1-6 In some embodiments, R 3d In some embodiments, R 3d In some embodiments, R 3d is optionally selected from one, two or three R 9d C 1-6 alkyl.

[0125] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, R 2 and R 3d Combined to form C 2-9 Heterocycloalkyl or C 2-9 Heteroaryl, wherein C 2-9 Heterocycloalkyl and C 2-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d In some embodiments, R 2 and R 3d In some embodiments, R 2 and R 3d In some embodiments, R 2 and R 3d Combination to form optionally one, two or three selected from R 9d C 2-9 In some embodiments, R 2 and R 3d Combination to form optionally one, two or three selected from R 9d In some embodiments, R 2 and R 3d Combination to form optionally one, two or three selected from R 9d C 2-9 In some embodiments, R 2 and R 3d Combination to form optionally one, two or three selected from R 9d In some embodiments, or a pharmaceutically acceptable salt thereof, R 2 and R 3d Combination to form optionally one, two or three selected from R 9d The pyrrole ring is substituted with a group.

[0126] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), or (Ig), or a pharmaceutically acceptable salt thereof, each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6a independently selected from halogen and optionally substituted by one, two or three selected from R 9e C 1-6 In some embodiments, each R 6a In some embodiments, each R 6a Independently selected from optionally one, two or three selected from R 9e C 1-6 In some embodiments, R 6a , where each R 6a are independently optionally selected from one, two or three R 9e C 1-6 Halogenated alkyl.

[0127] In some embodiments of the compound of Formula (If) or (Ig), or a pharmaceutically acceptable salt thereof, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3.

[0128] In some embodiments, disclosed herein is a compound of formula (Igg) or a pharmaceutically acceptable salt thereof:

[0129]

[0130] in:

[0131] X 1 and X 2 independently selected from -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )- and -N(R 8c )-;

[0132] Each R 1 、R 2 、R 8a 、R 8b 、R 8c , Ring B and R 4 has the same meaning as herein.

[0133] In some embodiments of the compound of Formula (Iff) or (Igg), or a pharmaceutically acceptable salt thereof, X 2 In some embodiments, X2 In some embodiments, X 2 In some embodiments, X 2 In some embodiments, X 2 -C(R 8a )(R 8b )-. In some embodiments, X 2 In some embodiments, X 2 -N(R 8c )-. In some embodiments, X 2 It is -N(H)-.

[0134] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Ig), (Iff), or (Igg), or a pharmaceutically acceptable salt thereof, R 2 In some embodiments, R 2 C 1-6 alkyl.

[0135] In some embodiments of the compound of Formula (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, X 1 In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 -C(R 8a )(R 8b )-. In some embodiments, X 1 In some embodiments, X 1 -N(R 8c )-. In some embodiments, X 1 It is -N(H)-.

[0136] In some embodiments of the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, Ring B is a monocyclic ring. In some embodiments, Ring B is a bicyclic ring. In some embodiments, Ring B is optionally substituted with one, two, or three rings selected from R 9b C 2-14In some embodiments, Ring B is unsubstituted C 2-14 In some embodiments, ring B is

[0137] In some embodiments of the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 3-12 In some embodiments, Ring B is optionally substituted with one, two or three selected from R 9b C 3-12 Cycloalkyl, wherein each R 9b In some embodiments, Ring B is unsubstituted C 3-12 In some embodiments, ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0138] In some embodiments of the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 1-9 Heteroaryl.

[0139] In some embodiments of the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 6-10 In some embodiments, Ring B is optionally substituted by one, two or three selected from R 9b A phenyl group substituted with a group.

[0140] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, R 1 is optionally selected from one, two or three R 9a C 1-6 In some embodiments, R 1 is optionally substituted by one, two or three selected from -OH and C 1-6 Alkoxy group substituent substituted C 1-6 In some embodiments, R 1 C is substituted by a -OH group 1-6 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is -CH2CH2CH2OH.

[0141] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, R 1 is optionally selected from one, two or three R 9a C 3-6 Cycloalkyl.

[0142] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, R 4 In some embodiments, R 4 C 1-6 alkyl.

[0143] In some embodiments of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), (Icc), (Id), (Idd), (Ie), (Iee), (If), (Iff), (Ig), or (Igg), or a pharmaceutically acceptable salt thereof, R 2 In some embodiments, R 2 C 1-6alkyl.

[0144] In some embodiments, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0145]

[0146] in:

[0147] Ring A is selected from C 2-14 Heterocycloalkyl, C 2-14 Heteroaryl and C 6-10 Aryl, where C 2-14 Heterocycloalkyl, C 2-14 Heteroaryl and C 6-10 The aryl group is optionally substituted with one or more R 6a group substitution;

[0148] Ring D is selected from a 5- to 6-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring, and a 5- to 6-membered cycloalkyl ring;

[0149] L 1 Selected from -S(O)2- and -C(O)-;

[0150] L 2 Selected from bond, -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )-、-OC(R 8a )(R 8b )-、-C(R 8a )(R 8b )O- and -N(R 8c )-;

[0151] R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three groups selected from R 9a The group substitution;

[0152] Each R 1a are independently selected from halogen, -CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d The group substitution;

[0153] Ring B is selected from C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C1-9 Heteroaryl, wherein C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9b The group substitution;

[0154] R 3b and R 3c independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12)C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9c The group substitution;

[0155] R 4 Selected from hydrogen and C 1-6 alkyl;

[0156] Each R 6a Independently selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-C(O)N(R 10 )(R 11 )、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-; where C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0157] R 8a and R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution;

[0158] R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution;

[0159] Each R 9a 、R 9b 、R 9c 、R 9d 、R 9e and R 9f Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2;

[0160] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group;

[0161] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl;

[0162] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0163] Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 one, two or three groups substituted with heteroaryl; and

[0164] p is 0, 1, 2, or 3.

[0165] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, Ring D is a 5- to 6-membered heterocycloalkyl ring. In some embodiments, Ring D is a 5- to 6-membered heteroaryl ring. In some embodiments, Ring D is a 5- to 6-membered cycloalkyl ring.

[0166] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic ring. In some embodiments, Ring A is a bicyclic ring. In some embodiments, Ring A is a tricyclic ring. In some embodiments, Ring A is optionally substituted with one or more R 6a C 2-14 In some embodiments, Ring A is optionally substituted with one or more R 6a C 2-14 In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl. In some embodiments, Ring A is optionally substituted with one or more R 6a C 6-10 In some embodiments, ring A is phenyl, pyrimidinyl, pyridinyl, pyridazinone, 11-15 membered bicyclic heterocycle or 11-17 membered tricyclic heterocycle, wherein phenyl, pyrimidinyl, pyridinyl, pyridazinone, 11-15 membered bicyclic heterocycle and 11-17 membered tricyclic heterocycle are optionally replaced by one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, ring A is optionally substituted with one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a In some embodiments, ring A is optionally substituted with one or more R 6a In some embodiments, ring A is optionally substituted with one or more R 6a In some embodiments, Ring A is optionally substituted with one or more R 6a 11-17 membered tricyclic heterocycle substituted by a group.

[0167] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-; where C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6a In some embodiments, each R 6a Independently selected from optionally one, two or three selected from R 9e C 1-6 In some embodiments, each R 6a are independently optionally selected from one, two or three R 9e C 1-6 In some embodiments, or a pharmaceutically acceptable salt thereof, each R 6a is optionally selected from one, two or three R 9e C 3-6 In some embodiments, each R 6a is optionally selected from one, two or three R 9e C 2-9 In some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIcc), or (IIc), R 6 R 6aIn some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIcc), or (IIc), R 6b R 6a .

[0168] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, each R 1a independently selected from halogen and optionally substituted by one, two or three selected from R 9d C 1-6 alkyl.

[0169] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt thereof, p is 2. In some embodiments, p is 1. In some embodiments, p is 0. In some embodiments, disclosed herein are compounds of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0170]

[0171] in:

[0172] Is a single bond or a double bond;

[0173] Y 1 N, -C(R Ya )(R Yb )-or-C(R Ya )-;

[0174] Y 2 N, -C(R Ya )(R Yb )-or-C(R Ya )-;

[0175] Each R Ya and each R Yb independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d or R on the same carbon Ya and R Yb Together they form an oxo group;

[0176] L 1 Selected from -S(O)2- and -C(O)-;

[0177] L 2 Selected from bond, -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )-、-OC(R 8a )(R 8b )-、-C(R 8a )(R 8b )O- and -N(R 8c )-;

[0178] R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three groups selected from R 9a The group substitution;

[0179] Ring B is selected from C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9b The group substitution;

[0180] R 3b and R 3c are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9c The group substitution;

[0181] R 4 Selected from hydrogen and C 1-6 alkyl;

[0182] Each R 6 and R 6bare each independently hydrogen or independently selected from R 6a ;

[0183] Each R 6a are independently selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-C(O)N(R 10 )(R 11 )、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-; where C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution;

[0184] R 8a and R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution;

[0185] R 8c Selected from hydrogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution;

[0186] Each R 9a 、R 9b 、R 9c 、R 9d 、R 9e and R 9f Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10)(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2;

[0187] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group;

[0188] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl;

[0189] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0190] Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups in the heteroaryl group are substituted.

[0191] In some embodiments, disclosed herein is a compound of Formula (IIaa) or a pharmaceutically acceptable salt thereof:

[0192]

[0193] Each of the Y 2 、L 1 、L 2 、R1 、R 6b , Ring B and R 4 has the same meaning as herein.

