Spiroindoline inhibitors of KIF18A

Abstract

The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using the compounds and compositions thereof. More specifically, the present disclosure relates to indoline inhibitors of KIF18A and methods of their use in the treatment of diseases mediated by KIF18A, such as cancer. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202280069468.9 (application date: August 25, 2022, invention name: Spiroindoline inhibitors of KIF18A).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 237,275 filed on August 26, 2021; U.S. Provisional Patent Application No. 63 / 306,452 filed on February 3, 2022; and U.S. Provisional Patent Application No. 63 / 344,435 filed on May 20, 2022, the disclosures of each of which are hereby incorporated by reference in their entirety. Technical Field

[0004] The present disclosure generally relates to inhibitors of KIF18A, compositions thereof, and methods of using the compounds and compositions thereof. More specifically, the present disclosure relates to indoline inhibitors of KIF18A and methods of using the same for treating diseases mediated by KIF18A, such as cancer. Background Art

[0005] KIF18A is a kinesin involved in assisting kinetochore-microtubule (kt-MT) attachment and chromosome alignment during cell mitosis. Its payload domain directly binds to protein phosphatase 1 (PP1) and delivers it to the plus-end of MTs, where PP1 dephosphorylates the kinetochore complex component Hec1, further enhancing kt-MT attachment throughout metaphase and anaphase. Its MT-binding motor domain has ATPase activity, providing power for KIF18A translocation along the MT grid, which is enhanced by the C-terminal MT binding site of KIF18A, and capping and depolymerizing growing microtubules at the plus-end, thereby repressing MT dynamics. This regulation of MT dynamics by KIF18A usually occurs on the trailing (or trailing) sister chromatid, providing an opposing balancing tension for the movement of the leading sister chromatid catalyzed by another kinesin, Kif2C / MCAK. Loss of KIF18A function leads to defects in kt-MT attachment and loss of intraspindle tension in cells with high chromosomal instability (CIN), resulting in hyperstable, longer and multipolar spindles, mitotic arrest, centrosome fragmentation and activation of the spindle assembly checkpoint or cell death. Based on reanalysis of DEPMAP RNAi data, KIF18A was identified as one of the most important candidates essential for cells with high CIN. The reported comprehensive lethal screening also listed KIF18A as a potential anticancer target, and its knockdown preferentially made high CIN (but not low CIN), aneuploid and whole genome doubling cells susceptible to death. Cytotoxicity assays in isogenic cell lines confirmed the enhanced sensitivity of high CIN cells to KIF18A inhibitors. Ongoing in vivo mouse models using KIF18A inhibitors or knockdowns have demonstrated an inhibitory effect on tumor growth. Therefore, new compounds are needed for the treatment of diseases mediated by KIF18A. Summary of the invention

[0006] The present disclosure provides a compound of formula (I), a composition thereof, and a method of using the compound and the composition thereof to treat a disease or disorder associated with KIF18a. In one aspect, a compound of formula (I) is provided:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NRa6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups; R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; each R B The groups are independently halo, C 1-6 Alkyl, or C2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 Alkyl; R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0009] In another aspect, a compound of formula (II) is provided:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein: Ring A is (i) Where Z 1 , Z 2 , Z 3 and Z 4 are independently hydrogen or R D , where R D Halogen, -OH, -NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 、-P(O)(R a23 )(R a24 ), -C=NR a25 , or C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and optionally substituted by one or more halo or C 1-3 alkyl-substituted 3- to 10-membered heterocycloalkyl, provided that (1) when Z 4 When Z is hydrogen, 1 and Z 3 At least one of them is R D ; and (2) when Z 4 For R D When Z 1 For R D , or (ii) in is a single bond or a double bond, Z 5 is CH, N, O, S, or NX, wherein X is H or C 1-6 Alkyl, Z 6 For-NR a26C(O)NR a27 R a28 、-NR a29 C(O)OR a30 、-N=S(O)R a31 R a32 、-S(O)R a33 、-S(O)(NR a34 )R a35 、-S(O) 2 NR a36 R a37 、-S(O) 2 R a38 、-SR a39 , 3- to 10-membered heterocycloalkyl, -C(O)R a40 or -CH(Z 7 )(Z 8 ), where Z 7 is hydrogen or -OH, and Z 8 C 1-6 Alkyl, C optionally substituted by one or more halogen groups 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl optionally substituted by one or more halogen groups, and ring C is optionally substituted by one or more R E A 5- to 6-membered heteroaryl group substituted with a substituent, wherein each R E The substituents are independently selected from halo, -OH, and C 1-6 Alkyl group, or two R E The substituents together with the atoms to which they are attached form a C 5-6 Cycloalkyl, C 5-6 cycloalkenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl; R a4 -R a40 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; each R B The groups are independently halogen or C optionally substituted by one or more halogen groups. 1-6 Alkyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The groups together form =CR 1a3 R 1a4 Group, where R 1a3 and R 1a4 are independently hydrogen or C 1-6 Alkyl; m is 0, 1, 2, 3 or 4; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NRc14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 、-OS(O) 2 R c19 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 Alkyl, and R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: halogen, -O(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), and -OH; provided that (1) when ring B is an unsubstituted cyclopentyl group, then ring A is Where Z 1 -Z 4 At least one of them is -S(O) substituted by one or more halogen groups 2 -(3 to 10 membered heterocycloalkyl), (2) when ring B is unsubstituted cyclohexyl and ring A is When R C1 -R C4 At least one of them is R F , and (3) when ring B is optionally substituted by 1 to 4 R B When the 5- to 7-membered heterocycloalkyl is substituted, then Ring A is Where Z 1 -Z 4 At least one of them is -S(O) optionally substituted by one or more halogen groups 2 -(3- to 10-membered heterocycloalkyl).

[0012] On the other hand, a pharmaceutical composition is provided, comprising a compound of Formula (I), (I-1), (Ia1), (Ia2), (I-3), (Ia1), (Ia2) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0013] In another aspect, provided herein is a method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound or pharmaceutical composition as described herein.

[0014] In another aspect, provided herein is a method for treating or preventing a disease or disorder in an individual, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, the disease or disorder is mediated by KIF18A. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a cell proliferation disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figures 1A-1E Graph showing tumor volume in vehicle and compound treated mice plotted against time after initiation of treatment.

[0016] Figure 1A Shown is the treatment of HCC15-implanted SCID Beige mice with Compound 22 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID).

[0017] Figure 1B Shown is the treatment of OVCAR-3 implanted Balb / C nude mice with Compound 22 (10 mg / kg QD, 30 mg / kg QD, 60 mg / kg QD).

[0018] Figure 1C Shown is the treatment of HCC15-implanted SCID Beige mice with Compound 134 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID).

[0019] Figure 1D Compound 134 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) treatment of OVCAR-3 implanted Balb / C nude mice is shown.

[0020] Figure 1E Shown is the treatment of OVCAR-3 implanted Balb / C nude mice with Compound 134 (30 mg / kg BID, 30 mg / kg QD, 60 mg / kg QD). DETAILED DESCRIPTION

[0021] The following description is provided to enable one of ordinary skill in the art to formulate and use various embodiments. The description of specific devices, techniques, and applications is provided only as an example. Various modifications of the embodiments described herein are obvious to those of ordinary skill in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the embodiments described and shown herein, but to be given a scope consistent with the claims.

[0022] As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless the context of their use indicates otherwise.

[0023] Throughout this application, unless the context indicates otherwise, references to compounds of Formula (I), (I-1), (Ia1), (Ia2), (I-2), (I-3), (Ia1), (Ia2) or (II) include all subgroups defined herein, for example, Formula (I-1), (Ia1) or (Ia2), including all substructures, subgenera, preferences, embodiments, examples and specific compounds defined and / or described herein. In some embodiments, reference to compounds of Formula (I), (I-1), (Ia1), (Ia2), (I-2), (I-3), (Ia1), (Ia2) or (II) and subgroups thereof such as Formula (I-1), (Ia1) or (Ia2) includes their ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or protected forms. In some embodiments, references to compounds of Formula (I), (I-1), (Ia1), (Ia2), (I-2), (I-3), (Ia1), (Ia2), or (II) and subgroups thereof such as (I-1), (Ia1), or (Ia2) include polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II) and subgroups thereof such as (I-1), (Ia1), or (Ia2) include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to compounds of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II) and subgroups thereof such as (I-1), (Ia1), or (Ia2) include isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II) and subgroups thereof such as (I-1), (Ia1), or (Ia2) include solvates thereof.

[0024] "Alkyl" encompasses straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms. 1-6Alkyl encompasses straight and branched chain alkyl groups of 1 to 6 carbon atoms. When an alkyl residue having a particular number of carbons is named, it is intended to encompass all branched and straight chain forms having that number of carbons; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0025] When a range of values ​​is given (e.g., C 1-6 alkyl), including every value within the stated range and all intervening ranges. For example, "C 1-6 "Alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 and C 1-2 alkyl.

[0026] "Alkenyl" refers to an unsaturated branched or straight chain alkyl group having an indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in a cis or trans configuration (Z or E configuration) around the double bond. Alkenyl includes, but is not limited to, vinyl, propenyl (e.g., prop-1-ene-1-yl, prop-1-ene-2-yl, prop-2-ene-1-yl (allyl), prop-2-ene-2-yl), and butenyl (e.g., but-1-ene-1-yl, but-1-ene-2-yl, 2-methyl-prop-1-ene-1-yl, but-2-ene-1-yl, but-2-ene-1-yl, but-2-ene-2-yl, but-1,3-diene-1-yl, but-1,3-diene-2-yl).

[0027] "Alkynyl" refers to an unsaturated branched or straight chain alkyl group having an indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl includes, but is not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0028] "Cycloalkyl" indicates a non-aromatic, fully saturated carbocyclic ring with an indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms.Cycloalkyl can be monocyclic or polycyclic (for example, bicyclic, tricyclic).The example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and bridged and cage ring groups (for example, norbornane, bicyclic [2.2.2] octane). In addition, one ring of polycyclic cycloalkyl can be aromatic, as long as polycyclic cycloalkyl is attached to the parent structure via non-aromatic carbon.For example, 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the part is attached to the parent structure via non-aromatic carbon atoms) is cycloalkyl, and 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the part is attached to the parent structure via aromatic carbon atoms) is not considered as cycloalkyl.The example of polycyclic cycloalkyl composed of cycloalkyl fused to aromatic rings is described below.

[0029] "Cycloalkenyl" indicates a non-aromatic carbocyclic ring containing an indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo [2.2.2] octenes). In addition, one ring of polycyclic cycloalkenyl can be aromatic, as long as polycyclic cycloalkenyl is attached to the parent structure via non-aromatic carbon atoms. For example, indene-1-yl (wherein the part is attached to the parent structure via non-aromatic carbon atoms) is considered as cycloalkenyl, while indene-4-yl (wherein the part is attached to the parent structure via aromatic carbon atoms) is not considered as cycloalkenyl. The example of polycyclic cycloalkenyl composed of cycloalkenyl fused to an aromatic ring is described below.

[0030] "Aryl" indicates an aromatic carbocyclic ring with an indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, the two rings of the polycyclic aromatic group are aromatic (e.g., naphthyl). In other cases, the polycyclic aromatic group may include a non-aromatic ring fused to the aromatic ring, as long as the polycyclic aromatic group is bound to the parent structure via the atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the portion is bound to the parent structure via aromatic carbon atoms) is considered an aryl, while 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the portion is bound to the parent structure via non-aromatic carbon atoms) is not considered an aryl. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl groups). In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Additional examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0031] "Heteroaryl" indicates an aromatic ring containing an indicated number of atoms (e.g., 5 to 12, or 5 to 10 heteroaryl) consisting of one or more heteroatoms selected from N, O and S and the remaining ring atoms being carbon. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 1. Unless otherwise indicated, the heteroaryl group may be bonded to the parent structure by a carbon or nitrogen atom, as valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl.

[0032] In some cases, the heteroaryl group is a monocyclic ring. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

[0033] In certain instances, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolino[5,4-b]pyridine, isoxazolino[5,4-b]pyridine, [1,2,3]oxadiazolino[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolino[4,5-b]pyridine, isoxazolino[4,5-b]pyridine, [1,2,3]oxadiazolino[4,5-b]pyridine, furo[2,3-c] Pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3- c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0034] In other cases, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, as long as the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0035] "Heterocycloalkyl" indicates a non-aromatic, fully saturated ring having one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and the remaining ring atoms being carbon atoms (e.g., 3 to 10 or 3 to 7 heterocycloalkyl). Heterocycloalkyl may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl include oxirane, aziridine, azetidine, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S, S-dioxide. In addition, one ring of polycyclic heterocycloalkyl may be aromatic (e.g., aryl or heteroaryl), as long as polycyclic heterocycloalkyl is bound to the parent structure via non-aromatic carbon or nitrogen atoms. For example, 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl, while 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is attached to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl. Examples of polycyclic heterocycloalkyls consisting of a heterocycloalkyl fused to an aromatic ring are described below.

[0036] "Heterocycloalkenyl" refers to a non-aromatic ring having an indicated number of atoms (e.g., 3 to 10, or 3 to 7 membered heterocycloalkyl) consisting of one or more heteroatoms selected from N, O and S (e.g., 1, 2, 3 or 4 heteroatoms) and the remaining ring atoms being carbon, and at least one double bond derived by removing one hydrogen molecule from an adjacent carbon atom, an adjacent nitrogen atom, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. A heterocycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of the polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), as long as the polycyclic heterocycloalkenyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2-dihydroquinolin-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

[0037] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, yl, 2,3-dihydrobenzo[b]thienyl, 1,3-dihydrobenzo[c]thienyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3 (2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline -2,4(1H,3H)-dione, quinoxaline-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one.As discussed herein, whether each ring is considered to be aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is determined by the atom to which the moiety is attached to the parent structure.

[0038] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0039] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. The haloalkyl group may have a halogen substituent at any valence-allowed position on the alkyl group and may have any number of halogen substituents ranging from one to the maximum valence-allowed number. Particular haloalkyl groups have 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include, but are not limited to, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 Cl, -CHCl 2 , -CCl 3 、-CH 2 CH 2 Cl, -CH 2 CHCl 2 、-CH 2 CCl 3 .

[0040] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, mesoisomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other geometric asymmetric centers, it is desirable that the compounds include both E and Z isomers. When the compounds described herein contain a portion capable of tautomerism, and unless otherwise specified, it is desirable that the compounds include all possible tautomers.

[0041] "Protecting group" has the meaning usually associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound so that a chemical reaction can be selectively performed on another unprotected reactive site, and allows the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed in, for example, TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). For example, a "hydroxyl protected form" contains at least one hydroxyl protected with a hydroxyl protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0042] The term "pharmaceutically acceptable salt" refers to a salt of any compound herein that is known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compound described herein and is not biologically or otherwise inappropriate. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66 (1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0043] If the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0044] "Solvates" are formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (eg, ethanol). Solvates include hydrates of the compound and water in any ratio, such as monohydrates, dihydrates, and hemihydrates.

[0045] The term "substituted" means that the specified group or part carries one or more substituents, including but not limited to, for example, the following substituents: alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, sulfanyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, etc. The term "unsubstituted" means that the specified group does not carry a substituent. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any valence-allowed position on the system. When a group or part carries more than one substituent, it should be understood that the substituents may be the same or different from each other. In some embodiments, the substituted group or part carries one to five substituents. In some embodiments, the substituted group or part carries one substituent. In some embodiments, the substituted group or moiety has two substituents. In some embodiments, the substituted group or moiety has three substituents. In some embodiments, the substituted group or moiety has four substituents. In some embodiments, the substituted group or moiety has five substituents.

[0046] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it is understood by those skilled in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically infeasible, synthetically infeasible, and / or inherently unstable. It should also be understood that when a group or moiety is optionally substituted, the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0047] The compounds disclosed and / or described herein may be in an isotopically enriched form, e.g. 2 H. 3 H. 11 C. 13 C and / or 14 In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be produced, for example, by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy of the compounds disclosed and / or described herein and increase the duration of their effects. Deuterium substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0048] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical composition is contemplated. Auxiliary active ingredients may also be incorporated into the pharmaceutical composition.

[0049] The terms "patient," "individual," and "subject" refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient, individual, or subject is a human, such as a human who has been or will be the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be suitable for both human therapy and veterinary applications.

[0050] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that is sufficient to achieve treatment as defined herein when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to modulation (e.g., inhibition) of KIF18a. The therapeutically effective amount will vary depending on, for example, the subject and the disease condition being treated, the weight and age of the subject, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the administration schedule, the mode of administration, all of which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount can be determined experimentally, for example by measuring the blood concentration of the chemical entity, or theoretically, by calculating the bioavailability.

[0051] "Treatment" (and related terms, such as "treat," "treated," "treating") includes one or more of: inhibiting a disease or condition; slowing or arresting the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., causing clinical symptoms to remit or resolve). The term encompasses both complete and partial reduction of a disorder or condition, and complete or partial reduction of clinical symptoms of a disease or condition. Thus, the compounds described and / or disclosed herein can prevent an existing disease or condition from worsening, help control a disease or condition, or reduce or eliminate a disease or condition.

[0052] It should be understood that embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" the embodiments.

[0053] Compound

[0054] Compounds and salts thereof (e.g., pharmaceutically acceptable salts) are described in detail herein, including in the Summary of the Invention and the appended claims. Also provided are uses of all compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts and solvates of the compounds described herein, and methods of preparing such compounds. Any compound described herein may also be referred to as a drug.