[0194] In some embodiments, disclosed herein is a compound of formula (IIb) or a pharmaceutically acceptable salt thereof:

[0195]

[0196] Each of the Y 1 、Y 2 、L 1 、L 2 、R 1 、R 6 、R 6b 、R 3b 、R 3c , Ring B and R 4 has the same meaning as herein.

[0197] In some embodiments, disclosed herein is a compound of formula (IIbb) or a pharmaceutically acceptable salt thereof:

[0198]

[0199] Each of the Y 2 、L 1 、L 2 、R 1 、R 6 、R 6b , Ring B and R 4 has the same meaning as herein.

[0200] In some embodiments, disclosed herein is a compound of formula (IIbb') or a pharmaceutically acceptable salt thereof:

[0201]

[0202] Each of the Y 2 、L 1 、L 2 、R 1 、R 6b , Ring B and R 4 has the same meaning as herein.

[0203] In some embodiments, disclosed herein is a compound of formula (IIc) or a pharmaceutically acceptable salt thereof:

[0204]

[0205] Each of the Y 1 、Y 2 、L1 、L 2 、R 1 、R 6 、R 6b 、R 3b 、R 3c , Ring B and R 4 has the same meaning as herein.

[0206] In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt thereof, Y 1 -C(R Ya )(R Yb )-. In some embodiments, Y 1 is CH or CH2. In some embodiments, Y 1 -C(R Ya )-. In some embodiments, Y 1 is CH2. In some embodiments, Y 1 In some embodiments, Y 1 -NR 10 -. In some embodiments, Y 1 It is -NH-.

[0207] In some embodiments of the compound of Formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof, R 3b is selected from hydrogen, halogen, -CN and optionally substituted by one, two or three selected from R 9c C 1-6 In some embodiments, R 3b In some embodiments, R 3b In some embodiments, R 3b is optionally selected from one, two or three R 9c C 1-6 alkyl.

[0208] In some embodiments of the compound of Formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof, R 3c is selected from hydrogen, halogen, -CN and optionally substituted by one, two or three selected from R 9c C 1-6 In some embodiments, R 3c In some embodiments, R 3c In some embodiments, R 3c is optionally selected from one, two or three R 9c C1-6 alkyl.

[0209] In some embodiments of the compound of Formula (IIa), (IIb), (IIbb) or (IIc), or a pharmaceutically acceptable salt thereof, each R 6 are independently selected from hydrogen and R 6a In some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIcc), or (IIc), or a pharmaceutically acceptable salt thereof, each R 6b are independently selected from hydrogen and R 6a In some embodiments, R 6 In some embodiments, R 6 R 6b In some embodiments, one or more R 6 In some embodiments, one or more R 6 R 6b In some embodiments, R 6b In some embodiments, R 6b R 6a In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a Independently selected from optionally one, two or three selected from R 9e C 1-6 In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R6a are independently optionally selected from one, two or three R 9e C 1-6 In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a is optionally selected from one, two or three R 9e C 3-6 In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a is optionally selected from one, two or three R 9e C 2-9 In some embodiments, each R 6 and R 6b are independently selected from hydrogen and R 6a , where each R 6a Selected from -CH2CH2CF3, -CH2CH2CH2CF3, In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a Selected from -CH2CH2CF3, -CH2CH2CH2CF3, In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a is -CH2CH2CF3. In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a is -CH2CH2CH2CF3. In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a, where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for In some embodiments, each R 6 is hydrogen and R 6b R 6a , where R 6a for

[0210] In some embodiments, disclosed herein is a compound of formula (IIcc) or a pharmaceutically acceptable salt thereof:

[0211]

[0212] Each of the Y 2 、L 1 、L 2 、R 1 、R 6b , Ring B and R 4 has the same meaning as herein.

[0213] In some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, R 6b is hydrogen. In some embodiments, or a pharmaceutically acceptable salt thereof, R 6b R 6a In some embodiments, R 6b R 6a , and R 6a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 1-6 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 1-6 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 3-6 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e C 2-9 In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , and R 6a is optionally selected from one, two or three R 9e In some embodiments, R 6b R 6a , where R 6a Selected from -CH2CH2CF3, -CH2CH2CH2CF3, In some embodiments, R 6b R 6a , where R 6aIn some embodiments, R 6b R 6a , where R 6a In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for In some embodiments, R 6b R 6a , where R 6a for

[0214] In some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, Is a single bond. In some embodiments, For double bonds.

[0215] In some embodiments of the compound of Formula (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, Y 2 -C(R Ya )(R Yb )-. In some embodiments, Y 2 is CH or CH2. In some embodiments, Y 2 -C(R Ya)-. In some embodiments, Y 2 is CH2. In some embodiments, Y 2 For -N-.

[0216] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, L 1 In some embodiments, L 1 It is -C(O)-.

[0217] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 -C(R 8a )(R 8b )-. In some embodiments, L 2 In some embodiments, L 2 -OC(R 8a )(R 8b )-. In some embodiments, L 2 In some embodiments, L 2 -C(R 8a )(R 8b )O-. In some embodiments, L 2 In some embodiments, L 2 -N(R 8c )-. In some embodiments, L 2 It is -N(H)-.

[0218] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, Ring B is a monocyclic ring. In some embodiments, Ring B is a bicyclic ring. In some embodiments, Ring B is optionally substituted with one, two, or three rings selected from R 9b C 2-14 In some embodiments, Ring B is unsubstituted C 2-14In some embodiments, ring B is

[0219] In some embodiments of the compounds of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or pharmaceutically acceptable salts thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 3-12 In some embodiments, Ring B is optionally substituted with one, two or three selected from R 9b C 3-12 Cycloalkyl, wherein each R 9b In some embodiments, Ring B is unsubstituted C 3-12 In some embodiments, ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0220] In some embodiments of the compounds of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or pharmaceutically acceptable salts thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 1-9 Heteroaryl.

[0221] In some embodiments of the compounds of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or pharmaceutically acceptable salts thereof, Ring B is optionally substituted with one, two, or three selected from R 9b C 6-10 In some embodiments, Ring B is optionally substituted by one, two or three selected from R 9b A phenyl group substituted with a group.

[0222] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, R 1 is optionally selected from one, two or three R 9a C 1-6 In some embodiments, R 1is optionally substituted by one, two or three selected from -OH and C 1-6 Alkoxy group substituent substituted C 1-6 In some embodiments, R 1 C is substituted by a -OH group 1-6 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is -CH2CH2CH2OH.

[0223] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, R 1 is optionally selected from one, two or three R 9a C 3-6 Cycloalkyl.

[0224] In some embodiments of the compound of Formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIbb'), (IIc), or (IIcc), or a pharmaceutically acceptable salt thereof, R 4 In some embodiments, R 4 C 1-6 alkyl.

[0225] In some embodiments, each R 9a are independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11)-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments, each R9a are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9a are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0226] In some embodiments, each R 9b Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments, each R 9b are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9b are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0227] In some embodiments, each R 9c are independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11)-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments, each R 9c are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9c are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0228] In some embodiments, each R 9d Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R10 )(R 11 )-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R10 )2. In some embodiments, each R 9d are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9d are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0229] In some embodiments, each R 9e are independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments, each R 9e are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9e are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0230] In some embodiments, each R 9fare independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -CH2-5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, wherein alkyl, cycloalkyl, -CH2-cycloalkyl, heterocycloalkyl and -CH2-heterocycloalkyl are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments, each R 9f are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 In some embodiments, each R 9f are independently selected from halogen, oxo, amino, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0231] In some embodiments, R 8a and R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 8a In some embodiments, R 8a C 1-6 In some embodiments, R 8b In some embodiments, R 8b C 1-6 alkyl.

[0232] In some embodiments, R 8c Selected from hydrogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 8c In some embodiments, R8c C 1-6 alkyl.

[0233] In some embodiments, each R 1a are independently selected from halogen, -CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-C(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 ) and -N(R 12 )C(O)R 13 , wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one, two or three groups selected from R 9d In some embodiments, each R 1a Independently selected from halogen, -CN, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0234] In some embodiments, each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and C 2-9 In some embodiments, each R 10 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 10 In some embodiments, R 10 C 1-3 alkyl.

[0235] In some embodiments, R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 In some embodiments, R10 and R 11 Together with the nitrogen to which they are attached they form a 5-6 membered heterocycloalkyl.

[0236] In some embodiments, R 11 In some embodiments, R 11 C 1-6 In some embodiments, R 11 C 1-6 Halogenated alkyl.

[0237] In some embodiments, R 12 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 Halogenated alkyl.

[0238] In some embodiments, each R 13 Independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and C 2-9 In some embodiments, each R 13 Independently selected from C 1-6 Alkyl and C 1-6 In some embodiments, R 13 C 1-3 alkyl.

[0239] Any combination of the groups described above for each variable is contemplated herein. Throughout the present specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0240] In some embodiments, disclosed herein is a compound selected from the group consisting of:

[0241]

[0242]

[0243]

[0244] Other forms of the compounds disclosed herein

[0245] Isomers / stereoisomers

[0246] In some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis (cis), trans (trans), cis (syn), trans (anti), entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimers and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, enantiomers and / or mixtures of diastereoisomers produced from a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compound is made into its individual stereoisomers by reacting a racemic mixture of the compounds described herein with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered by any practical means that does not cause racemization along with a resolving agent.

[0247] Labeled compounds

[0248] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering these isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering these isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein comprise isotopically labeled compounds, wherein the compounds are identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically 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 chlorine, for example, respectively. 2 H(D), 3 H. 13 C. 14 C. l5 N.18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds (e.g., those incorporated into 3 H and 14 Compounds containing radioactive isotopes such as C) can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0249] In some embodiments, the deuterium abundance in each substituent 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% on a molar basis. In some embodiments, one or more substituents disclosed herein contain a percentage of deuterium that is greater than the natural deuterium abundance. In some embodiments, in one or more substituents disclosed herein, one or more 1 H is replaced by one or more deuteriums.

[0250] 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.

[0251] Pharmaceutically acceptable salts

[0252] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering these pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering these pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0253] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and 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 their solvates or stereoisomers, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0254] Examples of pharmaceutically acceptable salts include those prepared by reaction of the compounds described herein with mineral acids, organic acids, or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybenzoate, Butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 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, toluenesulfonate, undecanoate, and xylenesulfonate.

[0255] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such 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-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 (e.g., oxalic acid), while not pharmaceutically acceptable themselves, are used to prepare salts useful as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0256] In some embodiments, those compounds described herein that include free acid groups are reacted with a suitable base (e.g., hydroxide, carbonate, bicarbonate, sulfate) of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0257] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups contained therein. In some embodiments, water- or oil-soluble or dispersible products are obtained by quaternization.

[0258] Solvates

[0259] In some embodiments, the compounds described herein exist in the form of solvates. In some embodiments, the present disclosure provides methods of treating diseases by administering compounds in the form of such solvates. In some embodiments, the present disclosure provides methods of treating diseases by administering compositions comprising compounds in the form of such solvates. Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and in some embodiments, solvates are formed during a crystallization process using a pharmaceutically acceptable solvent.

[0260] Tautomers

[0261] In some cases, compounds exist as tautomers. The compounds described herein encompass all possible tautomers within the formulae described herein. Tautomers are compounds that can be interconverted by hydrogen atom migration with the conversion of single bonds to adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0262] Treatment

[0263] Disclosed herein is a method of treating a disease in which inhibition of KIF18A is beneficial, the method comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0264] Disclosed herein is a method of treating a disease or condition associated with KIF18A, comprising administering to a subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0265] Disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating cancer in a subject, the method comprises administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from (a) bladder cancer, endometrial cancer, squamous cell lung cancer, 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, stomach cancer, cervical cancer, or (b) a solid tumor or hematological tumor selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; (c) a myeloid hematopoietic tumor selected from the group consisting of acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannoma; (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma or a Kaposi's sarcoma. In some embodiments of the method of treating a solid tumor or hematological tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, 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 in a subject, the method comprises administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof.In some embodiments of the method of treating a hematopoietic neoplasm of the lymphoid lineage selected from leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma in a subject, the method comprises administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating a myeloid hematopoietic neoplasm 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 (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of 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 (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating a central and peripheral nervous system tumor selected from an astrocytoma, a neuroblastoma, a glioma, and a schwannoma in a subject, the method comprises administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof.In some embodiments of the method of treating melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma in a subject, the method comprises administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Iaa), (Ibb), (Icc), (Idd), (Iee), (Iff), (Igg), (II), (IIa), (IIb), (IIc), (IIaa), (IIbb), (IIbb'), or (IIcc) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0266] Drug administration

[0267] In certain embodiments, a composition containing a compound described herein is administered for therapeutic treatment. In certain therapeutic applications, a composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The amount effective for this application depends on the severity and course of the disease or condition, previous treatments, the patient's health, weight, and response to the drug, and the judgment of the treating physician. The amount of a given agent corresponding to such an amount depends on factors such as the specific compound, the disease condition and its severity, the attributes of the subject or host to be treated (e.g., weight, sex), but still needs to be determined based on the specific circumstances of the case, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0268] In various embodiments, dosage varies according to a number of variables including, but not limited to, the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0269] Route of administration

[0270] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0271] Pharmaceutical compositions / preparations

[0272] The compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, as a pharmaceutical composition, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0273] On the other hand, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically acceptable formulation. Suitable formulations depend on the selected route of administration. For an overview of the pharmaceutical compositions described herein, see, for example, Remington: The Science and Practice of Pharmacy, 19th ed. (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, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0274] Example

[0275] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

[0276] Unless otherwise indicated, as used above and throughout the specification of the present invention, the following abbreviations shall be understood to have the following meanings:

[0277] ACN or MeCN Acetonitrile

[0278] AcOH acetic acid

[0279] Ac acetyl

[0280] Bn benzyl

[0281] BOC or Boc tert-butyl carbamate

[0282] i-Bu isobutyl

[0283] t-Bu tert-butyl

[0284] CDI 1,1-Carbonyldiimidazole

[0285] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0286] DCE Dichloroethane (ClCH2CH2Cl)

[0287] DCM dichloromethane (CH2Cl2)

[0288] DIBAL-H Diisobutylaluminum hydride

[0289] DIPEA or DIEA diisopropylethylamine

[0290] DMAP 4-(N,N-dimethylamino)pyridine

[0291] DME 1,2-dimethoxyethane

[0292] DMF N,N-dimethylformamide

[0293] DMA N,N-dimethylacetamide

[0294] DMPU N,N′-dimethylpropylene urea

[0295] DMSO dimethyl sulfoxide

[0296] DPPA diphenylphosphoryl azide

[0297] Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene

[0298] EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide salt

[0299] acid salt

[0300] eq equivalent

[0301] Et ethyl

[0302] Et2O diethyl ether

[0303] EtOH

[0304] EA or EtOAc Ethyl acetate

[0305] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo

[0306] [4,5-b]pyridinium 3-oxide hexafluorophosphate

[0307] HOBt 1-Hydroxybenzotriazole

[0308] HPLC high-performance liquid chromatography

[0309] KOAc potassium acetate

[0310] KOtBu Potassium tert-butoxide

[0311] KHMDS Potassium bis(trimethylsilyl)amide

[0312] NaHMDS Sodium bis(trimethylsilyl)amide

[0313] LiHMDS Lithium bis(trimethylsilyl)amide

[0314] LAH / LiAlH4 Lithium Aluminum Hydride

[0315] LCMS liquid chromatography-mass spectrometry

[0316] Me methyl

[0317] MeOH methanol

[0318] MS

[0319] MTBE methyl tert-butyl ether

[0320] NBS N-bromosuccinimide

[0321] NMP N-Methyl-2-pyrrolidinone

[0322] NMR Nuclear Magnetic Resonance

[0323] PE petroleum ether

[0324] Ph Phenyl

[0325] iPr / i-Pr isopropyl

[0326] PyAOP (7-azabenzotriazol-1-yloxy)tripyrrole hexafluorophosphate

[0327] Alkylphosphonium

[0328] RP-HPLC reversed-phase high-pressure liquid chromatography

[0329] rt room temperature

[0330] SEM 2-(trimethylsilyl)ethoxymethyl

[0331] TBS tert-Butyldimethylsilyl

[0332] TEA triethylamine

[0333] TFA trifluoroacetic acid

[0334] THF Tetrahydrofuran

[0335] TLC thin layer chromatography

[0336] TMS trimethylsilyl

[0337] Intermediate 01: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (INT01)

[0338]

[0339] Step 1:

[0340] To a solution of 2-fluoro-4-iodobenzoic acid (1 g, 3.76 mmol) and 6-azaspiro[2.5]octane (0.71 g, 4.89 mmol) in DMSO (5 mL) was added K2CO3 (1.56 g, 11.28 mmol). Under an N2 atmosphere, the mixture was stirred at 140 ° C for 18 hours. The reaction was cooled to room temperature, diluted with water (100 mL) and washed with PE (100 mL×3). The aqueous phase was separated and acidified to pH=6 with HCl (1 M). The aqueous solution was concentrated under reduced pressure to give INT01 (700 mg). LCMS[M+H] + :358.0.

[0341] Intermediate 02: Synthesis of 1-((2-methoxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxylic acid (INT02)

[0342]

[0343] Step 1:

[0344] To a solution of 6-fluoro-1H-indole (20.0 g, 148 mmol) in AcOH (60 mL) was added NaBH3CN (18.6 g, 296 mmol). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was washed with an aqueous NaOH solution (2M, 1.5 L) and extracted with DCM (400 mL × 3). The combined organic layer was washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give INT02-1 (14.3 g). LCMS [M + H] + :138.3.

[0345] Step 2:

[0346] To a solution of INT02-1 (14.3 g, 104 mmol) in DCM (100 mL) was added TEA (29 mL, 209 mmol), DMAP (2.55 g, 20.9 mmol) and (Boc) O (35.9 mL, 156.4 mmol). The mixture was stirred at 25 ° C for 24 hours. The reaction mixture was washed with water (60 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (8 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give INT02-2 (22.0 g).

[0347] Step 3:

[0348] To a solution of INT02-2 (14.3 g, 60.3 mmol) in DMF (150 mL) was added NBS (12.9 g, 72.3 mmol). The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with water (300 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give INT02-3 (16.5 g).

[0349] Step 4:

[0350] Under N2 atmosphere, to a solution of INT02-3 (7.00 g, 22.1 mmol), NaOAc (5.45 g, 66.4 mmol) in DMF (70 mL) and MeOH (70 mL) was added Pd (dppf) Cl2 (3.24 g, 4.43 mmol). The suspension was degassed and purged with CO 3 times. The mixture was stirred at 80 ° C for 24 hours under a CO atmosphere (50 Psi). The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give INT02-4 (5.5 g).