[0055] In one aspect, there is provided a compound of formula (I):

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein:

[0058] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0059] R a1 -R a22 are independently hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0060] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0061] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0062] m is 0, 1, 2, 3 or 4;

[0063] Y 1 N or CR C1 ;

[0064] Y 2 N or CR C2 ;

[0065] Y 3 N or CR C3 ;

[0066] Y 4 N or CR C4 ;

[0067] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0068] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0069] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0070] In one aspect, a compound of formula (I-1) is provided:

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein:

[0073] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ;

[0074] R a1 -R a20 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0075] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0076] Each R B The groups are independently halogen, C1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0077] m is 0, 1, 2, 3 or 4;

[0078] Y 1 N or CR C1 ;

[0079] Y 2 N or CR C2 ;

[0080] Y 3 N or CR C3 ;

[0081] Y 4 N or CR C4 ;

[0082] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0083] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0084] R c1 -R c13 are independently hydrogen, C 3-10Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0085] In another aspect, there is provided herein a compound of formula (I-2)

[0086]

[0087] or a pharmaceutically acceptable salt thereof, wherein:

[0088] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0089] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0090] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0091] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0092] m is 0, 1, 2, 3 or 4;

[0093] Y 1 N or CR C1 ;

[0094] Y 2 N or CR C2 ;

[0095] Y 3 N or CR C3 ;

[0096] Y 4 N or CR C4 ;

[0097] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0098] RC1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0099] R c1 -R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0100] In another aspect, there is provided herein a compound of formula (I-3):

[0101]

[0102] or a pharmaceutically acceptable salt thereof, wherein:

[0103] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )Ra13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0104] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0105] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0106] m is 2;

[0107] Two R's B The group is attached to the same carbon atom on ring B and together with the carbon atom to which it is attached forms C 3-7 Cycloalkyl;

[0108] Y 1 N or CR C1 ;

[0109] Y 2 N or CR C2 ;

[0110] Y 3 N or CR C3 ;

[0111] Y 4 N or CR C4 ;

[0112] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0113] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0114] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0115] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or pharmaceutically acceptable salts thereof, Ring A is substituted with one, two, three, four, five or more substituents independently selected from the group consisting of: -SR a21 、-C(O)R a22 , and C substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted with one, two, three, four, five or more halo. In some embodiments, Ring A is substituted with: -SR a21 、-C(O)R a22 , or C substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted with one, two, three, four, five or more halo. a21 and R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl.

[0116] In some embodiments of Formula (I), Formula (I-1), Formula (I-2) and Formula (I-3) or pharmaceutically acceptable salts thereof, one or more R B The groups are independently C substituted by one, two, three, four, five or more halo groups. 1-6 In some embodiments, RB The group is C substituted by one, two, three, four, five or more halogen groups. 1-6 alkyl.

[0117] In some embodiments of Formula (I), Formula (I-1), Formula (I-2) and Formula (I-3) or pharmaceutically acceptable salts thereof, R C2 For-NR c14 C(O)OR c15 , where R c14 and R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0118] In some embodiments, the cycloalkyl or heterocycloalkyl includes a spiro group. In some embodiments, the cycloalkyl or heterocycloalkyl includes a fused group.

[0119] In some embodiments of Formula (I), Formula (I-1), Formula (I-2) and Formula (I-3) or pharmaceutically acceptable salts thereof, Ring A is C 6-14 In some embodiments, ring A is an optionally substituted C 6-14 In some embodiments, ring A is an optionally substituted phenyl. In some embodiments, ring A is an optionally substituted 5 to 12 membered heteroaryl. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an indolyl, indazolyl, pyridyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolyl, each of which is optionally substituted. In some embodiments, ring A is an optionally substituted thienyl.

[0120] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (II), Ring A is optionally substituted with one, two, three, four, five or more substituents independently selected from the group consisting of: halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-ORa10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted with one or more halo groups. a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one, two, three, four, five or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl.

[0121] In some embodiments, the 3- to 10-membered heterocycloalkyl is piperidinyl. In some embodiments, the 3- to 10-membered heterocycloalkyl is In some embodiments, R a1 is hydrogen or C 1-6 In some embodiments, R a1 In some embodiments, R a2 and Ra3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a2 and R a3 Each is independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, R a4 is hydrogen or C 1-6 In some embodiments, R a4 In some embodiments, R a5 is hydrogen or C 1-6 In some embodiments, R a5 In some embodiments, R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6 In some embodiments, R a6 and R a7 Each is independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. In some embodiments, -N=S(O)R a8 R a9 for In some embodiments, R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a8 and R a9 Each is independently methyl or cyclopentyl. In some embodiments, -OR a10 for In some embodiments, R a10 C 3-10 In some embodiments, R a10 In some embodiments, -S(O)R a11 for In some embodiments, R a11 C 3-10 In some embodiments, R a11 In some embodiments, -S(O)(NR a12 )R a13 for In some embodiments, R a12 is hydrogen or C 1-6 In some embodiments, R a12 is hydrogen or methyl. a13 C 3-10In some embodiments, R a13 In some embodiments, -S(O) 2 NR a14 R a15 for

[0122] In some embodiments, -S(O) 2 NR a14 R a15 for

[0123]

[0124] In some embodiments, R a14 and R a15 are each independently hydrogen; C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one, two, three, four, five or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one, two, three, four, five or more C 1-6 In some embodiments, R a14 and R a15 are independently hydrogen or C1-6 In some embodiments, R a14 is hydrogen and R a15 In some embodiments, R a15 In some embodiments, -S(O) 2 R a16 for In some embodiments, -S(O) 2 R a16 for In some embodiments, R a16 C 3-10 or a 3- to 12-membered heterocycloalkyl group, which is optionally substituted by one, two, three, four, five or more independently selected from C 1-6 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 -C(O)NR a19 R a20 or -(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 -C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 For-(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, R a17 and R a18 are independently hydrogen or C 1-6 In some embodiments, R a17 and R a18 In some embodiments, R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C3-10 In some embodiments, R a19 and R a20 Each is independently hydrogen or cyclopropyl. In some embodiments, -SR a21 for In some embodiments, R a21 C 3-10 In some embodiments, -C(O)R a22 for In some embodiments, R a22 C 3-10 In some embodiments, the optionally substituted C 1-6 The alkyl group is In some embodiments, C 1-6 The alkyl group is optionally substituted with one, two, three, four, five or more substituents independently selected from the group consisting of: -OH, cyano, C 3-10 In some embodiments, the 3 to 10 membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five or more halogen groups. In some embodiments, the 3 to 10 membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five or more halogen groups. In some embodiments, the 3 to 10 membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five or more fluorine groups. In some embodiments, the 3 to 10 membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five or more fluorine groups.

[0125] In some embodiments, Ring A is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OH, amino,

[0126] In some embodiments, Ring A is optionally substituted with one, two, three, four, five or more substituents independently selected from the group consisting of fluoro, chloro, -OH, amino,

[0127]

[0128] In some embodiments of Formula (I), Formula (I-1), Formula (I-2) and Formula (I-3) or pharmaceutically acceptable salts thereof, Ring B is C 5-7 Cycloalkyl, C 5-7cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon. 5-7 In some embodiments, Ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring B is Wherein * represents the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3). In some embodiments, Ring B is C 5-7 In some embodiments, Ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, Ring B is wherein * represents the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3). In some embodiments, Ring B is Wherein * represents the point of connection with the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3). In some embodiments, Ring B is a 5- to 7-membered heterocycloalkyl. In some embodiments, Ring B is a 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms of the 5- to 7-membered heterocycloalkyl are each oxygen and the remaining ring atoms are each carbon. In some embodiments, Ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, Ring B is wherein * represents the point of connection to the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3).

[0129] In some embodiments, Ring B is replaced by m R B group substituted, where each R B The groups are independently halo, optionally substituted by one, two, three, four, five or more halo groups. 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 In some embodiments, R B The group is methyl or ethyl. In some embodiments, two adjacent R B The group together with the carbon atom to which it is attached forms a cyclopropyl group. B The group together with the carbon atom to which it is attached forms a cyclopropyl group.

[0130] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0131] In some embodiments, the compound of formula (I), formula (I-1), formula (I-2) or formula (I-3) for Wherein * represents the point of connection with the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3). In some embodiments, for wherein * represents the point of connection to the rest of Formula (I), Formula (I-1), Formula (I-2) or Formula (I-3).

[0132] In some embodiments of Formula (I), Formula (I-1), Formula (I-2) and Formula (I-3) or pharmaceutically acceptable salts thereof, Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; and Y 4 N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N. In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than two of them are N. In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than one of them is N. In some embodiments, Y 1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 In some embodiments, Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y4 CR C4 In some embodiments, Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4 .

[0133] In some embodiments, R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R c1 -R c18 are independently hydrogen, C 3-10 cycloalkyl, or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0134] In some embodiments, R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NRc5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R c1 -R c15 are independently hydrogen, C 3-10 cycloalkyl, or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0135] In some embodiments, R C1 In some embodiments, R C1 is hydrogen or fluorine. C3 In some embodiments, R C4 is hydrogen or -NH 2 In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[0136] In some embodiments, R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 , In some embodiments, R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 , In some embodiments, R C2 For cyano, -OH, halogen, -NO 2 、C(O)NR c1 R c2 、-NR c3 R c4、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R C2 For cyano, -OH, halogen, -NO 2 、C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0137] In some embodiments, -C(O)NR c1 R c2 for In some embodiments, R c1 and R c2 are independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 Each is independently hydrogen, methyl, or ethyl. In some embodiments, -NRc3 R c4 for In some embodiments, R c3 and R c4 are independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 Each is independently hydrogen, methyl, or ethyl. In some embodiments, -NR c5 S(O) 2 R c6 for In some embodiments, R c5 is hydrogen or C 1-6 In some embodiments, R c5 is hydrogen, methyl, or ethyl. c6 is hydrogen or C optionally substituted by one, two, three, four, five or more substituents independently selected from halo and -OH 1-6 In some embodiments, R c5 Methyl or -CH 2 CH 2 OH. In some embodiments, R c5 In some embodiments, R c6 In some embodiments, -P(O)R c7 R c8 for In some embodiments, R c7 and R c8 Each independently is C 1-6 In some embodiments, R c7 and R c8 In some embodiments, -N=S(O)R c9 R c10 for In some embodiments, R c9 and R c10 Each independently is C 1-6 In some embodiments, R c9 and R c10 In some embodiments, -S(O)(NR c11 )R c12 for In some embodiments, R c11 is hydrogen or C 1-6 In some embodiments, R c11 is hydrogen or methyl. c12C 1-6 Alkyl or C 3-10 In some embodiments, R c12 In some embodiments, -S(O) 2 R c13 for In some embodiments, R c13 C 1-6 In some embodiments, R c13 In some embodiments, NR c14 C(O)OR c15 for In some embodiments, R c14 and R c15 are independently hydrogen or C 1-6 In some embodiments, R c14 In some embodiments, R c15 In some embodiments, -NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 for In some embodiments, -NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 For-NR c16 S(O) 2 (CH 2 ) 1-3 NR c17 C(O)R c18 In some embodiments, R c16 , R c17 and R c18 are independently hydrogen or C 1-6 In some embodiments, R c16 and R c17 In some embodiments, R c18 It is methyl.

[0138] In one aspect, a compound of formula (Ia1) is provided:

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , Ring B, R B, m, and R C2 As defined for Formula (I) or any variation or embodiment thereof. In some embodiments, R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 or C optionally substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 In some embodiments, R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R C2 For-NR c5 S(O) 2 R c6 In some embodiments, R c5 is hydrogen and R c6 C1-6 In some embodiments, R c5 is hydrogen and R c6 In some embodiments, R c5 In some embodiments, R c6 In some embodiments, R c6 In some embodiments, R a14 is hydrogen and R a15 C 1-6 In some embodiments, R a14 is hydrogen and R a15 In some embodiments, R a14 In some embodiments, R a15 In some embodiments, ring B is wherein * represents the point of attachment to the rest of formula (Ia1). for

[0141] In one aspect, provided is a compound of formula (Ia2):

[0142]

[0143] or a pharmaceutically acceptable salt thereof, wherein R a16 , Ring B, R B , m, and R C2 As defined for Formula (I) or any variation or embodiment thereof. In some embodiments, R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NRc17 C(O)R c18 or C optionally substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 In some embodiments, R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0144] In some embodiments, Ring B is not wherein * represents the point of attachment to the rest of formula (I). C1 In some embodiments, R C2 is not hydrogen. In some embodiments, Ring B is not wherein * represents the point of attachment to the rest of formula (I); or R C1 Not fluorine; or R C2 Not hydrogen.

[0145] In some embodiments, the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole] [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; or [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea.

[0146] In some embodiments, the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]- [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; or [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea.

[0147] In another aspect, there is provided herein a compound of formula (II):

[0148]

[0149] or a pharmaceutically acceptable salt thereof, wherein:

[0150] Ring A is

[0151] (i) Where Z 1 , Z 2 , Z 3 and Z 4 are independently hydrogen or R D , where R D Halogen, -OH, -NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 、-P(O)(R a23 )(R a24 ), -C=NR a25 , or C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and optionally substituted by one or more halo or C 1-3 alkyl-substituted 3- to 10-membered heterocycloalkyl,

[0152] The condition is

[0153] (1) When Z 4 When Z is hydrogen, 1 and Z 3 At least one of them is R D ;and

[0154] (2) When Z 4 For R D When Z 1 For R D ,or

[0155] (ii) in

[0156] is a single bond or a double bond,

[0157] Z 5 is CH, N, O, S, or NX, wherein X is H or C 1-6 alkyl.

[0158] Z 6 For-NR a26 C(O)NR a27 R a28 、-NR a29 C(O)OR a30 、-N=S(O)R a31 R a32 、-S(O)R a33 、-S(O)(NR a34 )R a35 、-S(O) 2 NR a36 R a37 、-S(O) 2 R a38 、-SR a39 、-C(O)R a40 , 3 to 10 membered heterocycloalkyl, or -CH(Z 7 )(Z 8 ), where Z 7 is hydrogen or -OH, and Z 8 C 1-6 Alkyl, C optionally substituted by one or more halogen groups 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl group optionally substituted by one or more halo groups, and

[0159] Ring C is optionally substituted with one or more R E A 5- to 6-membered heteroaryl group substituted with a substituent, wherein each R E The substituents are independently selected from halo, -OH, and C 1-6 Alkyl group, or two R E The substituents together with the atoms to which they are attached form a C 5-6 Cycloalkyl, C 5-6 cycloalkenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl;

[0160] R a4 -R a40 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0161] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0162] Each R B The groups are independently halogen or C optionally substituted by one or more halogen groups. 1-6 Alkyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The groups together form =CR 1a3 R 1a4 Group, where R 1a3 and R 1a4 are independently hydrogen or C 1-6 alkyl;

[0163] m is 0, 1, 2, 3 or 4;

[0164] Y 1 N or CR C1 ;

[0165] Y 2 N or CR C2 ;

[0166] Y 3 N or CR C3 ;

[0167] Y 4 N or CR C4 ;

[0168] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0169] R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 、-OS(O) 2 R c19 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 Alkyl, and

[0170] R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: halogen, -O(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), and -OH;

[0171] The condition is

[0172] (1) When ring B is an unsubstituted cyclopentyl group, ring A is Where Z 1 -Z 4 At least one of them is -S(O) substituted by one or more halogen groups 2-(3- to 10-membered heterocycloalkyl),

[0173] (2) When ring B is an unsubstituted cyclohexyl group and ring A is When R C1 -R C4 At least one of them is R F ,and

[0174] (3) When ring B is optionally substituted with 1 to 4 R B When the 5- to 7-membered heterocycloalkyl is substituted, then Ring A is Where Z 1 -Z 4 At least one of them is -S(O) optionally substituted by one or more halogen groups 2 -(3- to 10-membered heterocycloalkyl).

[0175] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, one, two, three or four Z 1 -Z 4 Independently selected from the group consisting of: -SR a21 、-C(O)R a22 , and C substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted with one, two, three, four, five or more halo. In some embodiments, Ring A is substituted with: -SR a21 、-C(O)R a22 , or C substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted with one, two, three, four, five or more halo. a21 and R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl.

[0176] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Z 1 , Z 2 , Z 3 and Z 4 are independently hydrogen or R D , where R D Halogen, -OH, -NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 、-P(O)(R a23 )(R a24 ), -C=NR a25 , or C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and optionally substituted by one or more halo or C 1-3 alkyl-substituted 3- to 10-membered heterocycloalkyl, wherein R a4 -R a25 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl.

[0177] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Z 4 is hydrogen and Z 1 and Z 3 At least one of them is R D , where R D As defined elsewhere herein. In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Z 4 For Z 4 For R D And Z 1 For R D When R D As defined elsewhere herein.

[0178] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Z 5 is CH, N, O, S, or NX, wherein X is H or C 1-6 In some embodiments, X is H. In some embodiments, X is C 1-6 In some embodiments, X is methyl. In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Z 5 is CH, N, O, S, or NX, wherein X is H or C 1-6 Alkyl, Z 6 For-NR a26 C(O)NR a27 R a28 、-NR a29 C(O)OR a30 、-N=S(O)R a31 R a32 、-S(O)R a33、-S(O)(NR a34 )R a35 、-S(O) 2 NR a36 R a37 、-S(O) 2 R a38 、-SR a39 , 3- to 10-membered heterocycloalkyl, C(O)R a40 , or -CH(Z 7 )(Z 8 ), where Z 7 is hydrogen or -OH, and Z 8 C 1-6 Alkyl, C optionally substituted by one or more halogen groups 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl optionally substituted by one or more halogen groups, and ring C is optionally substituted by one or more R E A 5- to 6-membered heteroaryl group substituted with a substituent, wherein each R E The substituents are independently selected from halo, -OH, and C 1-6 Alkyl group, or two R E The substituents together with the atoms to which they are attached form a C 5-6 Cycloalkyl, C 5-6 cycloalkenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl; and R a26 -R a40 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl.

[0179] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, one or more RB The groups are independently C substituted by one, two, three, four, five or more halo groups. 1-6 In some embodiments, R B The group is C substituted by one, two, three, four, five or more halogen groups. 1-6 alkyl.