[0351] Step 5:

[0352] To a solution of INT02-4 (2.00 g, 6.77 mmol) and K2CO3 (4.68 g, 33.9 mmol) in DMSO (40 mL) was added 6-azaspiro[2.5]octane (3.77 g, 33.9 mmol). Under an N2 atmosphere, the mixture was stirred at 130°C for 12 hours. The reaction mixture was diluted with water (40 mL), filtered, and concentrated under reduced pressure to give INT02-5 (725 mg). LCMS [M+H] + :387.3.

[0353] Step 6:

[0354] To a solution of INT02-5 (700 mg, 1.81 mmol) in THF (15 mL) was added LiOH (4.53 mL, 9.06 mmol) in water (2 mL). The mixture was stirred at 85 ° C for 12 hours. The mixture was cooled to 25 ° C and washed with water (20 mL). The aqueous phase was acidified to pH = 1 with 1M HCl and extracted with EtOAc (35 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give INT02-6 (800 mg). LCMS [M + H] + :371.2.

[0355] Step 7:

[0356] A solution of INT02-6 (1.00 g, 2.68 mmol) in HCl / dioxane (10 mL) was stirred at 25° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give INT02-7 (800 mg). LCMS [M+H] + :273.2.

[0357] Step 8:

[0358] To a solution of INT02-7 (800 mg, 2.93 mmol) in DCM (2 mL) was added DIEA (2.91 mL, 17.6 mmol) and 2-methoxyethane-1-sulfonyl chloride (931 mg, 5.87 mmol). The mixture was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give INT02 (130 mg). LCMS [M + H] + :395.1.

[0359] Example 1: 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-4-yl)benzamide (EX01)

[0360]

[0361] Step 1:

[0362] To a solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (123 mg, 0.566 mmol) in THF (5 mL) was added NaH (45 mg, 1.13 mmol). The reaction was stirred at 0 ° C for 1 hour, and then 2-chloro-3-fluoro-4-nitropyridine (100 mg, 0.566 mmol) in THF (5 mL) was added. The resulting mixture was stirred at 0 ° C for 12 hours. The reaction was quenched with NH4Cl aqueous solution (10 mL) and extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give EX01-1 (580 mg). LCMS [M + Na] + :396.0.

[0363] Step 2:

[0364] To a mixture of EX01-1 (420 mg, 1.12 mmol) and NH4Cl (420 mg, 7.86 mmol) in EtOH (4 mL) and H2O (4 mL) was added iron powder (439 mg, 7.86 mmol) in three batches. The resulting mixture was stirred at 80 ° C for 3 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and then diluted with EtOAc (50 mL) and H2O (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel chromatography to obtain EX01-2 (360 mg). LCMS [M+H] + :344.2.

[0365] Step 3:

[0366] To a solution of EX01-2 (360 mg, 1.04 mmol) in DCM (10 mL) was added HCl / MeOH (10 mL). The reaction mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give EX01-3 (351 mg). LCMS [M+H] + :244.1.

[0367] Step 4:

[0368] To a solution of EX01-3 (50.0 mg, 0.183 mmol) in dioxane (20 mL) was added CsCO (1.20 mg, 3.69 mmol), Xantphos (142 mg, 0.246 mmol) and Pd(dba) (112 mg, 0.123 mmol) under N2 atmosphere. The reaction was stirred at 80 ° C for 2 hours under N2 atmosphere. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (50 mL×2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give EX01-4 (140 mg). LCMS [M+H] + :208.2.

[0369] Step 5:

[0370] To a solution of EX01-4 (189 mg, 0.531 mmol) and INT01 (110 mg, 0.531 mmol) in DCM (5 mL) at 0 ° C., pyridine (0.43 mL, 5.30 mmol) and POCl3 (0.15 mL, 1.59 mmol) were added. The reaction was stirred at 25 ° C. for 2 hours. The reaction mixture was quenched with water (20 mL) at 25 ° C. and extracted with EtOAc (30 mL × 3). The combined organic layer was concentrated under reduced pressure and purified by preparative TLC to give EX01-5 (110 mg). LCMS [M + H] + :547.3.

[0371] Step 6:

[0372] A mixture of EX01-5 (100 mg, 0.183 mmol), 2-hydroxyethane-1-sulfonamide (23 mg, 0.183 mmol), K PO (116 mg, 0.549 mmol), CuI (35 mg, 0.183 mmol) and sarcosine (26 mg, 0.183 mmol) in DMF (2 mL) was stirred at 110° C. under N atmosphere for 1 hour. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC to give EX01 (44.4 mg). 1H NMR (400MHz, CD3OD) δ8.03(d,J=8.6Hz,1H),7.98(d,J=5.8Hz,1H),7.69(d,J=5.7Hz,1H),7.27( d,J=2.2Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),4.43(dd,J=10.8,2.9Hz,1H),4.23(dd,J=12.8,2.3 Hz,1H),4.07–3.99(m,2H),3.98–3.91(m,3H),3.65(td,J=11.8,2.8Hz,1H),3.57–3.46(m,1H),3 .38–3.32(m,3H),3.03(q,J=5.0Hz,4H),2.93(td,J=12.5,3.6Hz,1H),1.65(s,4H),0.41(s,4H). LCMS[M+H] + :544.2.

[0373] Example 2: 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -9-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX02)

[0374]

[0375] Step 1:

[0376] At 0 ° C, DIAD (4.68 mL, 23.8 mmol) was slowly added to a solution of tert-butyl (3-hydroxypropyl) (methyl) carbamate (3.00 g, 15.9 mmol) and 2-chloro-4-nitropyridine-3-ol (3.04 g, 17.4 mmol) and PPh (6.24 g, 23.8 mmol) in THF (30 mL). The reaction was stirred for 3 hours at 25 ° C. The reaction mixture was poured into water (80 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain EX02-1 (5.1 g).

[0377] To a solution of EX02-1 (5.10 g, 14.7 mmol) in DCM (50 mL) was added TFA (10 mL, 14.7 mmol). The reaction was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give EX02-2 (6.0 g). LCMS [M+H] + :246.3.

[0378] Step 2:

[0379] Under N2 atmosphere, Cs2CO3 (15.9 g, 48.8 mmol) was added to a solution of EX02-2 (1.50 g, 6.11 mmol) and XPhosPd G3 (0.78 g, 0.92 mmol) in dioxane (20 mL). The reaction was stirred at 100 ° C for 6 hours under N2 atmosphere. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (40 mL×4). The combined organic layer was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give EX02-3 (550 mg). LCMS [M+H] + :210.2.

[0380] Step 3:

[0381] To a suspension of Pd / C (10 wt%, 0.61 g, 5.74 mmol) in MeOH (10 mL) was added EX02-3 (0.60 g, 2.87 mmol). The mixture was stirred at 25° C. under a H 2 atmosphere for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give EX02-4 (400 mg). LCMS [M+H] + :180.2.

[0382] Step 4:

[0383] EX02 (15 mg) was prepared as described in Example 1 (EX01), steps 5-6, except that EX02-4 was used in step 5 instead of EX01-4. 1 H NMR (400MHz, CD3OD) δ7.96(d,J=5.7Hz,1H),7.91(d,J=8.6Hz,1H),7.73(d,J=5.7Hz,1H),7.15(d,J=2.1Hz,1H),6.98(dd,J=8.6,2.1Hz,1H),4.35(t, J=6.1Hz,2H),3.96(t,J=6.6Hz,2H),3.55–3.48(m,3H),3.31–3.28(m,2H) ,3.07(d,J=6.1Hz,7H),2.15(p,J=6.0Hz,2H),1.67(brs,4H),0.40(s,4H). LCMS[M+H] + :516.2.

[0384] Example 3: 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-2-yl)benzamide (EX03)

[0385]

[0386] Step 1:

[0387] At 0 ° C under N2 atmosphere, to a solution of 6-chloro-2-iodopyridine-3-ol (2.35g, 9.21mmol), PPh3 (3.62g, 13.81mmol) and tert-butyl 3-(hydroxymethyl)morpholine-4-formate (2.00g, 9.21mmol) in THF (40mL) was slowly added DIAD (2.79g, 13.8mmol, 2.68mL) in THF (40mL). The mixture was stirred at 20 ° C under N2 atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain EX03-1 (600mg). LCMS[M+H] + :455.7.

[0388] Step 2:

[0389] A mixture of EX03-1 (600 mg, 1.32 mmol) and HCl / MeOH (4 M, 1.65 mL) in MeOH (6 mL) was stirred at 25° C. under N2 atmosphere for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give EX03-2 (450 mg). LCMS [M+H] + :355.0.

[0390] Step 3:

[0391] A mixture of EX03-2 (450 mg, 1.83 mmol), CuI (69.8 mg, 367 umol) and K3PO4 (2.18 g, 10.27 mmol) in DMSO (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 ° C for 3 hours under N2 atmosphere. The mixture was filtered, the filtrate was diluted with water (10 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give EX03-3 (350 mg). LCMS[M+H] + :227.1.

[0392] Step 4:

[0393] A mixture of EX03-3 (400 mg, 1.76 mmol), tert-butyl carbamate (289 mg, 2.47 mmol), Cs2CO3 (1.72 g, 5.29 mmol), Pd2(dba)3 (323 mg, 353 umol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (336 mg, 706 umol) in toluene (5 mL) was degassed and purged with N2 three times. The mixture was stirred at 85 ° C for 12 hours under N2 atmosphere. The mixture was filtered, and the filtrate was diluted with water (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give EX03-4 (180 mg). LCMS[M+H] + :308.2.

[0394] Step 5:

[0395] A mixture of EX03-4 (180 mg, 0.781 mmol) in DCM (2 mL) and TFA (89 mg, 0.78 mmol) was stirred at 25° C. under N2 atmosphere for 3 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give EX03-5 (160 mg). LCMS [M+Na] + :230.3.