[0180] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5 to 7 membered heterocycloalkyl, wherein one or two ring atoms of the 5 to 7 membered heterocycloalkyl are each oxygen and the remaining ring atoms are each carbon. In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, one or more R B The groups are independently halogen or C optionally substituted by one or more halogen groups. 1-6 In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The groups together form =CR 1a3 R 1a4 Group, where R 1a3 and R 1a4 are independently hydrogen or C 1-6 alkyl.

[0181] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, R C2 For-NR c14 C(O)OR c15 , where R c14 and R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0182] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 Rc4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 、-OS(O) 2 R c19 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 alkyl; and R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: halogen, -O(C 1-6 Alkyl), -NHC(O)(C 1-6 In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 Alkyl, and R c1 -R c19 As defined elsewhere herein. In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, R C1 -R C4 Each independently is -OS(O) 2 R c19 , where R c19 As defined elsewhere herein.

[0183] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring B is unsubstituted cyclopentyl and Z 1 -Z 4 At least one of them is -S(O) substituted by one or more halogen groups 2 -(3 to 10 membered heterocycloalkyl). In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted cyclohexyl group, Ring A is And R C1 -R C4 At least one of them is R F , where R C1 -R C4 and R F As defined elsewhere herein. In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring B is optionally substituted with 1-4 R B substituted 5- to 7-membered heterocycloalkyl, and Z 1 -Z 4 At least one of them is -S(O) optionally substituted by one or more halogen groups 2 -(3 to 10 membered heterocycloalkyl), wherein R B As defined elsewhere herein.

[0184] In some embodiments, the cycloalkyl or heterocycloalkyl includes a spiro group. In some embodiments, the cycloalkyl or heterocycloalkyl includes a fused group.

[0185] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring A is C 6-14 In some embodiments, ring A is an optionally substituted C 6-14In some embodiments, ring A is an optionally substituted phenyl. In some embodiments, ring A is an optionally substituted 5 to 12 membered heteroaryl. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an indolyl, indazolyl, pyridyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolyl, each of which is optionally substituted. In some embodiments, ring A is an optionally substituted thienyl.

[0186] In some embodiments of formula (II) or a pharmaceutically acceptable salt thereof, Ring A is an optionally substituted phenyl. In some embodiments, Ring A is an optionally substituted 5- to 12-membered heteroaryl. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl. In some embodiments, Ring A is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring A is a pyridyl, thienyl, furanyl, pyrazolyl, pyrrolyl, or oxazolyl. In some embodiments, Ring A is

[0187] In some embodiments of Formula (II), R a4 is hydrogen or C 1-6 In some embodiments, R a4 In some embodiments, R a5 is hydrogen or C 1-6 In some embodiments, R a5 In some embodiments, R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6 In some embodiments, R a6 and R a7 Each is independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. In some embodiments, -N=S(O)R a8 R a9 for In some embodiments, R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a8 and R a9 Each is independently methyl or cyclopentyl. In some embodiments, -OR a10 for In some embodiments, R a10 C 3-10In some embodiments, R a10 In some embodiments, -S(O)R a11 for In some embodiments, R a11 C 3-10 In some embodiments, R a11 In some embodiments, -S(O)(NR a12 )R a13 for In some embodiments, R a12 is hydrogen or C 1-6 In some embodiments, R a12 is hydrogen or methyl. a13 C 3-10 In some embodiments, R a13 In some embodiments, -S(O) 2 NR a14 R a15 for

[0188] In some embodiments, -S(O) 2 NR a14 R a15 for

[0189] In some embodiments, -S(O) 2 NR a14 R a15 for In some embodiments, R a14 and R a15 are each independently hydrogen; C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one, two, three, four, five or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one, two, three, four, five or more C 1-6 In some embodiments, R a14 and R a15 are independently hydrogen or C 1-6 In some embodiments, R a14 is hydrogen and R a15 In some embodiments, R a15 In some embodiments, -S(O) 2 R a16 for

[0190] In some embodiments, -S(O) 2 R a16 for In some embodiments, -S(O) 2 R a16 for In some embodiments, R a16 C 3-10 or a 3- to 12-membered heterocycloalkyl group, which is optionally substituted by one, two, three, four, five or more independently selected from C 1-6 In some embodiments, -(CR a17 R a18 ) 0- 1 C(O)NR a19 R a20-C(O)NR a19 R a20 or -(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 -C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 For-(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, R a17 and R a18 are independently hydrogen or C 1-6 In some embodiments, R a17 and R a18 In some embodiments, R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a21 For hydrogen, C 3-10 Cycloalkyl, or optionally substituted by one or more C 3-10 Cycloalkyl substituted C 1-6 In some embodiments, -SR a21 for In some embodiments, R a22 For hydrogen, C 3-10 Cycloalkyl, or optionally substituted by one or more C 3-10 Cycloalkyl substituted C 1-6 In some embodiments, -C(O)R a22 for In some embodiments, R a23 and R a24 are independently hydrogen, C 3-10 Cycloalkyl, or optionally substituted by one or more C 3-10 Cycloalkyl substituted C 1-6 In some embodiments, -P(O)(R a23 )(R a24 )for In some embodiments, R 24 For hydrogen, C 3-10 Cycloalkyl, or optionally substituted by one or more C 3-10 Cycloalkyl substituted C 1-6 In some embodiments, -C=NR a25 for In some embodiments, Z 1 -Z 4 are each independently C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and optionally substituted by one or more halo or C 1-3 In some embodiments, Z 1 -Z 4 Each independently

[0191] In some embodiments of Formula (II), Z 6 is a 3- to 10-membered heterocycloalkyl. 6 for In some embodiments, R a26 is hydrogen or C 1-6 In some embodiments, R a27 In some embodiments, R a27 and R a28 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a27 and R a28 Each is independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, R a29 is hydrogen or C 1-6 In some embodiments, R a29 In some embodiments, R a30 is hydrogen or C 1-6 In some embodiments, R a30 In some embodiments, -N=S(O)R a31 R a32 for In some embodiments, R a31 and R a32 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a31 and R a32Each is independently methyl or cyclopentyl. In some embodiments, -S(O)R a33 for In some embodiments, R a33 C 3-10 In some embodiments, R a33 In some embodiments, -S(O)(NR a34 )R a35 for or In some embodiments, R a34 is hydrogen or C 1-6 In some embodiments, R a34 is hydrogen or methyl. a35 C 3-10 In some embodiments, R a35 In some embodiments, -S(O) 2 NR a34 R a35 for

[0192] In some embodiments, -S(O) 2 NR a34 R a35 for In some embodiments, -S(O) 2 NR a34 R a35 for

[0193] In some embodiments, R a36 and R a37 are each independently hydrogen; C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one, two, three, four, five or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one, two, three, four, five or more C 1-6 In some embodiments, R a36 and R a37 are independently hydrogen or C 1-6 In some embodiments, R a36 is hydrogen and R a37 In some embodiments, R a37 In some embodiments, -S(O) 2 R a38 for In some embodiments, -S(O) 2 R a38 for

[0194]

[0195] In some embodiments, -S(O) 2 R a38 for In some embodiments, R a38 C 3-10 Cycloalkyl; or optionally substituted by one, two, three, four, five or more independently selected from C 1-6 alkyl or halogen. In some embodiments, -SR a39 for In some embodiments, R a39 C 3-10 In some embodiments, R a40 C 3-10 In some embodiments, -C(O)R a40 for In some embodiments, -CH(Z 7 )(Z 8 ), where Z 7 is hydrogen or -OH, and Z 8 C 1-6 Alkyl, C optionally substituted by one or more halogen groups 3-10 cycloalkyl, or 3 to 10 membered heterocycloalkyl optionally substituted with one or more halo groups. 7 In some embodiments, Z 7 is H. In some embodiments, Z 8 C 1-6 In some embodiments, Z 8 is C optionally substituted by one or more halogen groups 3-10 In some embodiments, Z 8 is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more halo groups. 7 )(Z 8 )for

[0196] In some embodiments of Formula (II), Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from the group consisting of fluorine, chlorine, -OH, amino, -CH 2 OH,

[0197]

[0198] In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from the group consisting of: -CH 2 OH, In some embodiments, Ring A is a disubstituted phenyl. In some embodiments, Ring A is selected from the group consisting of:

[0199] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Ring B is C 5-7 Cycloalkyl, C 5-7cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon. 5-7 In some embodiments, Ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring B is wherein * represents the point of attachment to the rest of formula (II). In some embodiments, ring B is C 5-7 In some embodiments, Ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, Ring B is wherein * represents the point of attachment to the rest of formula (II). In some embodiments, ring B is wherein * represents the point of attachment to the rest of formula (II). In some embodiments, ring B is a 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is a 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms of the 5- to 7-membered heterocycloalkyl are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, ring B is wherein * indicates the point of attachment to the rest of formula (II).

[0200] In some embodiments of Formula (II), Ring B is replaced by m R B group substituted, where each R B The groups are independently halo, optionally substituted by one, two, three, four, five or more halo groups. 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 In some embodiments, R B The group is methyl or ethyl. In some embodiments, two adjacent R B The group together with the carbon atom to which it is attached forms a cyclopropyl group. B The group together with the carbon atom to which it is attached forms a cyclopropyl group.

[0201] In some embodiments of Formula (II), m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0202] In some embodiments, the for Wherein * represents the point of connection with the rest of formula (II). In some embodiments, for Wherein * represents the point of connection with the rest of formula (II). In some embodiments, for wherein * indicates the point of attachment to the rest of formula (II).

[0203] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; and Y 4 N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N. In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than two of them are N. In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 No more than one of them is N. In some embodiments, Y 1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 In some embodiments, Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 In some embodiments, Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4.

[0204] In some embodiments of Formula (II), R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 、-OS(O) 2 R c19 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 alkyl.

[0205] In some embodiments of Formula (II), R C1 In some embodiments, R C1 is hydrogen or fluorine. C3 In some embodiments, R C4 is hydrogen or -NH 2 In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[0206] In some embodiments of Formula (II), R C2 For cyano, -OH, -CH 2 OH, fluorine, bromine, -NO 2 , In some embodiments, RC2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 , In some embodiments, R C2 for In some embodiments, R C2 For cyano, -OH, halogen, -NO 2 、C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R C2 For cyano, -OH, halogen, -NO 2 、C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15, or C optionally substituted by one, two, three, four, five or more substituents independently selected from the group consisting of halo and -OH 1-6 In some embodiments, R C2 For-OS(O) 2 R c19 .

[0207] In some embodiments, -C(O)NR c1 R c2 for In some embodiments, R c1 and R c2 are independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 Each is independently hydrogen, methyl, or ethyl. In some embodiments, -NR c3 R c4 for In some embodiments, R c3 and R c4 are independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 Each is independently hydrogen, methyl, or ethyl. In some embodiments, -NR c5 S(O) 2 R c6 for In some embodiments, -NR c5 S(O) 2 R c6 for In some embodiments, R c5 is hydrogen or C 1-6 In some embodiments, R c5 is hydrogen, methyl, or ethyl. c6 is hydrogen or C optionally substituted by one, two, three, four, five or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O(C 1-6 alkyl), and -NHC(O)(C 1-6 In some embodiments, R c5 Methyl or -CH 2 CH 2 OH. In some embodiments, R c5 In some embodiments, R c6 In some embodiments, R c6 -CH2 CH 2 F. In some embodiments, R c6 OCH 3 In some embodiments, -P(O)R c7 R c8 for In some embodiments, R c7 and R c8 Each independently is C 1-6 In some embodiments, R c7 and R c8 In some embodiments, -N=S(O)R c9 R c10 for In some embodiments, R c9 and R c10 Each independently is C 1-6 In some embodiments, R c9 and R c10 In some embodiments, -S(O)(NR c11 )R c12 for In some embodiments, R c11 is hydrogen or C 1-6 In some embodiments, R c11 is hydrogen or methyl. c12 C 1-6 Alkyl or C 3-10 In some embodiments, R c12 In some embodiments, -S(O) 2 R c13 for In some embodiments, R c13 C 1-6 In some embodiments, R c13 In some embodiments, NR c14 C(O)OR c15 for In some embodiments, R c14 and R c15 are independently hydrogen or C 1-6 In some embodiments, R c14 In some embodiments, R c15 In some embodiments, -NR c16 S(O) 2 (CH 2 ) 1-6 NRc17 C(O)R c18 for In some embodiments, -NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 For-NR c16 S(O) 2 (CH 2 ) 1-3 NR c17 C(O)R c18 In some embodiments, R c16 , R c17 and R c18 are independently hydrogen or C 1-6 In some embodiments, R c16 and R c17 In some embodiments, R c18 It is methyl.

[0208] In some embodiments, provided herein are compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0209] Table 1.

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] In some embodiments, provided herein are compounds described in Table 2 and salts thereof. In some embodiments, the compound described herein is not a compound of Table 2.

[0282] Table 2.

[0283]

[0284]

[0285] In some variations, any compound described herein, such as a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or any variation thereof, or a compound of Table 1 or Table 2, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of corresponding non-deuterated compounds. Hydrogen atoms can also be replaced with deuterium atoms using other methods known in the art.

[0286] Any formula given herein, such as formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), is intended to represent compounds having structures depicted by the structural formula and certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered to be within the scope of the formula. Therefore, any formula given herein is intended to represent racemates, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomer forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. In addition, any formula given herein also means any of the hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0287] Representative examples of compounds detailed herein, including intermediates and final compounds, are described in the Tables and elsewhere herein. It should be understood that in one aspect, any compound can be used in the methods detailed herein, including intermediate compounds that can be isolated and administered to individuals, where appropriate.

[0288] The compounds described herein may exist as salts, even if no salts are described, and it should be understood that the compositions and methods provided herein include all salts and solvates of the compounds described herein, as well as non-salt and non-solvate forms of the compounds, as is well recognized by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0289] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier are provided. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0290] The ring A, ring B, ring C, and R provided in this article a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , Ra9 、R a10 、R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 、R a23 、R a24 、R a25 、R a26 、R a27 、R a28 、R a29 、R a30 、R a31 、R a32 、R a33 、R a34 、R a35 、R a36 、R a37 、R a38 、R a39 、R a40 、R 1a1 、R 1a2 、R 1a3 、R 1a4 、R B 、m、X、Y 1 、Y 2 、Y 3 、Y 4 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、R C1 、R C2 、R C3 、R C4 、R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 、R c9 、R c10 、R c11 、R c12 、R c13 、Rc14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F Any variation or embodiment may be combined with ring A, ring B, ring C, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 、Ra23、R a24 , R a25 , R a26 , R a27 , R a28 , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a35 , R a36 , R a37 , R a38 , R a39 , R a40 , R 1a1 , R 1a2 , R 1a3 , R 1a4 , R B , m, X, Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8, R C1 , R C2 , R C3 , R C4 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , R c14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F All other variations or combinations of embodiments are described herein as if each combination were individually and specifically described.

[0291] As used herein, when any variable occurs more than one time in a formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0292] The compound names provided herein, including the compound names in Table 1 and Table 2, are provided by Chemaxon Marvin Structure to Name 20 or ChemDraw Professional 20. Those skilled in the art understand that compounds can be named or identified using various commonly recognized naming systems and symbols. For example, compounds can be named or identified using common names, systematic or non-systematic names. Generally recognized naming systems and symbols in the chemical field include, for example, Chemical Abstracts Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0293] Composition

[0294] Compositions, such as pharmaceutical compositions, are also provided, which comprise compounds disclosed and / or described herein and one or more additional pharmaceutical agents, medicaments, adjuvants, carriers, excipients, etc. Suitable pharmaceutical agents and medicaments include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, containing one or more compounds described herein or pharmaceutically acceptable salts thereof are provided.

[0295] In some embodiments, a pharmaceutically acceptable composition is provided, comprising a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain a synthetic intermediate that can be used to prepare the compounds described herein. The compositions described herein may contain any other suitable active or inactive agent.

[0296] Any composition described herein may be sterile or contain sterile components. Sterilization may be achieved by methods known in the art. Any composition described herein may contain one or more substantially pure compounds.

[0297] Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0298] How to use

[0299] As described herein, the compounds of the present disclosure are inhibitors of KIF18A. In one aspect, the compounds and pharmaceutical compositions herein can be used to inhibit KIF18A. In another aspect, the compounds and pharmaceutical compositions herein can be used to treat or prevent a disease or disorder in an individual.

[0300] The inhibitory activity of the compounds described herein against KIF18A can be determined and measured by methods known in the art, including but not limited to, inhibition of ATP hydrolysis in the presence of microtubules (Hackney DD, Jiang W. (2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (ed.) Kinesin Protocols. Methods in Molecular Biology TM, Volume 164, Humana Press. https: / / doi.org / 10.1385 / 1-59259-069-1:65).

[0301] In one aspect, provided herein is a method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound as described herein or a pharmaceutical composition. In some embodiments, provided herein is a method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound of formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound of formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In one variation of the foregoing embodiment, the cell is contacted in vitro. In other variations of the foregoing embodiment, the cell is contacted in vivo.

[0302] In another aspect, the compounds and pharmaceutical compositions herein can be used to treat or prevent a disease or disorder in an individual, comprising administering an effective amount of a compound or pharmaceutical composition as described herein. When used in a preventive manner, the compounds disclosed and / or described herein can prevent a disease or disorder in an individual at risk of developing a disease or disorder, or reduce the extent of a disease or disorder that can be developed.

[0303] In some embodiments, provided herein is a method for treating or preventing a disease or disorder in an individual, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, provided herein is a method for treating or preventing a disease or disorder in an individual, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating or preventing a disease or disorder in an individual, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the disease or disorder is mediated by KIF18A. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a cell proliferation disorder, including uncontrolled cell growth, abnormal cell cycle regulation, centrosome abnormalities (structural and / or numerical abnormalities, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (especially Graves' disease) and cysts (e.g., hypervascularity of the ovarian stroma, which is a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid and blood-derived tumors, such as carcinomas, may include, but are not limited to, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer (including squamous cell carcinoma and small cell lung cancer), pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer and skin cancer (including squamous cell carcinoma), hematopoietic system tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma), hematopoietic neoplasms of myeloid lineage (including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia), hematopoietic neoplasms of any lineage, myeloma, tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, as well as other sarcomas, such as soft tissue and bone), central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schwannoma), tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors (including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma, Ewing's sarcoma sarcoma), Kaposi's sarcoma, and other cancer-related conditions resulting from the presence or progression of cancer, such as tumor-induced pleural or pericardial effusions and malignant ascites.

[0305] In some embodiments, a method of treating or preventing cancer in an individual is provided, the method comprising administering a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof to an individual in need thereof. In some embodiments, a method of treating or preventing cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a subject.

[0306] In some embodiments, provided herein is a method of treating cancer, comprising administering to an individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0307] In some embodiments, provided herein are methods of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described herein.

[0308] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, the cancer is selected from the group consisting of carcinoma, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer, pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer, or skin cancer, hematopoietic system tumors of lymphoid lineage, hematopoietic system tumors of myeloid lineage, hematopoietic system tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcoma, central and peripheral nervous system tumors, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, and other cancer-related conditions caused by the presence or progression of cancer.

[0309] dose

[0310] The compounds and compositions disclosed and / or described herein are administered in a therapeutically effective dose, e.g., a dose sufficient to provide treatment of a disease state. Although human dosage levels remain to be optimized for the chemical entities described herein, generally, the daily dose is in the range of about 0.01 to 100 mg / kg body weight; in some embodiments, about 0.05 to 10.0 mg / kg body weight, and in some embodiments, about 0.10 to 1.4 mg / kg body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range is about 0.7 to 7000 mg / day; in some embodiments, about 3.5 to 700.0 mg / day, and in some embodiments, about 7 to 100.0 mg / day. The amount of the chemical entity administered will depend, for example, on the subject being treated and the disease state, the severity of the ailment, the mode of administration and the time course, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg / day, and an exemplary intravenous dosage range is about 5 mg to about 500 mg / day, each depending on the pharmacokinetics of the compound.

[0311] The administration of the compounds and compositions disclosed and / or described herein can be via any recognized mode of administration of the therapeutic agent, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0312] Pharmaceutically acceptable compositions include solid, semisolid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms), so as to be administered at a predetermined rate for a long time and / or pulsed. In some embodiments, the composition is provided in a unit dosage form suitable for a single administration of a precise dose.

[0313] The compounds disclosed and / or described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended mode of administration, the pharmaceutical composition contains about 0.005% to 95% by weight, or about 0.5% to 50% by weight of the compounds disclosed and / or described herein. The actual methods for preparing such dosage forms are known or are obvious to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0314] In some embodiments, the composition is in the form of a pill or tablet, and thus, along with the compounds disclosed and / or described herein, the composition may contain one or more of a diluent (e.g., lactose, sucrose, dibasic calcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders, pellets (marume), solutions or suspensions (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in gelatin capsules.

[0315] Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing or suspending the compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous glucose solution, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injections can be prepared in conventional forms as liquid solutions or suspensions, as emulsions or solid forms suitable for dissolving or suspending in liquids before injection. The percentage of the compound contained in such parenteral compositions depends on, for example, the physical properties of the compound, the activity of the compound and the needs of the subject. However, the percentage of 0.01% to 10% of the active ingredient in the solution is available, and if the composition is a solid subsequently diluted to another concentration, the percentage can be higher. In some embodiments, the composition comprises about 0.2% to 2% of the compound disclosed and / or described herein in the solution.

[0316] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as an ultrafine powder for insufflation, alone or in combination with an inert carrier such as lactose. In this case, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0317] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein and one or more additional pharmaceutical agents, medicaments, adjuvants, etc. Suitable pharmaceutical agents and medicaments include those described herein.

[0318] Pill Box

[0319] Also provided are articles and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles may include containers with labels. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed of a variety of materials, such as glass or plastic. The containers may hold pharmaceutical compositions provided herein. The labels on the containers may indicate that the pharmaceutical compositions are used to prevent, treat, or inhibit the conditions described herein, and may also indicate guidelines for in vivo or in vitro use.

[0320] In one aspect, provided herein are kits containing compounds or compositions described herein and instructions for use. The kits may contain instructions for use for treating any disease or disorder described herein in an individual in need. The kits may additionally contain any materials or equipment that can be used to administer the compounds or compositions, such as vials, syringes, or IV bags. The kits may also contain sterile packaging.

[0321] combination

[0322] The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other therapies and / or therapeutic agents useful for treating the aforementioned conditions.

[0323] The compounds and compositions described and / or disclosed herein can be combined with one or more other therapies to treat the diseases or disorders described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a cell proliferation disorder, including uncontrolled cell growth, abnormal cell cycle regulation, centrosome abnormalities (structural and / or numerical abnormalities, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (especially Grave's disease) and cysts (e.g., ovarian stroma hypervascularity, which is a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid and blood-derived tumors, such as carcinomas, may include, but are not limited to, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer (including squamous cell carcinoma and small cell lung cancer), pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer and skin cancer (including squamous cell carcinoma), hematopoietic system tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt lymphoma), myeloid lineage tumors, Hematopoietic neoplasms (including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia), hematopoietic neoplasms of any lineage, myeloma, tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and bone), central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma and schwannoma), tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors (including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Ewing sarcoma, Kaposi sarcoma) and other cancer-related conditions due to the presence or progression of cancer, such as pleural or pericardial effusions and malignant ascites caused by tumors.

[0324] General Synthesis Methods

[0325] Compounds of formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II) are now described with reference to the following exemplary synthetic schemes for their general preparation and the following specific examples. Those skilled in the art recognize that in order to obtain the various compounds herein, the starting materials can be appropriately selected so that the final desired substituent is conveyed in the reaction scheme with or without protection, as appropriate, to produce the desired product. Alternatively, in place of the final desired substituent, it may be necessary or desirable to use a suitable group that can be conveyed in the reaction scheme and replaced with the desired substituent when appropriate. In addition, those skilled in the art recognize that protecting groups can be used to protect certain functional groups (amino, carboxyl, or side chain groups) from the effects of reaction conditions, and such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are defined as above with reference to formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II).

[0326] When it is necessary to obtain a specific enantiomer of a compound, this can be achieved using any suitable conventional procedure for separating or resolving enantiomers, from the corresponding mixture of enantiomers. Therefore, for example, diastereomeric derivatives can be produced by the reaction of a mixture of enantiomers such as a racemate and a suitable chiral compound. Then, the diastereomers can be separated by any convenient means, such as by crystallization and the desired enantiomer is recovered. In another resolution process, the racemate can be separated using chiral high performance liquid chromatography. Alternatively, when necessary, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes.

[0327] When it is desired to obtain a specific isomer of a compound or to otherwise purify a reaction product, chromatography, recrystallization and other conventional separation procedures may also be used on the intermediates or final products.

[0328] General methods for preparing the compounds described herein are described in the following exemplary methods. The variable groups in the schemes provided herein are as defined for Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II) or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0329] In some embodiments, the compounds provided herein can be synthesized according to Scheme 1, Scheme 2, Scheme 3 and / or Scheme 4. As shown in Schemes 1-4 below, Ring A, Ring B, Y 1 , Y 2 , Y 3 , Y 4 ,m,R B , and R C As defined for compounds of formula I.

[0330] Solution 1.

[0331]

[0332] Scheme 1 summarizes an exemplary route for synthesizing compounds of Formula I. Compounds of Formula I are prepared by reacting a coupling reagent such as HATU with a base such as iPr 2 It can be prepared by reacting a carboxylic acid of formula A (e.g., X=OH) with an indoline of formula B in the presence of NEt, or EDCI and HOBt or DMAP. Alternatively, an acid scavenger such as Et 3 N, reacting an acyl halide of formula A (eg, X═Cl or F) directly with a compound of formula B.

[0333] Solution 2.

[0334]

[0335] Indoline intermediates of formula B can be prepared via the Fisher indole synthesis as described in Scheme 2. Aromatic hydrazines of formula C (e.g., formula Ci, formula C-ii, and formula C-iii) are reacted with a substituted carboxaldehyde of ring B of formula D in the presence of an acid, followed by a reducing agent such as NaBH 4 , Pd / C and H 2 Gas, or Et 3 SiH reaction. Aromatic hydrazines of formula Ci that are monosubstituted in the para position provide indolines of formula Bi, while hydrazines of formula C-ii that contain at least one meta substituent and are unsubstituted in the ortho position provide mixtures of indolines of formulas B-ii-a and B-ii-b. Aromatic hydrazines of formula C-iii that are substituted in one ortho position provide indolines of formula B-iii.

[0336] Solution 3.

[0337]

[0338] Indolines of formula B can also be prepared via the 3,3-dialkylation method described in Scheme 3. Indoles of formula D are reacted with optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chains (formula E) having two terminal leaving groups "LG". LG can be Cl, Br, I, or sulfonate, or another suitable group that can be displaced by a nucleophile. The conversion can be carried out by trialkylboranes such as Et 3 B and a base such as potassium tert-butoxide. The spiroannulation reaction is followed by a reducing agent such as NaBH 4 , Pd / C and H 2 Gas, or Et 3 Reaction of SiH.

[0339] Solution 4.

[0340]

[0341] Indoline of formula B can also be prepared via alkylation of the enolate of indolin-2-one of formula F. Indolin-2-one of formula F is deprotonated with a strong base such as butyl lithium, sodium hexamethyldisilazide, or potassium tert-butoxide and reacted with an optionally substituted 3-6 atom aliphatic and heteroaliphatic straight chain (formula E) having two terminal leaving groups "LG". LG can be Cl, Br, I, or sulfonate, or another suitable group that can be displaced by a nucleophilic substance. This reaction can be mediated by additives such as tetramethyldiaminoethane or hexamethylphosphoric triamide. The spiro ring-increasing reaction is followed by reaction with a reducing agent such as LiAlH 4 or the reaction of borane.

[0342] List implementation plans

[0343] The following enumerated embodiments represent some aspects of the invention.

[0344] 1. A compound of formula (I)

[0345]

[0346] or a pharmaceutically acceptable salt thereof, wherein:

[0347] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ;

[0348] R a1 -R a20are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0349] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0350] Each R B The groups are independently halogen, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0351] m is 0, 1, 2, 3 or 4;

[0352] Y 1 N or CR C1 ;

[0353] Y 2 N or CR C2 ;

[0354] Y 3 N or CR C3 ;

[0355] Y 4 N or CR C4 ;

[0356] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0357] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0358] R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0359] 2. The compound as described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1, [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1'-(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[0360] 3. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted C 6-14 Aryl.

[0361] 4. The compound according to embodiment 3, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted phenyl.

[0362] 5. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 5- to 10-membered heteroaryl group.

[0363] 6. The compound as described in Embodiment 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is indolyl, indazolyl, pyridinyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0364] 7. A compound as described in any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein R a1 is hydrogen or C 1-6 Alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a4 is hydrogen or C 1-6 Alkyl; R a5 is hydrogen or C1-6 Alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6 alkyl-substituted 5- to 12-membered heteroaryl; R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a10 C 3-10 Cycloalkyl; R a11 C 3-10 Cycloalkyl; R a12 is hydrogen or C 1-6 Alkyl; R a13 C 3-10 Cycloalkyl; R a16 C 3-10 cycloalkyl or 3 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected from C 1-6 Substituted by a substituent consisting of an alkyl group or a halogen group; R a17 and R a18 are independently hydrogen or C 1-6 alkyl; and R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl.

[0365] 8. A compound as described in any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R a14 and R a15 are each independently hydrogen; C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one or more C 1-6 Alkyl-substituted 3- to 12-membered heterocycloalkyl.

[0366] 9. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, -OH, methyl, amino,

[0367]

[0368] 10. The compound as described in any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein ring B is C 5-7 Cycloalkyl.

[0369] 11. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 7-membered heterocycloalkyl.

[0370] 12. A compound as described in any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein ring B is wherein * indicates the point of attachment to the rest of formula (I).

[0371] 13. A compound as described in any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein the formula (I) for wherein * indicates the point of attachment to the rest of formula (I).

[0372] 14. A compound as described in any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[0373] 15. A compound as described in any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y4 CR C4 .

[0374] 16. A compound as described in any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4 .

[0375] 17. A compound as described in any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[0376] 18. A compound as described in any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 ,

[0377] 19. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

[0378] 20. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds of Table 2.

[0379] 21. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0380] 22. A method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 21.

[0381] 23. A method of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 21.

[0382] 24. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 21.

[0383] 25. The method of embodiment 24, wherein the cancer is selected from the group consisting of carcinoma, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer, pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer, or Skin cancer, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, central and peripheral nervous system tumors, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, and other cancer-related conditions resulting from the presence or progression of cancer.

[0384] 26. A compound of formula (I)

[0385]

[0386] or a pharmaceutically acceptable salt thereof, wherein:

[0387] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CRa17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0388] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0389] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0390] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0391] m is 0, 1, 2, 3 or 4;

[0392] Y 1 N or CR C1 ;

[0393] Y 2 N or CR C2 ;

[0394] Y 3 N or CR C3 ;

[0395] Y 4 N or CR C4 ;

[0396] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0397] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0398] R c1 -R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0399] 27. A compound of formula (I-1)

[0400]

[0401] or a pharmaceutically acceptable salt thereof, wherein:

[0402] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ;

[0403] R a1 -R a20 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0404] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0405] Each R B The groups are independently halogen, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0406] m is 0, 1, 2, 3 or 4;

[0407] Y 1 N or CR C1 ;

[0408] Y 2 N or CR C2 ;

[0409] Y 3 N or CR C3 ;

[0410] Y 4 N or CR C4 ;

[0411] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0412] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0413] R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0414] 28. A compound as described in embodiment 26 or 27, or a pharmaceutically acceptable salt thereof, wherein the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea -1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1'-(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[0415] 29. The compound of embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted C 6-14 Aryl.

[0416] 30. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted phenyl.

[0417] 31. The compound of embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 5- to 10-membered heteroaryl.

[0418] 32. A compound as described in embodiment 31, or a pharmaceutically acceptable salt thereof, wherein ring A is indolyl, indazolyl, pyridinyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0419] 33. A compound as described in any one of embodiments 26 and 28-32, or a pharmaceutically acceptable salt thereof, wherein R a1 is hydrogen or C 1-6 Alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a4 is hydrogen or C 1-6 Alkyl; R a5 is hydrogen or C 1-6 Alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6 alkyl-substituted 5- to 12-membered heteroaryl; R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a10 C 3-10 Cycloalkyl; R a11 C 3-10 Cycloalkyl; R a12 is hydrogen or C 1-6 Alkyl; R a13 C 3-10 Cycloalkyl; R a16 C 3-10 cycloalkyl or 3 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected from C 1-6 Substituted by a substituent consisting of an alkyl group or a halogen group; R a17 and R a18 are independently hydrogen or C 1-6 Alkyl; R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a21 C 3-10 cycloalkyl; and R a22 C 3-10 Cycloalkyl.

[0420] 34. A compound as described in any one of embodiments 26 and 28-33, or a pharmaceutically acceptable salt thereof, wherein R a14 and R a15are each independently hydrogen; C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one or more C 1-6 Alkyl-substituted 3- to 12-membered heterocycloalkyl.

[0421] 35. A compound as described in any one of embodiments 26 and 28-34, or a pharmaceutically acceptable salt thereof, wherein R a14 is hydrogen and R a15 It is tert-butyl.

[0422] 36. A compound as described in any one of embodiments 26 and 28-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OH, methyl, amino,

[0423]

[0424] 37. A compound as described in any one of embodiments 26 and 28-36, or a pharmaceutically acceptable salt thereof, wherein ring A is Substituted phenyl.

[0425] 38. A compound as described in any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein Ring B is C 5-7 Cycloalkyl.

[0426] 39. The compound of any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- to 7-membered heterocycloalkyl.

[0427] 40. A compound as described in any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein ring B is wherein * indicates the point of attachment to the rest of formula (I).

[0428] 41. A compound as described in any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein the formula (I) for wherein * indicates the point of attachment to the rest of formula (I).

[0429] 42. The compound of embodiment 41, or a pharmaceutically acceptable salt thereof, wherein the for

[0430] 43. A compound as described in any one of embodiments 25 and 28-42, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[0431] 44. The compound of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[0432] 45. The compound of embodiment 43 or 44, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 Each is hydrogen.

[0433] 46. ​​A compound as described in any one of embodiments 25 and 28-41, or a pharmaceutically acceptable salt thereof, wherein Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[0434] 47. A compound as described in any one of embodiments 25 and 28-41, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4 .

[0435] 48. A compound as described in any one of embodiments 25 and 28-47, or a pharmaceutically acceptable salt thereof, wherein R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 ,

[0436] 49. The compound of embodiment 48, or a pharmaceutically acceptable salt thereof, wherein R C2 for

[0437] 50. The compound of embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

[0438] 51. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 2.

[0439] 52. A pharmaceutical composition comprising a compound according to any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0440] 53. A method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound of any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 52.

[0441] 54. A method of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 26-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 52.

[0442] 55. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 26-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 52.

[0443] 56. The method of embodiment 55, wherein the cancer is selected from the group consisting of carcinoma, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer, pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer, or Skin cancer, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, central and peripheral nervous system tumors, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, and other cancer-related conditions resulting from the presence or progression of cancer.