[0396] Step 6:

[0397] EX03 (77 mg) was prepared as described in Example 1 (EX01), steps 5-6, except that EX03-5 was used in step 5 instead of EX01-4. 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),10.16(s,1H),8.06(d,J=8.6Hz,1H),7.53(d,J=8.4Hz,1H),7.26( d,J=2.2Hz,1H),7.11(dd,J=8.6,2.2Hz,1H),7.06(d,J=8.3Hz,1H),4.93(s,1H),4.28–4.18(m,2H),3.9 8(dd,J=11.4,3.4Hz,1H),3.93–3.83(m,2H),3.75(t,J=6.6Hz,2H),3.57(td,J=11.8,2.7Hz,1H),3.49– 3.41(m,1H),3.35(t,J=6.5Hz,2H),3.23–3.13(m,2H),2.96(t,J=5.2Hz,4H),1.75(s,4H),0.37(s,4H). LCMS[M+H] + :544.4.

[0398] Example 4: 4-((2-hydroxyethyl)sulfonamido)-N-(2-oxo-1-(4,4,4-trifluorobutyl)-1,2-dihydropyridin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX04)

[0399]

[0400] Step 1:

[0401] To a solution of 3-nitropyridine-2 (1H) -one (1.40 g, 9.99 mmol) in DMF (50 mL) was added CsCO (6.51 g, 19.98 mmol) and 4-bromo-1,1,1-trifluorobutane (2.00 g, 10.47 mmol). The reaction was stirred at 70 ° C for 5 hours. The reaction mixture was cooled to room temperature, quenched with NH4Cl aqueous solution (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain EX04-1 (500 mg). 1 H NMR (400MHz, DMSO-d6) δ8.40 (dd, J=7.6, 2.0Hz, 1H), 8.21 (dd, J=6.8, 2.0Hz, 1H), 6.45 (dd,J=7.6,6.63Hz,1H),4.09(t,J=7.2Hz,2H),2.26–2.38(m,2H),1.87–1.95(m,2H). LCMS[M+H] +:251.1.

[0402] Step 2:

[0403] To a stirred solution of EX04-1 (500 mg, 2.00 mmol) in EtOH (20 mL) was added a solution of NH4Cl (321 mg, 6.00 mmol) in water (4 mL), and then iron powder (558 mg, 10.0 mmol) was added in portions. The mixture was stirred at 50 ° C for 5 hours. The mixture was cooled to room temperature, filtered through celite, and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to give EX04-2 (440 mg). LCMS [M+H] + :221.2.

[0404] Step 3:

[0405] EX04 (62 mg) was prepared as described in Example 1 (EX01) Steps 5-6, except that EX04-2 was used in Step 5 instead of EX01-4. 1 H NMR (400MHz, CD3OD) δ8.60 (dd, J=7.6, 1.8Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.33 (dd, J=6.9,1.8Hz,1H),7.23(d,J=2.2Hz,1H),7.07(dd,J=8.6,2.1Hz,1H),6.40(t,J=7 .2Hz,1H),4.16(t,J=7.1Hz,2H),3.94(t,J=6.3Hz,2H),3.36(t,J=6.3Hz,2H),3.0 3(t,J=5.4Hz,4H),2.36–2.17(m,2H),2.13–1.99(m,2H),1.69(s,4H),0.34(s,4H). LCMS [M+H] + :557.3.

[0406] Example 5: 4-((2-hydroxyethyl)sulfonamido)-N-(6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridazin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX05)

[0407]

[0408] Step 1:

[0409] To a solution of 6-chloropyridazine-3-ol (1.00 g, 7.66 mmol) and 4-iodotetrahydro-2H-pyran (2.27 g, 10.7 mmol) in DMF (10 mL) was added K2CO3 (2.12 g, 15.3 mmol). The reaction was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (30 mL × 4). The combined organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative TLC to give EX05-1 (520 mg). LCMS [M + H] + :215.2.

[0410] Step 2:

[0411] To a suspension of EX05-1 (500 mg, 2.33 mmol), tert-butyl carbamate (546 mg, 4.66 mmol), Pd2(dba)3 (427 mg, 0.47 mmol) and XPhos (444 mg, 0.93 mmol) in toluene (15 mL) was added Cs2CO3 (2276 mg, 6.99 mmol). The reaction was stirred at 90 ° C for 12 hours under N2. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give EX05-2 (600 mg). LCMS[M+H] + :296.2.

[0412] Step 3:

[0413] To a solution of EX05-2 (500 mg, 1.69 mmol) in dioxane (10 mL) was added HCl (2 mL, 1.69 mmol). The reaction was stirred at 25 ° C for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM / MeOH (20: 1, 30 mL × 4). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give EX05-3 (320 mg). LCMS [M + H] + :196.3.

[0414] Step 4:

[0415] EX05 (40 mg) was prepared as described in Example 1 (EX01) Steps 5-6, except that EX05-3 was used in Step 5 instead of EX01-4. 1H NMR (400MHz, CD3OD) δ8.55(d,J=9.8Hz,1H),8.15(d,J=8.6Hz,1H),7.35(d,J=2.1Hz,1H ),7.19(dd,J=8.7,2.2Hz,1H),7.09(d,J=9.9Hz,1H),5.16(tt,J=11.6,3.8Hz,1H),4.11 (dd,J=11.8,4.5Hz,2H),3.97(t,J=6.2Hz,2H),3.63(t,J=11.9Hz,2H),3.39(t,J=6.3H z,2H),3.19–3.04(m,4H),2.19(qd,J=12.2,4.3Hz,2H),2.01–1.60(m,6H),0.49(s,4H). LCMS[M+H] + :532.4.

[0416] Example 6: 4-((2-hydroxyethyl)sulfonamido)-N-(6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX06)

[0417]

[0418] Step 1:

[0419] To a solution of 5-nitropyridin-2(1H)-one (1 g, 7.138 mmol) in dioxane (5 mL) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g, 7.852 mmol) was added Cu(OAc)2 (0.26 g, 1.428 mmol) and TEA (3.969 mL, 28.551 mmol). The reaction mixture was stirred at 80 ° C for 3 hours under N2 atmosphere. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give EX06-1 (1.3 g). LCMS[M+H] + :223.2.

[0420] Step 2:

[0421] To a mixture of EX06-1 (1.00 g, 4.50 mmol) and NH4Cl (1.69 g, 31.5 mmol) in EtOH (10 mL) and H2O (10 mL) was added iron powder (1.76 g, 31.5 mmol) in three batches. The mixture was stirred at 80 ° C for 3 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain EX06-2 (700 mg).

[0422] Step 3:

[0423] EX06-3 (90 mg) was prepared as described in Example 1 (EX01) steps 5-6, except that EX06-2 was used instead of EX01-4 in step 5. LCMS [M+H] + :532.3.

[0424] Step 4:

[0425] A solution of EX06-3 (100 mg, 2.36 mmol) and Pd / C (1.0 g, 10 wt%) in MeOH (10 mL) was degassed and flushed with H 2 , and the reaction mixture was stirred under H 2 atmosphere at 25° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give EX06 (20 mg). 1 H NMR (400MHz, CDCl3) δ12.52(s,1H),8.70(d,J=2.7Hz,1H),8.20(d,J=8.5Hz,1H),7.72(s,1H),7.39(d,J =2.1Hz,1H),7.29(dd,J=9.6,2.8Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),6.69(d,J=9.5Hz,1H),5.20(tt,J= 12.2,4.4Hz,1H),4.12(dt,J=10.6,4.6Hz,4H),3.61(t,J=11.3Hz,2H),3.33(t,J=5.1Hz,2H),3.06(t,J =5.3Hz, 5H), 2.00 (qd, J = 12.1, 4.5Hz, 2H), 1.90 (dd, J = 12.7, 3.9Hz, 2H), 1.65–1.57 (m, 4H), 0.46 (s, 4H). LCMS[M+H] + :531.3.

[0426] Example 7: N-(8,8-difluoro-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX07)

[0427]

[0428] Step 1:

[0429] EX07 (3.3 mg) was prepared as described in Example 3 (EX03) steps 1-6, except that tert-butyl 4,4-difluoro-2-(hydroxymethyl)piperidine-1-carboxylate was used in step 1 instead of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate. 1 H NMR (400MHz, CD3OD) δ8.12(d,J=8.5Hz,1H),7.59(d,J=8.4Hz,1H),7.31(s,1H),7 .14(d,J=8.7Hz,1H),7.05(d,J=8.4Hz,1H),4.32(dd,J=11.2,2.9Hz,1H),4.03(dd ,J=11.2,6.2Hz,1H),3.95(t,J=6.2Hz,2H),3.61–3.49(m,1H),3.36(t,J=6.3Hz,2 H), 3.08 (t, J = 5.4Hz, 4H), 2.93 (t, J = 12.7Hz, 1H), 2.23–1.71 (m, 8H), 0.44 (s, 4H). LCMS [M+H] + :578.4.

[0430] Example 8: 4-((2-hydroxyethyl)sulfonamido)-N-(6-oxo-1-(4,4,4-trifluorobutyl)-1,6-dihydropyridazin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX08)

[0431]

[0432] Step 1:

[0433] EX08 (50 mg) was prepared as described in Example 5 (EX05) steps 1-4, except that 4-bromo-1,1,1-trifluorobutane was used in step 1 instead of 4-iodotetrahydro-2H-pyran. 1H NMR (400MHz, CD3OD) δ8.53(d,J=9.9Hz,1H),8.13(d,J=8.7Hz,1H),7.35(d,J=2.2Hz,1H),7.18(dd,J=8.7,2.2Hz,1H),7.09(d,J=9.9Hz,1H),4.24(t,J =6.9Hz,2H),3.96(t,J=6.3Hz,2H),3.38(t,J=6.3Hz,3H),3.10(t,J=5.4Hz ,5H),2.39–2.24(m,2H),2.21–2.08(m,2H),1.92–1.64(m,4H),0.46(s,4H). LCMS[M+H] + :558.4.

[0434] Example 9: N-(1-(4,4-difluorocyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX09)

[0435]

[0436] Step 1:

[0437] To a solution of 3-nitropyridin-2(1H)-one (1 g, 7.13 mmol) in dioxane (5 mL) was added TEA (3.96 mL, 28.5 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g, 7.85 mmol) and Cu(OAc)2 (0.26 g, 1.42 mmol). The reaction mixture was stirred at 80 ° C for 3 hours. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give EX09-1 (1.3 g). LCMS[M+H] + :257.2.

[0438] Step 2:

[0439] A mixture of EX09-1 (1.00 g, 4.50 mmol) and Pd / C (10 wt%, 1.69 g, 31.5 mmol) in EtOH (10 mL) was stirred at 25 ° C. under H2 atmosphere for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give EX09-2 (700 mg). LCMS [M+H] + :229.1.

[0440] Step 3:

[0441] EX09 (20 mg) was prepared as described in Example 1 (EX01), steps 5-6, except that EX09-2 was used in step 5 instead of EX01-4. 1 H NMR (400MHz, CD3OD) δ8.60 (dd, J=7.4, 1.7Hz, 1H), 7.99 (d, J=8.6Hz, 1H), 7.42 (d d,J=7.1,1.8Hz,1H),7.27(d,J=2.2Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),6.45(t, J=7.3Hz,1H),5.06(p,J=7.0,6.5Hz,1H),3.96(t,J=6.3Hz,2H),3.38(t,J=6.3H z, 2H), 3.06 (t, J = 5.4Hz, 4H), 2.32–1.91 (m, 8H), 1.86–1.53 (m, 4H), 0.38 (s, 4H). LCMS [M+H] + :565.5.

[0442] Example 10: N-(8,8-difluoro-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX10)

[0443]

[0444] Step 1:

[0445] EX10 (20 mg) was prepared as described in Example 1 (EX01) steps 1-6, except that tert-butyl 4,4-difluoro-2-(hydroxymethyl)piperidine-1-carboxylate was used in step 1 instead of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate. 1H NMR (400MHz, CD3OD) δ8.05(d,J=8.6Hz,1H),8.01(d,J=5.7Hz,1H),7.74(d,J=5.7Hz,1H),7.29( d,J=2.1Hz,1H),7.12(dd,J=8.6,2.1Hz,1H),4.77(d,J=13.7Hz,1H),4.50(dd,J=11.0,2.8Hz,1 H),4.25(dd,J=11.1,5.4Hz,1H),3.96(t,J=6.2Hz,2H),3.67(d,J=12.0Hz,1H),3.38(t,J=6.2H z,2H),3.12–2.94(m,5H),2.31–2.09(m,2H),2.06–1.85(m,2H),1.82–1.50(m,4H),0.44(s,4H). LCMS[M+H] + :578.4.

[0446] Example 11: N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX11)

[0447]

[0448] Step 1:

[0449] EX11 (30 mg) was prepared as described in Example 5 (EX05) steps 1-4, except that 4-bromo-1,1-difluorocyclohexane was used in step 1 instead of 4-iodotetrahydro-2H-pyran. 1 H NMR (400MHz, CD3OD) δ8.56(d,J=9.9Hz,1H),8.16(d,J=8.6Hz,1H),7.37(d,J=2.2Hz,1H),7.20(dd,J=8.7,2.2Hz,1H),7.09(d,J=9.9Hz,1H) ,5.14–5.03(m,1H),3.97(t,J=6.2Hz,2H),3.39(t,J=6.2Hz,2H),3.10(t,J=5.3Hz,4H),2.28–2.17(m,4H),2.18–1.70(m,8H),0.48(s,4H). LCMS[M+H] + :566.5.

[0450] Example 12: N-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (EX12)

[0451]

[0452] Step 1:

[0453] EX12 (10 mg) was prepared as described in Example 5 (EX05) steps 1-4, except that 3-chloro-1,1-difluorocyclobutane was used in step 1 instead of 4-iodotetrahydro-2H-pyran. 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),10.25(brs,1H),8.40(d,J=10.0Hz,1H),8.04(d,J=8.6Hz,1H),7.29(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H ),7.07(d,J=10.0Hz,1H),5.39–5.25(m,1H),4.95(brs,1H),3.76(t,J=6.5 Hz,2H),3.40–3.35(m,2H),3.12–2.93(m,8H),1.68(brs,4H),0.38(s,4H). LCMS[M+H] + :538.3.

[0454] Example 13: 1-((2-methoxyethyl)sulfonyl)-N-(6-morpholinopyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX13)

[0455]

[0456] Step 1:

[0457] A mixture of morpholine (5.04 mL, 76.6 mmol) and 6-bromopyridin-2-amine (2.50 g, 14.5 mmol) was stirred at 150° C. for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure and purified by preparative TLC to give EX13-1 (2.3 g). LCMS [M+H] + :180.2.

[0458] Step 2:

[0459] To a solution of INT02-6 (550 mg, 1.48 mmol) in DCM (5 mL) was added DMF (0.12 mL, 1.48 mmol) and (COCl) (0.15 mL, 1.77 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The mixture solution was slowly added to a solution of EX13-1 (266 mg, 1.48 mmol) and TEA (448 mg, 4.430 mmol) in DCM (5 mL) at 0 ° C. The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine (8 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give EX13-2 (250 mg). LCMS [M + H] + :534.4.

[0460] Step 3:

[0461] To a solution of EX13-2 (200 mg, 0.38 mmol) in MeOH (1 mL) was added HCl (1 M in MeOH, 0.38 mL, 0.38 mmol). The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give EX13-3 (115 mg). LCMS [M+H] + :434.4.

[0462] Step 4:

[0463] To a solution of EX13-3 (100 mg, 0.23 mmol) in DCM (5 mL) was added 2-methoxyethane-1-sulfonyl chloride (73 mg, 0.46 mmol) and DIPEA (0.23 mL, 1.38 mmol). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (8 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give EX13 (150 mg). 1H NMR (400MHz, CD3OD) δ8.04(s,1H),7.78(t,J=8.2Hz,1H),7.53(s,1H),7.22(s,1H),6.75(d,J=8.6Hz,1H),4.13(t,J=8.6Hz,2H),3.84(t, J=4.9Hz,4H),3.74(t,J=5.9Hz,2H),3.64–3.49(m,6H),3.20(t,J=8.6Hz,2H),3.11(s,3H),2.66(s,4H),1.99–1.45(m,4H),0.50(s,4H). LCMS[M+H] + :556.4.

[0464] Example 14: 1-((2-Hydroxyethyl)sulfonyl)-N-(6-morpholinopyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX14)

[0465]

[0466] Step 1:

[0467] To a solution of EX-13 (100 mg, 0.18 mmol) in DCM (5 mL) was added dropwise BBr (45 mg, 0.18 mmol) at -45 ° C under N2 atmosphere. The mixture was stirred at -45 ° C for 3 hours under N2 atmosphere. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (8 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give EX-14 (9.5 mg). 1 H NMR (400MHz, CD3OD) δ8.13(s,1H),7.96(t,J=8.4Hz,1H),7.68(s,1H),7.16(s,1H),6.96(d,J=8.9Hz,1H),4.23(t,J=8.7Hz,2H),3.98(t,J=5 .5Hz,2H),3.92–3.85(m,4H),3.71–3.67(m,4H),3.67–3.55(m,4H),3. 53(t,J=5.5Hz,2H),3.29–3.25(m,2H),2.36–1.43(m,4H),0.59(s,4H). LCMS[M+H] + :542.3.

[0468] Example 15: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX15)

[0469]

[0470] Step 1:

[0471] EX15 (8 mg) was prepared as described in Example 13 (EX13) steps 1-4 and Example 14 (EX14) step 1, except that 4,4-difluoropiperidine and 2-chloro-6-methylpyrimidin-4-amine were used instead of morpholine and 6-bromopyridin-2-amine in Example 13 step 1. 1 H NMR (400MHz, DMSO-d6) δ13.69(s,1H),7.98(s,1H),7.41(s,1H),7.29(s,1H),4.08(t,J=8.5Hz,2H),3.92(t,J=5.8Hz,4H),3.78(t,J=5.9 Hz,2H),3.46(t,J=5.9Hz,2H),3.15(t,J=8.6Hz,2H),2.98(t,J=5.3Hz,4H),2.32(s,3H),2.06–1.93(m,4H),1.76(brs,4H),0.40(s,4H). LCMS[M+H] + :591.5.

[0472] Example 16: 1-((2-hydroxyethyl)sulfonyl)-N-(6-oxo-1-(4,4,4-trifluorobutyl)-1,6-dihydropyridazin-3-yl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX16)

[0473]

[0474] Step 1:

[0475] EX16-1 (920 mg) was prepared as described in Example 5 (EX05) steps 1-3, except that 4-bromo-1,1,1-trifluorobutane was used instead of 4-iodotetrahydro-2H-pyran in step 1. LCMS [M+H] + :222.1.