[0444] 57. A compound of formula (I)

[0445]

[0446] or a pharmaceutically acceptable salt thereof, wherein:

[0447] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0448] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0449] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0450] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0451] m is 0, 1, 2, 3 or 4;

[0452] Y 1 N or CR C1 ;

[0453] Y 2 N or CR C2 ;

[0454] Y 3 N or CR C3 ;

[0455] Y 4 N or CR C4 ;

[0456] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0457] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0458] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0459] 58. A compound of formula (I-2)

[0460]

[0461] or a pharmaceutically acceptable salt thereof, wherein:

[0462] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0463] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2, and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0464] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0465] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0466] m is 0, 1, 2, 3 or 4;

[0467] Y 1 N or CR C1 ;

[0468] Y 2 N or CR C2 ;

[0469] Y 3 N or CR C3 ;

[0470] Y 4 N or CR C4 ;

[0471] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0472] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0473] R c1 -R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0474] 59. A compound of formula (I-1)

[0475]

[0476] or a pharmaceutically acceptable salt thereof, wherein:

[0477] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ;

[0478] R a1 -R a20 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0479] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[0480] Each R B The groups are independently halogen, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[0481] m is 0, 1, 2, 3 or 4;

[0482] Y 1 N or CR C1 ;

[0483] Y 2 N or CR C2 ;

[0484] Y 3 N or CR C3 ;

[0485] Y4 N or CR C4 ;

[0486] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[0487] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[0488] R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[0489] 60. A compound as described in embodiment 57 or 58, or a pharmaceutically acceptable salt thereof, wherein the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane -1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1'-(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[0490] 61. The compound of embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted C6-14 aryl group.

[0491] 62. The compound of embodiment 61, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted phenyl.

[0492] 63. The compound of embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 5- to 10-membered heteroaryl.

[0493] 64. A compound as described in embodiment 63, or a pharmaceutically acceptable salt thereof, wherein Ring A is indolyl, indazolyl, pyridinyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0494] 65. A compound as described in any one of embodiments 57 and 60-64, or a pharmaceutically acceptable salt thereof, wherein R a1 is hydrogen or C 1-6 Alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a4 is hydrogen or C 1-6 Alkyl; Ra5 is hydrogen or C 1-6 Alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6 alkyl-substituted 5- to 12-membered heteroaryl; R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a10 C 3-10 Cycloalkyl; R a11 C 3-10 Cycloalkyl; R a12 is hydrogen or C 1-6 Alkyl; R a13 C 3-10 Cycloalkyl; R a16 C 3-10 cycloalkyl or 3 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected from C 1-6 Substituted by a substituent consisting of an alkyl group or a halogen group; R a17 and R a18 are independently hydrogen or C 1-6 Alkyl; R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a21 C 3-10 cycloalkyl; and R a22 C 3-10 Cycloalkyl.

[0495] 66. A compound as described in any one of embodiments 57 and 60-65, or a pharmaceutically acceptable salt thereof, wherein R a14 and R a15 are each independently hydrogen; C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1R 1a2 , and optionally one or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one or more C 1-6 Alkyl-substituted 3- to 12-membered heterocycloalkyl.

[0496] 67. A compound as described in any one of embodiments 57 and 60-66, or a pharmaceutically acceptable salt thereof, wherein R a14 is hydrogen and R a15 It is tert-butyl.

[0497] 68. A compound as described in any one of embodiments 57 and 60-67, or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OH, methyl, amino,

[0498]

[0499] 69. A compound as described in any one of embodiments 57 and 60-68, or a pharmaceutically acceptable salt thereof, wherein ring A is Substituted phenyl.

[0500] 70. A compound as described in any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein Ring B is C 5-7 Cycloalkyl.

[0501] 71. The compound of any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- to 7-membered heterocycloalkyl.

[0502] 72. A compound as described in any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein ring B is wherein * indicates the point of attachment to the rest of formula (I).

[0503] 73. A compound as described in any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein the formula (I) for wherein * indicates the point of attachment to the rest of formula (I).

[0504] 74. The compound as described in embodiment 73, or a pharmaceutically acceptable salt thereof, wherein the for

[0505] 75. A compound as described in any one of embodiments 57 and 60-74, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[0506] 76. The compound of embodiment 75, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[0507] 77. A compound as described in embodiment 75 or 76, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 Each is hydrogen.

[0508] 78. A compound as described in any one of embodiments 57 and 60-74, or a pharmaceutically acceptable salt thereof, wherein Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[0509] 79. A compound as described in any one of embodiments 57 and 60-74, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4 .

[0510] 80. A compound as described in any one of embodiments 57 and 60-79, or a pharmaceutically acceptable salt thereof, wherein R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 ,

[0511] 81. The compound of embodiment 80, or a pharmaceutically acceptable salt thereof, wherein R C2 for

[0512] 82. The compound of embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

[0513] 83. A compound as described in Embodiment 57, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds in Table 2.

[0514] 84. A pharmaceutical composition comprising a compound according to any one of embodiments 57-83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0515] 85. A method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of a compound of any one of embodiments 57-83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 84.

[0516] 86. A method of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 57-83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 84.

[0517] 87. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 57-83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 84.

[0518] 88. The method of embodiment 87, wherein the cancer is selected from the group consisting of carcinoma, anal cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, appendix cancer, kidney cancer, renal pelvis cancer, ureter cancer, urothelial cancer, liver cancer, lung cancer, pleural cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, oral cancer, laryngeal cancer, bile duct cancer, gallbladder cancer, ovarian cancer, testicular cancer, germ cell cancer, uterine cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, salivary gland cancer, or Skin cancer, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, central and peripheral nervous system tumors, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary site, other tumors including retinoblastoma, melanoma, seminoma, teratoma, osteosarcoma, and other cancer-related conditions resulting from the presence or progression of cancer.

[0519] Example

[0520] The following examples are provided to illustrate but not limit the compositions, uses, and methods provided herein. The compounds were prepared using the general methods described above.

[0521] Abbreviations:

[0522] BSA: bovine serum albumin

[0523] DAST: diaminosulfur trifluoride

[0524] dba: dibenzylideneacetone

[0525] DMF: dimethylformamide

[0526] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0527] ESIMS: Electrospray Mass Spectrometry

[0528] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0529] HOBT: 1-Hydroxybenzotriazole

[0530] HPLC: High Performance Liquid Chromatography

[0531] IC 50 : 50% inhibition concentration

[0532] LDA: lithium diisopropylamide

[0533] mCPBA: meta-chloroperbenzoic acid

[0534] MsCl: Methanesulfonyl chloride

[0535] MTBE: Methyl tert-butyl ether

[0536] NCS: N-chlorosuccinimide

[0537] NCI: N-iodosuccinimide

[0538] NMR: Nuclear Magnetic Resonance

[0539] PE: Petroleum ether

[0540] THF: Tetrahydrofuran

[0541] TFA: trifluoroacetic acid

[0542] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran

[0543] Xphos Pd G4: dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphonium; methanesulfonic acid; N-methyl-2-phenylaniline; palladium (CAS: 1599466-81-5)

[0544] Synthesis of intermediates

[0545] Synthesis of 3-(piperidin-1-ylsulfonyl)benzoic acid (A-01)

[0546]

[0547] Step 1. Piperidine (0.25 mL, 2.6 mmol), CH 2 Cl 2 (5.0mL), iPr 2 A mixture of NEt (1.3 mL, 7.7 mmol) and methyl 3-chlorosulfonylbenzoate (900 mg, 3.84 mmol, 1.5 eq) was stirred for 2 h, concentrated, and poured into H 2 O (20 mL) and extracted with EtOAc (2 x 10 mL). The extracts were combined, washed with brine (10.0 mL), and purified by Na 2 SO 4 Dry, filter, and concentrate to give methyl 3-(1-piperidinylsulfonyl)benzoate (0.95 g).

[0548] Step 2. Methyl 3-(1-piperidinylsulfonyl)benzoate (0.90 g, 3.2 mmol), THF (6.0 mL), and H 2 O (2.0 mL), and LiOH·H 2O (0.67 g, 16 mmol) was stirred for 2 h and then concentrated. The mixture was treated with HCl (4 N) to bring the pH to 3 and poured into H 2 O (10 mL) and extracted with EtOAc (2 x 10 mL). The extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 Dry, filter, and concentrate to obtain 3-(1-piperidinylsulfonyl)benzoic acid (A-01, 0.72 g). ESIMS m / z: 270.0 (M+H) + .

[0549] The compounds in Table 3 were prepared in the same manner as A-01 from the indicated sulfonyl chlorides and amines.

[0550] Table 3

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561] Synthesis of 3-(cyclopentylsulfinyl)benzoic acid (A-51)

[0562]

[0563] Step 1. Methyl 3-cyclopentylthiobenzoate (0.50 g, 2.1 mmol), CH 2 Cl 2 (25 mL), and MnO 2 A mixture of (0.37 g, 4.2 mmol) was stirred at 20°C for 16 h. The mixture was extracted with EtOAc (100 mL x 3), and the extracts were combined and purified by Na 2 SO 4Dry, filter, and concentrate.The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give methyl 3-cyclopentylsulfinylbenzoate (0.52 g).

[0564] Step 2. Methyl 3-cyclopentylsulfinylbenzoate (0.50 g, 2.0 mmol), THF (10 mL), and H 2 A mixture of 1H 2O (10 mL), and LiOH (95 mg, 4.0 mmol) was stirred at 25 °C for 2 h and then concentrated. The pH was adjusted to pH 3 with 2M HCl, and the mixture was extracted with EtOAc (50 mL x 3). The combined extracts were purified by Na 2 SO 4 Dry, filter, and concentrate to give 3-cyclopentylsulfinylbenzoic acid (A-51, 83 mg).

[0565] Synthesis of 3-(cyclopentylsulfonyl)benzoic acid (A-52)

[0566]

[0567] Step 1. To a mixture of methyl 3-cyclopentylthiobenzoate (0.50 g, 2.1 mmol) in HOAc (3.0 mL) was added H 2 O 2 (30%, 1.2 mL, 13 mmol). The mixture was stirred at 80 °C for 12 h, and H 2 O (20 mL), and the mixture was extracted with EtOAc (10 mL x 3). The extracts were combined and washed with saturated Na 2 CO 3 (20mL x 3), and Na 2 SO 3 The extract was washed with aqueous solution (20 mL x 3) and brine (30 mL). 2 SO 4 Dry, filter, and concentrate to give methyl 3-cyclopentylsulfonylbenzoate (260 mg).

[0568] Step 2. Methyl 3-cyclopentylsulfonylbenzoate (0.28 g, 1.0 mmol), THF (5.0 mL), and H 2 A mixture of O (5 mL), and LiOH (50 mg, 2.1 mmol) was stirred at 25 °C for 2 h. The reaction mixture was extracted with MTBE (10 mL x 2). The pH of the aqueous phase was adjusted to 3 with HCl and extracted with EtOAc (3 x 20 mL). The extracts were combined, washed with 20 mL of brine, and purified by Na 2 SO 4Dry, filter, and concentrate to give 3-cyclopentylsulfonylbenzoic acid (0.29 g).

[0569] Synthesis of 3-(N-methylcyclopentanesulfonylimide)benzoic acid (A-53)

[0570]

[0571] Step 1. To methyl 3-cyclopentylthiobenzoate (0.85 g, 3.6 mmol), EtOH (2 mL), and PhI(OAc) was added. 2 (3.5 g, 11 mmol) was added to the mixture 4 OAc (1.1 g, 14 mmol). The mixture was stirred at 20 °C for 2 h, concentrated, and washed with H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / petroleum ether) gave methyl 3-(cyclopentylsulfonylimino)benzoate (0.50 g).

[0572] Step 2. To a 0°C mixture of methyl 3-(cyclopentylsulfonylimino)benzoate (0.25 g, 0.94 mmol) and DMF (2 mL) was added NaH (60% in mineral oil, 45 mg, 1.1). The mixture was stirred at 0°C for 0.5 h, and MeI (64 μL, 1.0 mmol) was added. The mixture was stirred at 20°C for 12 h, and H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 The residue was dried and concentrated to obtain 3-(S-cyclopentyl-N-methyl-sulfonylimino)benzoic acid (A-53, 0.25 g).

[0573] Synthesis of 3-(cyclopentanecarbonyl)benzoic acid (A-54)

[0574]

[0575] Step 1. To a mixture of methyl 3-cyanobenzoate (1.0 g, 6.2 mmol), CuI (0.37 g, 1.9 mmol), and THF (30 mL) at -50 °C was slowly added cyclopentylmagnesium bromide (1 M in THF, 24 mL, 24 mmol). The mixture was stirred at -50 °C for 5 h, then at 20 °C for 1 h, and saturated NH 4Cl aqueous solution (10 mL). EtOAc (20 mL) was added and the layers were separated. The aqueous washings were extracted with EtOAc (10 mL), and the extracts were combined, washed with brine (15 mL x 2), and filtered through Na 2 SO 4 Dry, filter, concentrate, and purify by silica gel chromatography (0-20% EtOAc / petroleum ether) to give methyl 3-(cyclopentanecarbonyl)benzoate (0.22 g).

[0576] Step 2. Methyl 3-(cyclopentanecarbonyl)benzoate (0.22 g, 0.95 mmol), LiOH (0.11 g, 4.7 mmol), THF (0.9 mL), and H 2 The degassed mixture of 2,4-dihydro-1,4-dihydro- ... 2 O (10 mL) and extracted with MTBE (2 mL). The pH of the aqueous phase was adjusted to between 2 and 3 with 2N HCl. The resulting precipitate was filtered and dried under vacuum to give 3-(cyclopentanecarbonyl)benzoic acid (A-54, 120 mg).

[0577] Synthesis of 3-(cyclobutanecarbonyl)benzoic acid (A-77)

[0578]

[0579] 3-(Cyclobutanecarbonyl)benzoic acid was prepared in the same manner as A-54 from methyl 3-cyanobenzoate and cyclobutanemagnesium bromide.

[0580] Synthesis of 3-(2-cyclobutylacetyl)benzoic acid (A-75)

[0581]

[0582] Step 1. At -50°C, add CuI (2.1 g, 11 mmol) and bromo(cyclobutylmethyl)magnesium (1 M, 13.2 mL) to a mixture of 3-bromobenzonitrile (2.0 g, 11 mmol) and THF (10 mL). Stir the mixture at -50°C for 5 h and then at 20°C for 1 h. Pour the mixture into H 2 O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (20 mL) and purified by Na2 S O 4 Drying, concentration, and purification by silica gel chromatography (0-20% EtOAC / PE) gave 1-(3-bromophenyl)-2-cyclobutylethan-1-one (1.3 g).

[0583] Step 2. Under CO (50 psi), 1-(3-bromophenyl)-2-cyclobutylethan-1-one (1.1 g, 4.4 mmol), MeOH (4 mL), DMF (16 mL), Et 3 N (1.8 mL, 13 mmol), 3-diphenylphosphanylpropyl-(diphenyl)phosphane (0.36 g, 0.87 mmol), and Pd(OAc) 2 A mixture of (0.20 g, 0.87 mmol) was stirred at 90°C for 12 h. The mixture was poured into water (30 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-20% EtOAc / PE) gave methyl 3-(2-cyclobutylacetyl)benzoate (0.80 g).

[0584] Step 3. Methyl 3-(2-cyclobutylacetyl)benzoate (0.50 g, 2.2 mmol), THF (0.6 mL), and H 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (0.2 mL), and LiOH (0.16 g, 6.7 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated to remove THF, and HCl (0.5 M, 5 mL) was added. The mixture was extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Drying and concentration gave 3-(2-cyclobutylacetyl)benzoic acid (0.36 g, 46% purity).

[0585] Synthesis of 3-(cyclopentyldifluoromethyl)benzoate (A-76)

[0586]

[0587] Step 1. To methyl 3-(cyclopentanecarbonyl)benzoate (0.16 mg, 0.69 mmol) and CH 2 Cl 2 BF (1 mL) was added to the mixture 3 ·Et 2 O (0.64 mL, 5.2 mmol) and ethane-1,2-dithiol (0.10 mL, 1.2 mmol). The mixture was stirred at 20 °C for 18 h, poured into water (20 mL), and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4Drying, concentration and purification by preparative TLC (10% EtOAc / PE) gave methyl 3-(2-cyclopentyl-1,3-dithiolan-2-yl)benzoate (0.20 g).

[0588] Step 2. At -70 °C, methyl 3-(2-cyclopentyl-1,3-dithiolan-2-yl)benzoate (0.20 g, 0.65 mmol) and CH 2 Cl 2 To the mixture of 10 mL of NIS (0.29 g, 1.3 mmol) and pyridine hydrofluoride (0.33 mL, 2.6 mmol) were added. The mixture was stirred at -70 °C for 0.5 h and poured into H 2 O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by preparative TLC (10% EtOAc / PE) gave methyl 3-[cyclopentyl(difluoro)methyl]benzoate (80 mg).

[0589] Step 3. Methyl 3-[cyclopentyl(difluoro)methyl]benzoate (80 mg, 0.32 mmol), THF (3 mL), and H 2 A mixture of 1H 2O (1 mL), and LiOH (23 mg, 0.94 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated, combined with HCl (0.5 M, 5 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), purified by Na 2 SO 4 The residue was dried and concentrated to obtain 3-[cyclopentyl(difluoro)methyl]benzoic acid (A-76, 91 mg).

[0590] Synthesis of 3-(cyclopentanesulfonylimino)benzoic acid (A-72)

[0591]

[0592] Methyl 3-(cyclopentylsulfonylimino)benzoate (0.80 g, 3.0 mmol), THF (18 mL), and H 2 O (6 mL), and LiOH·H 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (0.38 g, 9.0 mmol) and 1,4-dihydro-1,4-dihydro-2-nitropropene (0.38 g, 9.0 mmol) was stirred at 25 °C for 12 h, then poured into water (20 mL) and extracted with EtOAc (2 x 10 mL). The organic phase was washed with brine (20 mL) and purified by Na 2 SO 4Drying and concentration gave 3-(cyclopentanesulfonylimino)benzoic acid (A-72, 0.3 g). 1 H NMR (DMSO-d 6 ,400MHz)δppm 13.72-13.06(m, 1H), 8.40-8.38(s, 1H), 8.20-8.17(m, 1H), 8.13-8.09(m, 1H) , 7.76-7.72(m, 1H), 3.68-3.60(m, 1H), 1.91-1.70(m, 4H), 1.62-1.47(m, 4H).

[0593] Synthesis of 2-(cyclopentyl(hydroxy)methyl)isonicotinic acid (A-78)

[0594]

[0595] Step 1. To a mixture of methyl 2-formylisonicotinate (1.0 g, 6.0 mmol) and THF (25 mL) at -60°C was added cyclopentylmagnesium bromide (1 M, 7.3 mL) over 15 min. The resulting mixture was stirred at -60°C for 1.75 h, poured into water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave methyl 2-(cyclopentyl(hydroxy)methyl)isonicotinate (0.20 g).

[0596] Step 2. Methyl 2-(cyclopentyl(hydroxy)methyl)isonicotinate (0.18 g, 0.77 mmol), THF (2 mL), and H 2 O (1 mL), and LiOH·H 2 A mixture of 2-(cyclopentyl(hydroxy)methyl)isonicotinic acid (A-78) was stirred at 25 °C for 2 h, poured into water (30 mL), and extracted with MTBE (2 x 20 mL). The aqueous layer was collected and the pH was adjusted to 5 by careful addition of 2N HCl. The mixture was concentrated to give 2-(cyclopentyl(hydroxy)methyl)isonicotinic acid (A-78).

[0597] Synthesis of 3-((3,3-difluorocyclobutyl)sulfonyl)benzoic acid (A-82)

[0598]

[0599] Step 1. 3-Bromobenzenethiol (3.4 mL, 33 mmol), 4-bromobut-1-ene (4.4 mL, 43 mmol), DMF (50 mL), and K 2 CO3 A mixture of (6.8 g, 49 mmol) was stirred at 60 °C for 4 h and then mixed with 1 M Na 2 S 2 O 3 Aqueous solution and saturated NaHCO 3 The aqueous solutions (30 mL) were combined and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate, and purify by silica gel chromatography (0-100% EtOAc / PE) to give 1-bromo-3-but-3-enylsulfanyl-benzene (6.50 g).

[0600] Step 2. To 1-bromo-3-but-3-enylsulfanyl-benzene (6.5 g, 27 mmol) and CH 2 Cl 2 To the mixture of 1% ethanol (50 mL) was added mCPBA (27 g, 0.13 mol, 85% purity). The mixture was stirred at 20°C for 12 h and then reacted with 1 M Na 2 S 2 O 3 Aqueous solution and saturated NaHCO 3 The aqueous solutions (30 mL) were combined and washed with CH 2 Cl 2 (2 x 30 mL), washed with brine (10 mL), and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave 2-[2-(3-bromophenyl)sulfonylethyl]oxirane (5.1 g).

[0601] Step 3. To a mixture of 2-[2-(3-bromophenyl)sulfonylethyl]oxirane (5.1 g, 18 mmol) and THF (50 mL) was added MeMgBr (3 M, 23 mL, 69 mmol) at -70°C. The mixture was stirred at 20°C for 12 h and poured into saturated NH 4 Cl aqueous solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave 3-(3-bromophenyl)sulfonylcyclobutanol (4.3 g).

[0602] Step 4. At 40°C, 3-(3-bromophenyl)sulfonylcyclobutanol (1.00 g, 3.4 mmol), H 2 O (10 mL), MeCN (5 mL), and CH 2 Cl 2 Add RuCl (5 mL) to the mixture 3 ·H 2 O (8 mg, 34 μmol) and NaIO 4 (3.7 g, 17 mmol). The mixture was stirred at 40 °C for 12 h, cold water (30 mL) was added, and the mixture was washed with CH 2 Cl 2 The combined extracts were washed with saturated NaHCO 3 The mixture was washed with aqueous solution and brine, and then with Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave 3-(3-bromophenyl)sulfonylcyclobutanone (0.64 g).

[0603] Step 5. At -70 °C, 3-(3-bromophenyl)sulfonylcyclobutanone (0.64 g, 2.2 mmol) and CH 2 Cl 2 To the mixture of 1% ethanol (6 mL) was added DAST (0.88 mL, 6.6 mmol). The mixture was stirred for 1 h, then allowed to warm to 20 °C and stirred for 16 h. The mixture was poured into saturated NaHCO 3 aqueous solution (10 mL) and treated with CH 2 Cl 2 The resulting mixture was extracted with 1% ethyl acetate (2 x 10 mL) and the combined extracts were washed with brine (10 mL), purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave 1-bromo-3-(3,3-difluorocyclobutyl)sulfonylbenzene (0.60 g).

[0604] Step 6. Bubble CO gas through 1-bromo-3-(3,3-difluorocyclobutyl)sulfonylbenzene (0.55 g, 1.8 mmol), Et 3 N (0.49 mL, 3.5 mmol), DMF (6 mL), MeOH (3 mL), bis(diphenylphosphino)propane (73 mg, 0.18 mmol), and Pd(OAc) 2(40 mg, 0.18 mmol) was stirred for 5 minutes, and then the mixture was heated at 80 °C for 12 h under 15 psi of CO atmosphere. The mixture was poured into water (30 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave methyl 3-(3,3-difluorocyclobutyl)sulfonylbenzoate (0.44 g).

[0605] Step 7. Methyl 3-(3,3-difluorocyclobutyl)sulfonylbenzoate (0.44 g, 1.5 mmol), THF (5 mL), and H 2 O (1.5 mL), and LiOH·H 2 A mixture of 2-nitropropene (0.25 g, 6.1 mmol) and 4-nitropropene (0.25 g, 6.1 mmol) was stirred at 40 °C for 2 h, concentrated, and then added with H 2 O (30 mL), 2N HCl was added until the pH was between 3 and 4, and the resulting mixture was extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), 2 SO 4 The residue was dried and concentrated to give 3-((3,3-difluorocyclobutyl)sulfonyl)benzoic acid (A-82, 0.33 g).

[0606] Synthesis of 5-(cyclopentylsulfonyl)thiophene-3-carboxylic acid (A-83)

[0607]

[0608] Step 1. Mix 5-bromothiophene-3-carboxylic acid methyl ester (1.0 g, 4.5 mmol), 1,4-dioxane (25 mL), iPr 2 NEt (2.0 mL, 11 mmol), Pd 2 (dba) 3 A mixture of 1,4-dimethoxy- ... 2 O (20 mL), extracted with EtOAc (2 x 10 mL), and the combined extracts washed with brine (20 mL), 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave methyl 5-cyclopentylthiothiophene-3-carboxylate (1.0 g).

[0609] Step 2. To methyl 5-cyclopentylthiothiophene-3-carboxylate (0.70 g, 2.9 mmol) and CH 2 Cl 2 mCPBA (2.4 g, 12 mmol, 85% purity) was added to the mixture (20 mL). The mixture was stirred at 20 °C for 12 h and poured into saturated Na 2 SO 3 (10 mL) and extracted with EtOAc (2 x 5 mL). The combined extracts were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave methyl 5-cyclopentylsulfonylthiophene-3-carboxylate (0.70 g).

[0610] Step 3. Methyl 5-cyclopentylsulfonylthiophene-3-carboxylate (0.71 g, 2.6 mmol), THF (9 mL), and H 2 O (3 mL), and LiOH·H 2 A mixture of 2-nitropropene (0.32 g, 7.7 mmol) and 4-nitropropene (0.4 g, 2.0 mmol) was stirred at 20 °C for 12 h and H 2 O (10 mL), and adjusted the pH to 3-4 with HCl (2N). The resulting mixture was extracted with EtOAc (2 x 5 mL). The extracts were combined, washed with brine (5 mL), and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) afforded 5-(cyclopentylsulfonyl)thiophene-3-carboxylic acid (A-83, 0.40 g).

[0611] Synthesis of 3-(Cyano(cyclopentyl)methyl)benzoic acid (A-85)

[0612]

[0613] Step 1. At 0°C, NaH (27 mg, 0.69 mmol, 285 uL, 60% purity, 1.2 eq) was added to a mixture of methyl 3-(cyanomethyl)benzoate (0.10 g, 0.58 mmol) and DMF (2 mL). After stirring for 0.5 h, bromocyclopentane (0.12 mL, 1.1 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 h, and saturated NH 4 Cl aqueous solution (2 mL) and H 2 O (10 mL). The mixture was extracted with EtOAc (10 mL x 3), and the combined extracts were washed with brine (10 mL x 3),2 SO 4 Dry, filter, concentrate and purify by silica gel chromatography (0-15% EtOAc / PE) to give methyl 3-(cyano(cyclopentyl)methyl)benzoate (0.10 g).

[0614] Step 2. Methyl 3-(cyano(cyclopentyl)methyl)benzoate (0.10 g, 0.41 mmol), THF (3 mL), and H 2 O (3 mL), and LiOH·H 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro- ...1,4-dihydro 2 SO 4 Dry, filter, and concentrate to give 3-(cyano(cyclopentyl)methyl)benzoic acid (A-85, 0.11 g).

[0615] Synthesis of 3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoic acid (A-86)

[0616]

[0617] Step 1. Then, methyl 3-acetylbenzoate (1.0 g, 5.6 mmol), 4,4-difluoropiperidine hydrochloride (0.88 g, 5.6 mmol), 1,2-dichloroethane (20 mL), Ti(OiPr) 4 A mixture of (6.6 mL, 23 mmol) was stirred at 80 °C for 12 h. NaBH(OAc) was added 3 (3.6 g, 17 mmol), and the mixture was stirred at 80 °C for 2 h, poured into water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (10 mL), 2 SO 4 Drying and concentration gave isopropyl 3-[1-(4,4-difluoro-1-piperidinyl)ethyl]benzoate (1.5 g).

[0618] Step 2. Isopropyl 3-[1-(4,4-difluoro-1-piperidinyl)ethyl]benzoate (1.4 g, 4.6 mmol) was dissolved in THF (14 mL), MeOH (3.3 mL), and H 2 A mixture of 2-nitropropene (3.3 mL) and LiOH (0.33 g, 14 mmol) was stirred at 25 °C for 2 h. The mixture was concentrated and added with H 2O (28 mL) and washed with EtOAc (2 x 28 mL). The aqueous solution was treated with 2M HCl until pH was 2, and the resulting mixture was concentrated to give 3-[1-(4,4-difluoro-1-piperidinyl)ethyl]benzoic acid (A-86, 0.91 g).

[0619] Synthesis of 6-((4,4-difluoropiperidin-1-yl)methyl)picolinic acid (A-87)

[0620]

[0621] Step 1. To a mixture of methyl 6-formylpyridine-2-carboxylate (0.50 g, 3.0 mmol) and 4,4-difluoropiperidine (477 mg, 3.0 mmol, 1.0 eq, HCl) in MeOH (10 mL) was added HOAc (545 mg, 9.1 mmol, 519 uL, 3.0 eq), NaOAc (745 mg, 9.1 mmol, 3.0 eq), and then stirred at 25 ° C for 1 hour. Then NaBH3CN (761 mg, 12.1 mmol, 4.0 eq) was added and the mixture was stirred at 25 ° C for 1 hour. The reactant was poured into water (10 mL), and the resulting mixture was extracted with EtOAc (2 x 10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give compound methyl 6-[(4,4-difluoro-1-piperidinyl)methyl]pyridine-2-carboxylate (500 mg, crude) as a yellow solid.

[0622] Synthesis of 3-((3,3-difluoropyrrolidin-1-yl)methyl)benzoic acid (A-92)

[0623]

[0624] 3-((3,3-Difluoropyrrolidin-1-yl)methyl)benzoic acid (A-92) was prepared from methyl 3-formylbenzoate in the manner described for the synthesis of A-87.

[0625] Synthesis of 2-((4,4-difluoropiperidin-1-yl)methyl)-6-methylpyrimidine-4-carboxylic acid (A-88)

[0626]

[0627] Potassium ((4,4-difluoropiperidin-1-yl)methyl)trifluoroborate (CAS: 1708960-44-4, 1.1 g, 4.6 mmol), 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (0.28 g, 1.5 mmol), H 2 O (2 mL), THF (8 mL), Cs 2CO 3 (1.5 g, 4.6 mmol), and Xphos Pd G4 (65 mg, 76 μmol). The mixture was stirred at 80 ° C for 12 h, diluted with water (10 mL), and extracted with EtOAc (10 mL×3). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, filter, concentrate and analyze by preparative HPLC (C18, H 2 The mixture was purified by HPLC-MS / MS (1-10% MeCN in 2[formic acid]) to afford 2-((4,4-difluoropiperidin-1-yl)methyl)-6-methylpyrimidine-4-carboxylic acid (A-88, 50 mg).

[0628] Synthesis of 3-(isoxazolidin-2-ylmethyl)benzoic acid (A-89)

[0629]

[0630] Step 1. Methyl 3-(bromomethyl)benzoate (0.30 g, 1.3 mmol), DMF (3 mL), isoxazolidine hydrochloride (0.14 g, 1.3), and iPr 2 A mixture of NEt (0.68 mL, 3.9 mmol) was stirred at 60 °C for 12 h. The mixture was mixed with 0 °C H 2 O (10 mL) and extracted with EtOAc (10 mL x 2). The combined extracts were washed with H 2 O (10 mL) and brine (10 mL), and 2 SO 4 Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave methyl 3-(isoxazolidin-2-ylmethyl)benzoate (0.17 g).

[0631] Step 2. Methyl 3-(isoxazolidin-3-ylmethyl)benzoate (0.17 g, 0.77 mmol), 1,4-dioxane (1.5 mL), and H 2 O (0.5 mL) and LiOH·H 2 A mixture of H O (32 mg, 0.77 mmol) was stirred at 20 °C for 12 h, and H 2 O (5 mL) and MTBE (10 mL). The aqueous phase was collected and the pH was adjusted to 6.0 by adding HCl (2N). The aqueous phase was concentrated to give 3-(isoxazolidin-3-ylmethyl)benzoic acid (A-89, 0.17 g, crude).

[0632] Synthesis of 3-((6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)methyl)benzoic acid (A-96)

[0633]

[0634] Synthesis of 3-((6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)methyl)benzoic acid (A-96) was prepared in the same manner as A-89 by replacing isoxazolidine hydrochloride with 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride.

[0635] Synthesis of 3-(cyclopentylamino)benzoic acid (A-90)

[0636]

[0637] Step 1. A mixture of methyl 3-aminobenzoate (1.0 g, 6.6 mmol), cyclopentanone (2.9 mL, 33 mmol), MeOH (10 mL), and HOAc (0.38 mL, 6.6 mmol) was stirred for 3 h, and NaBH 3 CN (0.62 g, 9.9 mmol). The resulting mixture was stirred for 11 h, poured into water (50 mL), and extracted with EtOAc (2 x 25 mL). The extract was washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave methyl 3-(cyclopentylamino)benzoate (1.33 g, 91.68% yield) as a white solid.

[0638] Step 2. Methyl 3-(cyclopentylamino)benzoate (0.10 g, 0.46 mmol), THF (0.9 mL), and H 2 O (0.3 mL), and LiOH·H 2 A mixture of 2-nitropropene (2-nitropropene) (96 mg, 2.3 mmol) was stirred at 60 °C for 6 h, and H 2 O (10 mL), and adjusted the pH to 5-6 with HCl (2N). The resulting mixture was extracted with EtOAc (2 x 5 mL), and the extract was washed with brine (5 mL), and then purified by Na 2 SO 4 Drying and concentration gave 3-(cyclopentylamino)benzoic acid (A-90, 53 mg).

[0639] Synthesis of 3-(cyclopentyl(methyl)amino)benzoic acid (A-91)

[0640]

[0641] Step 1. To a mixture of methyl 3-(cyclopentylamino)benzoate (0.50 g, 2.0 mmol), paraformaldehyde (0.41 mg, 5 mmol), and dichloroethane (5 mL) was added HOAc (0.16 mL, 3.0 mmol) dropwise at 20°C. After stirring for 1 h, NaBH(OAc) was added. 3 (0.97 g, 5 mmol), and the mixture was stirred at 60 ° C for 11 h. The reaction was poured into water (20 mL), and the resulting mixture was extracted with EtOAc (2 x 15 mL). The organic phase was washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave methyl 3-[cyclopentyl(methyl)amino]benzoate (0.42 g).

[0642] Step 2. Methyl 3-[cyclopentyl(methyl)amino]benzoate (0.23 g, 0.98 mmol), THF (3 mL), and H 2 O (1 mL), and LiOH·H 2 O (0.12 g, 3.0 mmol) was stirred at 60 °C for 2 h. The mixture was poured into water (10 mL), the pH was adjusted to 3-4 with HCl (2N), and extracted with EtOAc (2 x 5 mL). The extract was washed with brine (5 mL) and purified by Na 2 SO 4 Drying and concentration gave 3-(cyclopentyl(methyl)amino)benzoic acid (A-91, 0.30 g).

[0643] Synthesis of 3-(3,3-difluorocyclobutane-1-carbonyl)benzoic acid (A-93)

[0644]

[0645] Step 1. To a mixture of 1-bromo-3-iodo-benzene (1.3 mL, 10 mmol) and THF (20 mL) at -70°C was added BuLi (1 M, 10 mL) dropwise. The mixture was stirred for 30 min. and 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (1.5 g, 8.4 mmol) in THF (10 mL) was added dropwise at -70°C. The resulting mixture was stirred at 20°C for 1.5 h and poured into saturated NH 4 Cl aqueous solution (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4Drying, concentration, and purification by silica gel chromatography (0-100% EtOAc / PE) gave (3-bromophenyl)-(3,3-difluorocyclobutyl)methanone (1.1 g).