[0476] Step 2:

[0477] A mixture of EX16-1 (15 mg, 0.067 mmol), INTO2 (22 mg, 6.47 mmol) and pyridine (0.045 mL, 0.558 mmol) in DCM (1 mL) was stirred at 25 ° C. under N2 atmosphere for 5 hours. The reaction mixture was filtered, and the filtrate was diluted with water (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give EX16-2 (15 mg). LCMS [M+H] + :598.4.

[0478] Step 3:

[0479] EX16 (6 mg) was prepared as described in Example 14 (EX14), except that EX16-2 was used instead of EX13. 1 H NMR (400MHz, CD3OD) δ8.53(d,J=9.9Hz,1H),8.05(s,1H),7.47(s,1H),7.09(d,J=9.9Hz,1H),4.24(t,J=7.0Hz,2H),4.17(t,J=8.6Hz,2H),3.97(t,J =5.8Hz,2H),3.43(t,J=5.8Hz,2H),3.21(t,J=8.6Hz,2H),3.09(t,J=5.4H z,4H),2.38–2.24(m,2H),2.19–2.09(m,2H),1.78(brs,4H),0.47(s,4H). LCMS[M+H] + :584.5.

[0480] Example 17: 1-((2-hydroxyethyl)sulfonyl)-N-(6-oxo-1-(3,3,3-trifluoropropyl)-1,6-dihydropyridazin-3-yl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX17)

[0481]

[0482] Step 1:

[0483] EX17 (25 mg) was prepared as described in Example 16 (EX16) steps 1-3, except that 3-chloro-1,1,1-trifluoropropane was used instead of 4-bromo-1,1,1-trifluorobutane in step 1. 1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),8.35(d,J=10.0Hz,1H),7.95(s,1H),7.29(s, 1H),7.09(d,J=10.0Hz,1H),5.04(t,J=5.2Hz,1H),4.27(t,J=6.8Hz,2H),4.07(t,J =8.6Hz,2H),3.77(q,J=5.7Hz,2H),3.46(t,J=5.9Hz,2H),3.13(t,J=8.5Hz,2H),2. 98(t,J=5.3Hz,4H),2.81(dtd,J=17.9,11.4,6.6Hz,2H),1.66(s,4H),0.39(s,4H). LCMS[M+H] + :570.3.

[0484] Example 18: N-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX18)

[0485]

[0486] Step 1:

[0487] EX18 (3.4 mg) was prepared as described in Example 16 (EX16) steps 1-3, except that 3-bromo-1,1-difluorocyclobutane was used in step 1 instead of 4-bromo-1,1,1-trifluorobutane. 1 H NMR (400MHz, DMSO-d6) δ13.79(s,1H),8.41(d,J=10.0Hz,1H),7.97(s,1H),7.30(s,1H),7.07(d,J=10.0Hz,1H),5.30(tt,J=12.9,6.9Hz,1H), 4.08(t,J=8.6Hz,2H), 3.77(t,J=5.9Hz,2H), 3.46(t,J=5.9Hz,3H), 3.14(t,J=8.6Hz,2H), 3.11–2.95(m,8H), 1.91–1.47(m,4H), 0.40(s,4H). LCMS[M+H] + :564.2.

[0488] Example 19: N-(8,8-difluoro-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazin-4-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX19)

[0489]

[0490] Step 1:

[0491] EX19-1 (11 mg) was prepared as described in Example 1 (EX01) steps 1-4, except that tert-butyl 4,4-difluoro-2-(hydroxymethyl)piperidine-1-carboxylate was used instead of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate in step 1. LCMS [M+H] + :242.1.

[0492] Step 2:

[0493] EX19 (3 ​​mg) was prepared as described in Example 16 (EX16) steps 2-3, except that EX19-1 was used in step 2 instead of EX16-1. 1 H NMR (400MHz, CD3OD) δ8.00(d,J=5.8Hz,1H),7.97(s,1H),7.74(d,J=5.8Hz,1H),7.41(s,1H),4.77 (d,J=14.0Hz,1H),4.50(dd,J=11.3,2.6Hz,1H),4.24(dd,J=11.1,5.4Hz,1H),4.16(t,J=8.6Hz,2 H),3.97(t,J=5.8Hz,2H),3.67(d,J=12.2Hz,1H),3.42(t,J=5.9Hz,2H),3.19(t,J=8.6Hz,2H),3. 11–2.93(m,5H),2.18(dt,J=39.3,12.2Hz,2H),2.06–1.85(m,2H),1.81–1.48(m,4H),0.44(s,4H). LCMS[M+H] + :604.4.

[0494] Example 20: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX20)

[0495]

[0496] Step 1:

[0497] EX20-1 (90 mg) was prepared as described in Example 13 (EX13) steps 1-3, except that 4,4-difluoropiperidine and 2-chloro-6-methylpyrimidin-4-amine were used instead of morpholine and 6-bromopyridin-2-amine in step 1. LCMS [M+H] + :483.2.

[0498] Step 2:

[0499] EX20 (23 mg) was prepared as described in Example 13 (EX13), step 4, except EX20-1 and methanesulfonyl chloride were used instead of EX13-3 and 2-methoxyethane-1-sulfonyl chloride. 1 H NMR (400MHz, CD3OD) δ8.07(s,1H),7.45(s,1H),7.44(s,1H),4.07(t,J=8.5Hz,2H),3.99(t,J=5.9Hz,4H) ,3.20(t,J=8.4Hz,4H),3.06(t,J=5.3Hz,4H),3.02(s,3H),2.36(s,3H),2.05–1.89(m,6H),0.44(s,4H). LCMS[M+H] + :561.2.

[0500] Example 21: N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX21)

[0501]

[0502] Step 1:

[0503] EX21 (6 mg) was prepared as described in Example 16 (EX16) steps 1-3, except that 4-bromo-1,1-difluorocyclohexane was used in step 1 instead of 4-bromo-1,1,1-trifluorobutane. 1 H NMR (400MHz, DMSO-d6) δ13.93(s,1H),8.38(d,J=10.0Hz,1H),7.97(s,1H),7.30(s,1H),7.07(d,J=9.9Hz,1H),5.14–4.92(m,2H),4. 08(t,J=8.7Hz,2H),3.78(q,J=5.7Hz,2H),3.50–3.44(m,2H),3.14(t,J=8.5Hz,2H),2.98(brs,4H),2.24–1.57(m,12H),0.40(s,4H). LCMS[M+H]+ :592.4.

[0504] Example 22: 1-((2-Hydroxyethyl)sulfonyl)-N-(1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX22)

[0505]

[0506] Step 1:

[0507] EX22 (3 mg) was prepared as described in Example 16 (EX16) steps 1-3, except that 2-iodopropane was used in step 1 instead of 4-bromo-1,1,1-trifluorobutane. 1 H NMR (400MHz, DMSO-d6) δ13.90 (s, 1H), 8.35 (d, J = 9.9Hz, 1H), 7.97 (s, 1H), 7.29 (s,1H),7.02(d,J=9.9Hz,1H),5.17(p,J=6.6Hz,1H),5.06(t,J=5.1Hz,1H),4. 10–4.07(m,2H),3.80–3.74(m,2H),3.45(t,J=6.0Hz,2H),3.13(t,J=8.2Hz,3H ), 2.99 (t, J = 5.3Hz, 4H), 1.95–1.49 (m, 4H), 1.30 (d, J = 6.6Hz, 6H), 0.40 (s, 4H). LCMS [M+H] + :516.4.

[0508] Example 23: N-(2-(3,3-difluoropyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX23)

[0509]

[0510] Step 1:

[0511] EX23 (1.8 mg) was prepared as described in Example 13 (EX13) steps 1-4 and Example 14 (EX14), except that 3,3-difluoropyrrolidine and 2-chloro-6-methylpyrimidin-4-amine were used instead of morpholine and 6-bromopyridin-2-amine in Example 13 step 1. 1H NMR (400MHz, DMSO-d6) δ13.87(s,1H),7.98(s,1H),7.42(s,1H),7.29(s,1H),5.05(t,J=5.2Hz,1H),4.08(t,J=8.6Hz,2H),3.91(t,J=13.2Hz,2H) ,3.81–3.69(m,4H),3.47(t,J=5.9Hz,2H),3.15(t,J=8.5Hz,2H),3.02–2 .93(m,4H),2.63–2.54(m,2H),2.33(brs,4H),1.77(s,2H),0.39(s,4H). LCMS[M+H] + :577.4.

[0512] Example 24: N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-1-((2-hydroxyethyl)sulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX24)

[0513]

[0514] Step 1:

[0515] EX24 (28 mg) was prepared as described in Example 13 (EX13) steps 1-4 and Example 14 (EX14), except that 3,3-difluoroazetidine and 2-chloro-6-methylpyrimidin-4-amine were used instead of morpholine and 6-bromopyridin-2-amine in Example 13 step 1. 1 H NMR (400MHz, DMSO-d6) δ13.86(s,1H),7.96(s,1H),7.51(s,1H),7.28(s,1H),5.04(t,J=5.3Hz,1H),4.43(t,J=12.5Hz,4H),4.08(t,J=8.6H z, 2H), 3.77 (q, J = 5.6Hz, 2H), 3.47 (d, J = 5.9Hz, 2H), 3.14 (t, J = 8.5Hz, 2H), 2.97 (t, J = 5.3Hz, 4H), 2.33 (s, 3H), 1.74 (brs, 4H), 0.40 (s, 4H). LCMS[M+H] + :563.3.