[0646] Step 2. Under CO (50 psi), (3-bromophenyl)-(3,3-difluorocyclobutyl)methanone (1.0 g, 3.6 mmol), MeOH (5 mL), DMF (10 mL), Et 3 N (1.5 mL, 11 mmol), 3-diphenylphosphanepropyl(diphenyl)phosphane (0.30 g, 0.73 mmol), Pd(OAc) 2 A mixture of 2-(4-(4-(4-piperidin-2-yl)-1,2-deg.-butyl ... 2 O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by preparative TLC (10% EtOAc / PE) gave methyl 3-(3,3-difluorocyclobutanecarbonyl)benzoate (0.80 g).

[0647] Step 3. Methyl 3-(3,3-difluorocyclobutanecarbonyl)benzoate (0.80 g, 3.2 mmol), THF (0.6 mL), H 2 O (0.2 mL), and LiOH·H 2 The mixture was stirred at 20 ° C for 2 h, concentrated, and HCl (0.5 M, 5 mL) was added. The mixture was extracted with EtOAc (10 mL), and the extract was concentrated to give 3-(3,3-difluorocyclobutane-1-carbonyl)benzoic acid (A-93, 0.50 g).

[0648] Synthesis of 3-(1-methylcyclobutane-1-carbonyl)benzoic acid (A-94)

[0649]

[0650] 3-(1-Methylcyclobutane-1-carbonyl)benzoic acid (A-94) was prepared in the same manner as A-93.

[0651] Synthesis of 4-(cyclopentanecarbonyl)thiophene-2-carboxylic acid (A-98)

[0652]

[0653] nBuLi (2.5M, 3.9mL, 2.5eq) was added dropwise to 4-bromothiophene-2-carboxylic acid (0.80g, 3.9mmol) in THF (15mL) at -78°C over 5min. The mixture was stirred for 25min, and N-methoxy-N-methyl-cyclopentanecarboxamide (0.91g, 5.8mmol) was added at -78°C. The resulting mixture was stirred at 20°C for 12h, and at -78°C, it was mixed with saturated NH 4 Cl (1 mL) and H 2 O (5 mL) and extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, filter, concentrate and analyze by preparative HPLC (C18, H 2 Purification by 20-50% MeCN in O[HCl] gave 4-(cyclopentanecarbonyl)thiophene-2-carboxylic acid (A-98, 10%).

[0654] Synthesis of 5-(cyclopentyl(hydroxy)methyl)furan-2-carboxylic acid (A-99)

[0655]

[0656] To a mixture of furan-2-carboxylic acid (2.0 g, 18 mmol) and THF (20 mL) was added LDA (2 M, 13 mL) dropwise at -70°C. The mixture was stirred for 0.5 h, and cyclopentanecarboxaldehyde (2.6 g, 27 mmol) in THF (20 mL) was added dropwise at -70°C. The resulting mixture was stirred at 20°C for 1.5 h, and saturated NH 4 Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The aqueous phase was purified by preparative HPLC (0.1% FA condition) to give 5-(cyclopentyl(hydroxy)methyl)furan-2-carboxylic acid (A-99, 0.38 g).

[0657] The compounds in Table 3.1 were prepared from furan-2-carboxylic acid and the indicated aldehyde in the manner described for the synthesis of A-99.

[0658] Table 3.1.

[0659]

[0660] Synthesis of 3-(N-(3,3-difluorocyclobutyl)-N-methylsulfamoyl)benzoic acid (A-95)

[0661]

[0662] Step 1. At 0°C, NaH (59 and 20 mg, 1.5 and 0.5 mmol, 60% purity) was added to two mixtures of methyl 3-[(3,3-difluorocyclobutyl)sulfamoyl]benzoate (intermediate from the synthesis of A-36, 0.30 and 0.10 g, 0.98 and 0.33 mmol) and DMF (4.0 and 1.3 mL). The mixture was stirred for 30 min, MeI (73 and 24 μL, 1.2 and 0.4 mmol) was added, and the mixture was stirred at 20°C for 30 min. The mixture was combined and poured into water (10 mL), extracted with EtOAc (10 mL x 2), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (10-100% EtOAc / PE) gave 3-[(3,3-difluorocyclobutyl)-methyl-sulfamoyl]benzoic acid methyl ester (0.28 g).

[0663] Step 2. To 3-[(3,3-difluorocyclobutyl)-methyl-sulfamoyl]benzoic acid methyl ester (0.23 and 0.050 g, 0.72 and 0.16 mmol), THF (1.8 and 0.4 mL), H 2 LiOH·H O (0.6 and 0.13 mL) was added to the two mixtures. 2 O (91 and 20 mg, 2.2 and 0.48 mmol) and stirred at 20 °C for 4 h. The mixture was combined, partially concentrated, and the pH was adjusted to 3 by adding 2N HCl. The mixture was extracted with EtOAc (2 x 10 mL), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 The residue was dried and concentrated to obtain 3-(N-(3,3-difluorocyclobutyl)-N-methylsulfamoyl)benzoic acid (A-95, 0.29 g).

[0664] Synthesis of 3-((cyclobutylmethyl)(methyl)phosphoryl)benzoic acid (A-97)

[0665]

[0666] Step 1. At 0°C, NaH (0.87 g, 22 mmol, 60% purity) was added to a mixture of 1-bromo-3-ethoxyphosphonobenzene (1.8 g, 7.2 mmol) and DMF (20 mL). The mixture was stirred for 30 min, and iodomethylcyclobutane (1.6 mL, 14 mmol) was added. The mixture was stirred at 0-20°C for 60 min, and saturated NH 4Cl (20 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave 1-bromo-3-[cyclobutylmethyl(ethoxy)phosphoryl]benzene (0.85 g).

[0667] Step 2. To a mixture of 1-bromo-3-[cyclobutylmethyl(ethoxy)phosphoryl]benzene (0.68 g, 2.1 mmol) and THF (6 mL) at 0°C was added MeMgBr (3 M, 6.4 mL), stirred at 20°C for 4 h, and poured into saturated NH 4 Cl (20 mL) and extracted with EtOAc (2 x 15 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-50% EtOAc / PE) gave 1-bromo-3-[cyclobutylmethyl(methyl)phosphoryl]benzene (0.56 g).

[0668] Step 3. 1-Bromo-3-[cyclobutylmethyl(methyl)phosphoryl]benzene (0.49 g, 1.7 mmol), MeOH (4 mL), 1,4-dioxane (4 mL), Mo(CO) 6 (0.11 g, 0.43 mmol), K 3 PO 4 (0.36 g, 1.7 mmol), DMAP (0.10 g, 0.85 mmol), Xantphos (99 mg, 0.17 mmol), and Pd(OAc) 2 A mixture of (19 mg, 85 μmol) was stirred at 120 °C for 3 h. The reaction was poured into water (20 mL) and the resulting mixture was extracted with EtOAc (2 x 15 mL). The organic phase was washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate, and chromatograph on silica gel (5-10% MeOH / CH 2 Cl 2 ) to give methyl 3-[cyclobutylmethyl(methyl)phosphoryl]benzoate (0.34 g).

[0669] Step 4. Methyl 3-[cyclobutylmethyl(methyl)phosphoryl]benzoate (0.32 g, 1.2 mmol), THF (3 mL), and H 2 O (1 mL), and LiOH·H 2The mixture of 2-nitropropene (0.15 g, 3.6 mmol) was stirred for 12 h and H 2 O (10 mL), and HCl (2N) was added to adjust the pH to 3-4, and extracted with EtOAc (2 x 5 mL). The combined extracts were washed with brine (5 mL), 2 SO 4 Drying and concentration gave 3-((cyclobutylmethyl)(methyl)phosphoryl)benzoic acid (A-97, 0.17 g).

[0670] Synthesis of 4-(difluoromethyl)cyclohexane-1-carbaldehyde

[0671]

[0672] Step 1. To methyl 4-formylcyclohexanecarboxylate (5.0 g, 29 mmol) and CH 2 Cl 2 DAST (12 mL, 88 mmol) was slowly added to the mixture of 50 mL of 1% ethanol at 0 °C. The mixture was stirred at 20 °C for 12 h and poured into saturated NaHCO 3 aqueous solution (30 mL) and treated with CH 2 Cl 2 The combined extracts were washed with brine (30 mL) and purified by Na 2 SO 4 Drying, concentration and purification by silica gel chromatography (5-17% EtOAc / petroleum ether) gave methyl 4-(difluoromethyl)cyclohexanecarboxylate (3.2 g).

[0673] Step 2. A solution of 4-(difluoromethyl)cyclohexanecarboxylate (3.2 g, 17 mmol) in THF (10 mL) was slowly added to LiAlH 4 (1.3 g, 33 mmol), and then stirred at 25 °C for 2 h. H 2 O (1.3 mL), aqueous NaOH (85%, 1.3 mL), and additional H 2 O (1.3 mL), and the mixture was filtered. The filtrate was concentrated to give [4-(difluoromethyl)cyclohexyl]methanol (1.80 g).

[0674] Step 3. To [4-(difluoromethyl)cyclohexyl]methanol (1.6 g, 9.7 mmol), NaHCO 3 (6.6 g, 78 mmol), and CH 2 Cl 2To the mixture of 1% iodine (50 mL) was added Dess-Martin periodinane (8.3 g, 20 mmol). The mixture was stirred at 25 °C for 2 hours and then poured into saturated NaHCO 3 Aqueous solution (15 mL) and saturated Na 2 SO 3 The resulting mixture was filtered and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (5-17% EtOAc / petroleum ether) gave 4-(difluoromethyl)cyclohexanecarbaldehyde (1.4 g).

[0675] Synthesis of 4-fluoro-4-methylcyclohexane-1-carbaldehyde

[0676]

[0677] Step 1. To a mixture of ethyl 4-oxocyclohexanecarboxylate (4.7 mL, 29 mmol) in THF (30 mL) was slowly added MeLi (1 M, 41 mL) at -60°C. The mixture was stirred at -60°C for 1 h and poured into NH 4 Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (20 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (13-50% EtOAc / PE) gave 4-hydroxy-4-methyl-cyclohexanecarboxylic acid ethyl ester (2.20 g).

[0678] Step 2. To 4-hydroxy-4-methyl-cyclohexanecarboxylic acid ethyl ester (2.4 g, 13 mmol) and CH 2 Cl 2 DAST (1.7 mL, 13 mmol) was added to the solution of 1 M NaCl (1 mL). The mixture was stirred at -40 °C for 1 h and poured into 2 HCO 3 (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (15 mL) and purified by Na 2 SO 4 Drying, concentration, and purification by silica gel chromatography (15-50% EtOAc / PE) gave 4-fluoro-4-methyl-cyclohexanecarboxylic acid ethyl ester (1.60 g).

[0679] Step 3. To a mixture of 4-fluoro-4-methyl-cyclohexanecarboxylic acid ethyl ester (1.4 g, 7.4 mmol) and THF (30 mL) at 0 °C was added LiAlH 4 (0.57 g, 15 mmol). The mixture was stirred at 0 °C for 2 h, and 0.56 mL of H 2 O, 0.56 mL of 15% aqueous NaOH, and an additional 1.7 mL of H 2 The mixture was filtered, the filtrate was concentrated, and H 2 O (10 mL) and extracted with EtOAc (2 x 15 mL). The combined extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated to give (4-fluoro-4-methyl-cyclohexyl)methanol (0.80 g).

[0680] Step 4. (4-Fluoro-4-methyl-cyclohexyl)methanol (0.70 mg, 4.8 mmol), CH 2 Cl 2 (20 mL), NaHCO 3 A mixture of iodine (3.2 g, 38 mmol), and Dess-Martin periodinane (4.1 g, 9.6 mmol) was stirred at 25°C for 2 hours. The mixture was poured into saturated NaHCO 3 (5 mL) and saturated Na 2 SO 3 The resulting mixture was filtered and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Drying and concentration gave 4-fluoro-4-methyl-cyclohexanecarbaldehyde (0.60 mg).

[0681] Synthesis of 5"-nitrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline](B-01)

[0682]

[0683] Step 1. At 0°C, in N 2 Next, to ZnEt 2 (1 M in hexane, 180 mL), CH 2 Cl 2 Slowly add CH 2 Cl 2 (60 mL) CH 2 I 2(26 mL, 320 mmol). The mixture was stirred at 0 °C for 30 min, and CH 2 Cl 2 The mixture was stirred at 20°C for 12 h, cooled to 0°C, and saturated NH 4 The organic phase was separated, washed with water (50 mL x 2), brine (50 mL), and then purified by Na 2 SO 4 Dry, filter, concentrate, and chromatograph on silica gel (1-10% CH 2 Cl 2 / petroleum ether) to obtain the compound spiro[2.5]octane-6-carboxylic acid ethyl ester (10 g).

[0684] Step 2. At 0°C, in N 2 To a mixture of ethyl spiro[2.5]octane-6-carboxylate (10 g, 55 mmol) and THF (300 mL) was added LiAlH 4 (3.1 g, 81 mmol). The mixture was stirred at 0°C for 1 h and then at 22°C for another 1 h. 2M NaOH aqueous solution (3.0 mL) was slowly added to the stirred mixture, followed by Na 2 SO 4 (30 g). The suspension was filtered and the filtrate was concentrated to give spiro[2.5]octan-6-ylmethanol (7.5 g). 1 HNMR (DMSO-d 6 ,400MHz)δ3.51(d,J=6.38Hz,2H),1.82-1.68(m,4H),1.53(tdt,J=14.71,6.38,3.24Hz,1H),1 .40-1.29(m,1H),1.12-1.07(m,2H),0.96-0.84(m,2H),0.35-0.24(m,2H),0.23-0.12(m,2H).

[0685] Step 3. At 0 °C, spiro[2.5]octan-6-ylmethanol (7.5 g, 54 mmol) and CH 2 Cl 2 To the mixture of 1% iodine (250 mL) was added Dess-Martin periodinane (28 g, 66 mmol). The mixture was stirred for 5 h while the temperature was raised to 25° C. The mixture was filtered through celite, and the filtered solid was washed with CH 2 Cl 2The filtrate was concentrated and purified by silica gel chromatography (0-10% EtOAc / petroleum ether) to give spiro[2.5]octane-6-carbaldehyde (7.30 g). 1 HNMR (DMSO-d 6 ,400MHz)δ9.68(d,J=1.25Hz,1H),2.35-2.23(m,1H),1.97-1.85(m,2H),1 .70-1.51(m,4H),1.12-1.03(m,2H),0.35-0.27(m,2H),0.26-0.18(m,2H).

[0686] Step 4.a) (4-nitrophenyl)hydrazine (1.8 g, 12 mmol), TFA (4.5 mL, 61 mmol), CH 2 Cl 2 A mixture of spiro[2.5]octane-6-carbaldehyde (2.0 g, 15 mmol) and 40°C was stirred for 15 h. b) Additional TFA (6.3 mL, 85 mmol), CH 2 Cl 2 , and Et 3 SiH (6.3 mL, 4.6 mmol) was added, and the mixture was stirred at 25 °C for 2 h, then concentrated and purified by silica gel chromatography (0-15% [1:1 Me-THF / EtOAc] / petroleum ether) to give 5"-nitrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline] (B-01, 0.88 g).

[0687] Synthesis of Spiro[cyclopentane-1,3'-indoline](B-02)

[0688]

[0689] To a mixture of 1H-indole (1.0 g, 8.5 mmol) and THF (25 mL) was added t-BuOK (1 M in THF, 20 mL) dropwise, and the mixture was stirred at 20° C. for 0.5 h. Et 3 B (1 M in THF, 17 mL) was added, and the mixture was stirred for 0.5 h. 1,4-diiodobutane (1.2 mL, 9.4 mmol) was added, and the mixture was stirred at 70 °C for 13 h. MeOH (10 mL) and NaBH were added. 4 (0.97 g, 26 mmol), and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated and combined with EtOAc (20 mL) and 2N HCl (20 mL). Saturated NaHCO was slowly added 3The aqueous solution was added and the pH was adjusted to 9. The phases were separated and the aqueous washes were extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), and purified by Na 2 Drying over SO4, filtration, and concentration afforded spiro[cyclopentane-1,3'-indoline] (B-02). 1 H NMR: (DMSO-d6, 400MHz) δ6.98 (dd, J=7.32, 0.81Hz, 1H), 6.90 (td, J=7.57, 1.25Hz, 1H), 6.55 ( td,J=7.35,0.94Hz,1H),6.49(d,J=7.75Hz,1H),5.43(s,1H),3.22(s,2H),1.84-1.62(m,8H).

[0690] The compounds in Table 4 were prepared from indole and dihalide in the manner described for B-02.

[0691] Table 4.

[0692]

[0693] Synthesis of dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline](B-06)

[0694]

[0695] Step 1. Dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole] was prepared from phenylhydrazine and spiro[2.5]octane-6-carbaldehyde in the manner described in step 4a of the synthesis of B-01.

[0696] Step 2. To a mixture of dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole] (1.0 g, 4.7 mmol) in MeOH (15 mL) and THF (15 mL) was added NaBH portionwise at 0°C. 3 CN (0.90 g, 14 mmol). The mixture was stirred at 20 °C for 12 h, and NaBH 3 CN (0.50 g) and THF (15 mL), and the mixture was stirred at 40° C. for 2 h. The reaction mixture was concentrated and purified by chromatography (silica gel, 0-15% [1:1 THF / EtOAc] / petroleum ether) to give dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline] (B-06, 0.64 g).

[0697] The compounds in Table 5 were prepared by the methods described for the synthesis of B-06 from the indicated hydrazines and aldehydes.

[0698] Table 5.

[0699]

[0700]

[0701]

[0702] Synthesis of tert-butyl 5"-bromodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carboxylate (B-10) and N-(dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)-2-hydroxyethane-1-sulfonamide (B-11)

[0703]

[0704] Step 1. B-07 (0.2 M, 3.4 mL) and Boc 2 O (0.30 g, 1.4 mmol), MeCN (10 mL), and Et 3 N (0.40 mL, 2.9 mmol) was stirred at 25° C. for 12 h. The mixture was concentrated and purified by silica gel chromatography (0-20% MTBE / petroleum ether) to give tert-butyl 5″-bromo-1″,2″-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole]-1″-carboxylate (B-10, 0.23 g).