[0516] Example 25: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-(3-hydroxypropionyl)-6-(6-azaspiro[2.5]octan-6-yl)indoline-5-carboxamide (EX25)

[0517]

[0518] Step 1:

[0519] To a solution of EX20-1 (100 mg, 0.21 mmol) in DCM (5 mL) was added DIEA (0.21 mL, 1.24 mmol) and 3-methoxypropanoyl chloride (30 mg, 0.25 mmol). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (8 mL×3). The combined organic layer was washed with brine (15 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give EX25-1 (150 mg). LCMS [M+H] + :569.5.

[0520] Step 2:

[0521] EX25 (20 mg) was prepared as described in Example 14 (EX14), except EX25-1 was used instead of EX13. 1 H NMR(400MHz,DMSO-d6)δ13.92(s,1H),8.23(s,1H),7.97(s,1H),7.40(s,1H), 4.65(d,J=5.5Hz,1H),4.19(t,J=8.5Hz,2H),3.91(t,J=5.5Hz,4H),3.74(q,J= 5.6,5.2Hz,2H),3.17(t,J=8.5Hz,2H),2.96(t,J=5.3Hz,4H),2.65(t,J=6.5H z, 2H), 2.31 (s, 3H), 1.98 (tt, J = 13.6, 5.6Hz, 4H), 1.75 (brs, 4H), 0.39 (s, 4H). LCMS[M+H] + :555.5.

[0522] Example 26: KIF18A assay

[0523] The KIF18A assay was performed as follows:

[0524] 1.1. Prepare 1x kinase buffer

[0525] 1.2. Compound screening:

[0526] a) Add 40 μL of test compound to a 384-well dilution plate

[0527] b) The compounds were diluted in DMSO at a ratio of 1:3, with 10 points per column.

[0528] c) Use Echo to transfer 0.1 μL of the diluted compound solution to a 384-well assay plate, with each column containing 2 replicates.

[0529] d) Add 5 μL of enzyme working solution to a 384-well assay plate and centrifuge at 1000 RPM for 1 minute.

[0530] e) Incubate at 25°C for 15 minutes

[0531] f) Add 5 μL of ATP working solution to start the reaction

[0532] g) Incubate at 25°C for 60 minutes

[0533] h) Add 10 μL of ADP Glo reagent and centrifuge at 1000 RPM for 1 minute

[0534] i) Incubate at 25°C for 60 minutes

[0535] j) Add 20 μL of kinase detection reagent and centrifuge at 1000 RPM for 1 minute

[0536] k) Incubate at 25°C for 60 minutes

[0537] 1) Read the luminescent signal on an Envision 2104 plate reader.

[0538] 1.3. Data Analysis - Calculation of IC 50 And draw the dose-response curve of the compound:

[0539] IC was calculated by fitting the percent inhibition values ​​and the logarithm of compound concentration to a nonlinear regression (dose-response-variable slope) using GraphPad 6.0. 50 .

[0540] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0541] X: logarithm of inhibitor concentration; Y: inhibition %

[0542] The data of Example 26 are shown in Table 1.

[0543] Table 1

[0544]

[0545]

[0546] A=IC 50 >0 and ≤50nM;

[0547] B=IC 50>50nM and ≤500nM;

[0548] C=IC 50 >500nM and ≤15μM;

[0549] NT = Not Tested.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three groups selected from R 9a The group substitution; R 2 Selected from hydrogen and C 1-6 alkyl; Ring B is selected from C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9b The group substitution; R 3b and R 3c independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9c The group substitution; R 3d Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)2R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )-、C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d or R 2 and R 3d Combined to form C 2-9 Heterocycloalkyl or C 2-9 Heteroaryl, wherein the C 2-9 Heterocycloalkyl and C 2-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d The group substitution; R 4 Selected from hydrogen and C 1-6 alkyl; Ring A is a pyridone ring, a pyridazinone ring, a bicyclic heterocycle or a tricyclic heterocycle, wherein the pyridone ring, the pyridazinone ring, the bicyclic heterocycle and the tricyclic heterocycle are optionally replaced by one or more R 6a group substitution; Each R 6a are independently selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution; Each R 9a 、R 9b 、R 9c 、R 9d and R 9e Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 , -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 , -CH2S(O)2R 13 , -CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2; Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; and Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups in the heteroaryl group are substituted.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a pyridone ring or a pyridazinone ring, wherein the pyridone ring and the pyridazinone ring are optionally substituted with one or more R 6a Group substitution.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e substituted by a group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heterocycle or a tricyclic heterocycle, wherein the bicyclic heterocycle and the tricyclic heterocycle are optionally replaced by one or more R 6a Group substitution.

5. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heteroaryl ring or a tricyclic heteroaryl ring, wherein the bicyclic heteroaryl ring and the tricyclic heteroaryl ring are optionally substituted by one or more R 6a Group substitution.

6. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is an 11-15 membered bicyclic heterocycle or an 11-17 membered tricyclic heterocycle, wherein the 11-15 membered bicyclic heterocycle and the 11-17 membered tricyclic heterocycle are optionally replaced by one or more R 6a Group substitution.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl; wherein C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e substituted by a group.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen and R 3d For hydrogen.

9. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3d Combined to form C 2-9 Heterocycloalkyl or C 2-9 Heteroaryl, wherein the C 2-9 Heterocycloalkyl and C 2-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d substituted by a group.

10. A compound of formula (II) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from C 2-14 Heterocycloalkyl, C 2-14 Heteroaryl and C 6-10 Aryl, where C 2-14 Heterocycloalkyl, C 2-14 Heteroaryl and C 6-10 The aryl group is optionally substituted with one or more R 6a group substitution; Ring D is selected from a 5- to 6-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring, and a 5- to 6-membered cycloalkyl ring; L 1 Selected from -S(O)2- and -C(O)-; L 2 Selected key, -O-, -S-, -S(O)-, -S(O)2-, -C(R 8a )(R 8b )-, -OC(R 8a )(R 8b )-, -C(R 8a )(R 8b )O-sum-N(R 8c )-; R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three groups selected from R 9a The group substitution; Each R 1a are independently selected from halogen, -CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9d The group substitution; Ring B is selected from C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-12 Cycloalkyl, C 2-14 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9b The group substitution; R 3b and R 3c independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9c The group substitution; R 4 Selected from hydrogen and C 1-6 alkyl; Each R 6a are independently selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-C(O)N(R 10 )(R 11 )、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-; where C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9e The group substitution; R 8a and R 8b independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three selected from R 9f The group substitution; Each R 9a 、R 9b 、R 9c 、R 9d 、R 9e and R 9f Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)C(R 10 )(R 11 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 )-, -S(=O)(=NH)C(R 10 )(R 11 )-, -S(=O)(=NR 13 )R 13 -, -CH2C(O)N(R 10 )(R 11 )-, -CH2N(R 12 )C(O)R 13 -, -CH2S(O)2R 13 -, -CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2; Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 One, two or three groups are substituted in the heteroaryl group; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the nitrogen to which they are attached, they form C 2-9 heterocycloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide; Each R 13 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 one, two or three groups substituted with heteroaryl; and p is 0, 1, 2, or 3. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein ring D is a 5- to 6-membered heterocycloalkyl ring. 12 . The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein ring D is a 5- to 6-membered heteroaryl ring.

13. The compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with one or more R 6a The monocyclic, bicyclic or tricyclic ring is substituted with a group.

14. The compound according to any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with one or more R 6a C 2-14 Heteroaryl.

15. The compound according to any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyrimidinyl, pyridinyl, pyridazinone, 11-15 membered bicyclic heterocycle or 11-17 membered tricyclic heterocycle, wherein the phenyl, pyrimidinyl, pyridinyl, pyridazinone, 11-15 membered bicyclic heterocycle and 11-17 membered tricyclic heterocycle are optionally replaced by one or more R 6a Group substitution.

16. The compound according to any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with one or more R 6a C 2-14 Heterocycloalkyl.

17. The compound according to any one of claims 10 to 16, or a pharmaceutically acceptable salt thereof, wherein each R 6a independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-; where C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is optionally substituted by one, two or three groups selected from R 9e substituted by a group.

18. The compound according to any one of claims 10 to 17, or a pharmaceutically acceptable salt thereof, wherein L 1 It is -S(O)2-.

19. The compound according to any one of claims 10 to 17, or a pharmaceutically acceptable salt thereof, wherein L 1 It is -C(O)-.

20. The compound according to any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, wherein L 2 is the key.

21. The compound according to any one of claims 11 to 19 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -O-CH2-.

22. The compound according to any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -O-.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein ring B is a monocyclic ring. 24 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring B is a bicyclic ring.

25. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted by one, two or three selected from R 9b C 2-14 Heterocycloalkyl.

26. The compound according to any one of claims 1 to 22 or 24 to 25, or a pharmaceutically acceptable salt thereof, wherein ring B is 27. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted by one, two or three selected from R 9b C 3-12 Cycloalkyl.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted by one to three groups selected from -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl.

30. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 C is substituted with a -OH group 1-6 Alkylene.

31. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3, -CH2CH2OH or -CH2CH2CH2OH.

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3b For hydrogen.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 3c For hydrogen.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 4 For hydrogen.

35. A compound or a pharmaceutically acceptable salt thereof selected from:

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

37. A method of modulating kinase-like protein 18A (KIF18A) in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36.

38. A method of inhibiting kinase-like protein 18A (KIF18A) in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36.

39. The method of claim 37 or 38, wherein the subject has cancer.

40. A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound according to any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36.

41. The method of claim 40, wherein the cancer is selected from: (a) a solid tumor or a hematological tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, (c) a myeloid hematopoietic neoplasm selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; and (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi sarcoma.

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