[0705] Step 2.a) To a mixture of tert-butyl 5″-bromo-1″,2″-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole]-1″-carboxylate (0.11 g, 0.27 mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethane-1-sulfonamide (0.21 g, 0.88 mmol), and DMF (8.0 mL) were added CuI (57 mg, 0.30 mmol), K 3 PO 4 (0.21 g, 0.99 mmol), and N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (48 mg, 0.34 mmol). The reaction mixture was stirred at 140 °C in a microwave reactor for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with 1:1 EtOAc / THF (15 mL x 2). The extracts were combined and washed with H 2 O (10 mL x 3) and brine (10 mL), and 2 SO 4Dry, filter, concentrate, and purify by silica gel chromatography (0-10% [1:1 THF / EtOAc] / petroleum ether) to give 2-[(tert-butyldimethylsilyl)oxy]-N-{1",2"-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indol]-5"-yl}ethane-1-sulfonamide (70 mg).

[0706] Step 3. A mixture of 2-[(tert-butyldimethylsilyl)oxy]-N-{1",2"-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indol]-5"-yl}ethane-1-sulfonamide (60 mg, 0.11 mmol), MeOH (1.0 mL), and HCl (4 M in MeOH, 1.0 mL) was stirred at 25 °C for 5 h. The mixture was concentrated to give N-{1",2"-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indol]-5"-yl}-2-hydroxyethane-1-sulfonamide hydrochloride (B-11, 47 mg).

[0707] Separation of B-24 into diastereomers

[0708] Indoline B-24 was separated into (1s, 4s) and (1r, 4r) isomers by silica gel chromatography (0-100% EtOAc / PE). The configuration was not determined, and the first eluting isomer was B-24a and the second eluting isomer was B-24b.

[0709] Synthesis of tert-butyl 5'-bromospiro[cyclohexane-1,3'-indolin]-1'-carboxylate (B-12) and N-(spiro[cyclohexane-1,3'-indolin]-5'-yl)methanesulfonamide (B-13)

[0710]

[0711] Tert-butyl 5'-bromospiro[cyclohexane-1,3'-indoline]-1'-carboxylate (B-12) and N-(spiro[cyclohexane-1,3'-indoline]-5'-yl)methanesulfonamide (B-13) were prepared from B-03 in the same manner as B-10 and B-11.

[0712] The intermediates in Table 5.1 were prepared in the manner described for the synthesis of B-11 from the indicated indoline and sulfonamide.

[0713] Table 5.1

[0714]

[0715] Synthesis of Spiro[cyclohexane-1,3'-indolin]-5'-ol hydrochloride (B-15)

[0716]

[0717] Step 1. B-12 (0.35 g, 0.96 mmol), NMP (8 mL), H 2 O (4mL), KOH (0.16g, 2.9mmol), Pd 2 (dba) 3 A mixture of 1,2-di-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (81 mg, 0.19 mmol) was stirred at 110°C for 12 h, diluted with 10 mL of water, and extracted with EtOAc (5 mL x 3). The combined extracts were washed with brine (5 mL) and purified by Na 2 SO 4 Dry, filter, concentrate, and analyze by preparative TLC (SiO 2 , 25% EtOAc / petroleum ether) to give tert-butyl 5'-hydroxyspiro[cyclohexane-1,3'-indoline]-1'-carboxylate (80 mg).

[0718] Step 2. A mixture of tert-butyl 5'-hydroxyspiro[cyclohexane-1,3'-indoline]-1'-carboxylate (80 mg, 0.26 mmol) and 1 M HCl in EtOAc (2.0 mL) was stirred at 25 °C for 2 h and concentrated to give spiro[cyclohexane-1,3'-indoline]-5'-ol hydrochloride (B-15; 60 mg).

[0719] Synthesis of 3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-01)

[0720]

[0721] Step 1. 3-Benzylthiobenzoic acid (1.5 g, 6.1 mmol), DMF (10 mL), HATU (4.7 g, 13 mmol), and iPr 2 The mixture of NEt (3.2 mL, 18 mmol) was stirred at 25 °C for 15 min, and B-07 (1.8 g, 6.1 mmol) was added. The mixture was stirred at 25 °C for 2 h, then diluted with EtOAc (50 mL), washed with water (30 mL x 3) and brine (30 mL), and purified by Na 2 SO 4 Dry, filter, concentrate, and purify by silica gel chromatography (8-10% EtOAc / petroleum ether) to give (3-(benzylthio)phenyl)(5"-bromobispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (3.0 g).

[0722] Step 2. (3-(Benzylthio)phenyl)(5"-bromobispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-1"-yl)methanone (2.0 g, 3.9 mmol), DMF (10 mL), methanesulfonamide (1.1 g, 12 mmol), K 3 PO 4 (2.5 g, 12 mmol), N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (0.55 g, 3.9 mmol) and CuI (0.74 g, 3.9 mmol) was stirred at 160° C. for 2 h. The mixture was diluted with EtOAc (30 mL) and washed with H 2 O (30 mL x 3) and brine (30 mL), and 2 SO 4 Dried, filtered, concentrated, and purified by silica gel chromatography (29-31% EtOAc / petroleum ether) to give N-(1"-(3-(benzylthio)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (1.84 g).

[0723] Step 3. N-(1″-(3-(Benzylthio)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (1.0 g, 1.9 mmol), NCS (0.50 g, 3.8 mmol), HOAc (1.8 mL), and H 2 O (0.2 mL) was stirred at 30 °C for 2 h. The mixture was diluted with EtOAc (50 mL) and washed with H 2 O (30 mL x 3), saturated NaHCO 3 aqueous solution (30 mL), and brine (30 mL), and then washed with Na 2 SO 4 Dry, filter, concentrate, and purify by silica gel chromatography (25-35% EtOAc / petroleum ether) to give 3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-01, 0.36 g).

[0724] The compounds in Table 5.2 were prepared in the same manner as described for C-01 from the indicated carboxylic acids and indoline.

[0725] Table 5.2

[0726]

[0727] Synthesis of 2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-02)

[0728]

[0729] Step 1. 3-Benzylthio-4-methoxy-benzoic acid (0.32 mg, 1.2 mmol), B-14 (0.22 g, 0.73 mmol), DMF (3 mL), HOBt (0.26 g, 1.9 mmol), EDCI (0.37 g, 1.9 mmol), Et 3 The mixture of N (0.54 mL, 3.9 mmol) was stirred at 25 °C for 2 h. The reaction was poured into H 2 O (30 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts washed with brine (10 mL), 2 SO 4 Dry, concentrate, and purify by silica gel chromatography (40-45% EtOAc / PE) to give N-(1"-(3-(benzylthio)-4-methoxybenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.22 g).

[0730] Step 2. Resuspend N-(1"-(3-(benzylthio)-4-methoxybenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.22 g, 0.36 mmol), NCS (0.14 g, 1.1 mmol), H 2 A mixture of 2-H 2 O (0.05 mL), and HOAc (0.45 mL) was stirred at 25 °C for 2 h. The mixture was poured into H 2 O (10 mL) and saturated NaHCO 3 (10 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts washed with brine (10 mL), 2 SO 4 The reaction mixture was dried and concentrated to give 2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-02, 0.20 g).

[0731] Synthesis Example S-001

[0732] Synthesis of (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(4'-fluorospiro[cyclopentane-1,3'-indolin]-1'-yl)methanone (Compound 1)

[0733]

[0734] 3-[(4,4-difluoro-1-piperidinyl)sulfonyl]benzoic acid (88 mg, 0.28 mmol), DMF (1.5 mL), Et 3 A mixture of N (0.11 mL, 0.78 mmol), and HATU (0.20 g, 0.52 mmol) was stirred at 20 °C for 30 min, and 4'-fluorospiro[cyclopentane-1,3'-indoline] (50 mg, 0.26 mmol) in DMF (1.0 mL) was added. The resulting mixture was stirred at 20 °C for 3.5 h, concentrated, and purified by preparative HPLC (45-75% MeCN / H 2 O[10 mM NH 4 HCO 3 ]) to obtain (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(4'-fluorospiro[cyclopentane-1,3'-indoline]-1'-yl)methanone (Compound 1) (35 mg). ESIMS m / z: 479.2 (M+H).

[0735] The compounds in Table 6 were prepared by the method described for the synthesis of Compound 1 (Synthetic Example S-001) from the indicated carboxylic acids and indoline analogs.

[0736] Table 6.

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752] Synthesis Example S-002

[0753] Synthesis of N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indolin]-5'-yl)methanesulfonamide (Compound 18)

[0754]

[0755] Compound 2 (50 mg, 93 μmol), methanesulfonamide (13 mg, 0.14 mmol), CuI (9.0 mg, 46 μmol), K 3 PO 4 (59 mg, 0.28 mmol), N 1 ,N 2 A degassed mixture of 1,2-dimethylcyclohexane-1,2-diamine (7.0 mg, 46 μmol) and DMF (2.0 mL) was stirred at 150° C. in a microwave reactor for 2 h. 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (35-0% H 2 O[10 mM NH 4 CO 3 ] / MeCN) to give N-(1′-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3′-indoline]-5′-yl)methanesulfonamide (Compound 18, 8.6 mg).

[0756] Synthesis Example S-002a

[0757] Synthesis of N-(tert-butyl)-3-(5"-(ethylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 134).

[0758]

[0759] Compound 2 (1.0 g, 1.9 mmol), ethanesulfonamide (0.60 g, 5.5 mmol), CuI (0.37 g, 1.9 mmol), K 3 PO 4 (1.3 g, 6.0 mmol), N 1 ,N 2 A degassed mixture of 1,2-dimethylcyclohexane-1,2-diamine (0.27 g, 1.9 mmol) and DMF (14 mL) was stirred at 150 °C for 3 h. 2 O (40 mL) and combined. The resulting precipitate was filtered and washed with H 2 O (5 mL x 3), dissolved in EtOAc (50 mL), washed with water (20 mL x 2), 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (50-20% H 2 O [0.1% formic acid] / MeCN) to give N-(tert-butyl)-3-(5"-(ethylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 134, 1.3 g).

[0760] The compounds in Table 7 were prepared in the same manner as compound 18 from the indicated bromoindoline and the original sulfonamide.

[0761] Table 7.

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778] Synthesis of N-(tert-butyl)-3-(6"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide and N-(tert-butyl)-3-(4"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide

[0779]

[0780] A mixture of about 3 / 1 of compound 307 and compound 308 (0.55 g, 1.0 mmol), methanesulfonamide (0.29 g, 3.0 mmol), CuI (0.11 g, 0.60 mmol), DMF (5 mL), N1,N2-dimethylcyclohexane-1,2-diamine (85 mg, 0.60 mmol) and K 3 PO 4 (0.64 g, 3.0 mmol) was stirred at 160 °C for 2 h. The mixture was concentrated and added with H 2 O (10 mL), extracted with EtOAc (2 x 10 mL), and the combined extracts washed with brine (10 mL), 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (35-65% MeCN / H 2 O [formic acid]) to give N-(tert-butyl)-3-(6"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (compound 309, 23.2 mg) and N-(tert-butyl)-3-(4"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (compound 310, 5.1 mg).

[0781] Synthesis Example S-002b

[0782] Synthesis of N-(tert-butyl)-2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 297) and N-(tert-butyl)-2-hydroxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 298).

[0783]

[0784] Compound 296 (0.10 g, 0.18 mmol), methanesulfonamide (51 mg, 0.53 mmol), CuI (34 mg, 0.18 mmol), K 3 PO 4 (0.11 g, 0.53 mmol), N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol) and DMF (2 mL) was stirred at 150 °C for 1.5 h. The mixture was then poured into 30 mL of H 2 O, extracted with EtOAc (2 x 30 mL), and the extract was washed with brine (10 mL), 2 SO 4 Drying, filtration, concentration and purification by reverse phase HPLC (C18, 30-60% MeCN / water [0.1 mM formic acid]) afforded 13 mg of compound 297 and 26 mg of compound 298.

[0785] Synthesis Example S-003

[0786] Synthesis of N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indolin]-5'-yl)-2-hydroxyethane-1-sulfonamide (Compound 27)

[0787]

[0788] Step 1. Compound 2 (50 mg, 93 μmol), 2-((tert-butyldimethylsilyl)oxy)ethane-1-sulfonamide (33 mg, 0.14 mmol), CuI (9 mg, 46 μmol), K 3 PO 4 (59 mg, 0.28 mmol) and N 1 ,N 2A degassed mixture of 1,2-dimethylcyclohexane-1,2-diamine (7 mg, 46 μmol) and DMF (2.0 mL) was stirred at 150° C. in a microwave reactor for 2 h. The mixture was poured into water. 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 Drying and concentration gave 2-((tert-butyldimethylsilyl)oxy)-N-(1′-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3′-indolinoline]-5′-yl)ethane-1-sulfonamide (65 mg).

[0789] Step 2. A mixture of 2-((tert-butyldimethylsilyl)oxy)-N-(1′-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3′-indolinoline]-5′-yl)ethane-1-sulfonamide (65 mg, 93 μmol), MeOH (5.0 mL), and HCl (2 M, 5.0 mL) was stirred at 20° C. for 1 h, concentrated, and saturated NaHCO 3 The aqueous solution was added to bring the pH to 9. The mixture was extracted with EtOAc (2 x 30 mL), and the extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (30-60% MeCN / H 2 O[10 mM NH 4 HCO 3 ]) to give N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indoline]-5'-yl)-2-hydroxyethane-1-sulfonamide (Compound 27, 8.5 mg).

[0790] The compounds in Table 7.1 were prepared in the same manner as compound 29 from the indicated bromoindoline and 2-[(tert-butyldimethylsilyl)oxy]ethane-1-sulfonamide.

[0791] Table 7.1

[0792]

[0793]

[0794] Synthesis Example S-004

[0795] Synthesis of N-(1"-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 28)

[0796]

[0797] Step 1. Compound 12 (0.18 g, 0.33 mmol), Fe (0.20 g, 3.6 mmol), EtOH (10 mL), THF (10 mL), and H 2 To the mixture of NH 4 Cl (0.2 g, 3.7 mmol) was added, and the mixture was stirred at 80 °C for 3 h. The mixture was filtered through celite, and the filter cake was washed with THF (10 mL x 2) and MeOH (10 mL x 2). The filtrate was concentrated to about 20 mL, diluted with EtOAc (30 mL), and washed with H 2 O (15 mL x 2), washed with brine (15 mL), and then washed with Na 2 SO 4 Dry, filter, and concentrate to afford (5"-aminodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)methanone (0.17 g).

[0798] Step 2. To (5″-aminodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-yl)(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)methanone (0.15 g, 0.29 mmol), and Et 3 N (880.12 mL, 0.87 mmol), and CH 2 Cl 2 To the mixture of 14 mL was slowly added methanesulfonyl chloride (68 μg, 0.87 mmol) and CH 2 Cl 2 (1.0 mL) was added and the mixture was stirred at 20°C for 2 h. The reaction mixture was poured into ice water and washed with CH 2 Cl 2 (15 mL), and the extract was washed with H 2 O (5.0 mL x 2) and brine (5.0 mL), and 2 SO 4Dried, filtered, concentrated, and purified by preparative HPLC (40-70% MeCN / water [0.1% formic acid]) to give N-(1"-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 28, 55 mg).

[0799] Synthesis Example S-005

[0800] N-(1"-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)-2-hydroxyethane-1-sulfonamide (Compound 29)

[0801]

[0802] A-04 (16 mg, 53 μmol), DMF (1.0 mL), HATU (46 mg, 0.12 mmol) and iPr 2 A mixture of NEt (18 μg, 0.10 mmol) was stirred at 25°C for 15 min, and N-{1″,2″-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indol]-5″-yl}-2-hydroxyethane-1-sulfonamide (42 mg, 48 μmol), iPr 2 A mixture of NEt (89 μg, 0.51 μmol) and DMF (1.0 mL) was stirred at 25°C for 5 h, the mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (20-60% MeCN / H 2 O [0.1% formic acid]) to give N-(1"-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)-2-hydroxyethane-1-sulfonamide (Compound 29, 2 mg).

[0803] Synthesis Example S-006

[0804] Synthesis of (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(5"-(ethylamino)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (Compound 30)

[0805]

[0806] A mixture of compound 12 (0.15 g, 0.28 mmol), Pd / C (0.15 g, 10%) and EtOH (15 mL) was stirred under H2 (15 psi) and stirred at 25°C for 12 h. The mixture was heated with N 2 The product was rinsed and filtered through Celite, the filtrate was concentrated and the minor product was purified by preparative HPLC (45-80% MeCN / H 2 O[10 mM NH 4 HCO 3 ]) and separated by preparative HPLC (35-75% MeCN / H 2 O [0.1% formic acid]) was further separated to give (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(5"-(ethylamino)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (Compound 30, 7.9 mg).

[0807] Synthesis Example S-007

[0808] Isolation of N-(tert-butyl)-3-(4-ethyl-5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indoline]-3-ene-1'-carbonyl)benzenesulfonamide (Compound 31)

[0809]

[0810] Compound 31 was isolated as a by-product during the purification of compound 22: Preparative HPLC (40-60% MeCN / H 2 O[10 mM NH 4 HCO 3 ]).

[0811] Synthesis Example S-008

[0812] Preparation of N,N-dimethyl-3-(5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indoline]-1'-carbonyl)benzenesulfonamide (Compound 42)

[0813]

[0814] To a mixture of A-10 (50 mg, 0.22 mmol) and DMF (3 mL) were added HATU (0.12 g, 0.33 mmol) and iPr 2 NEt (0.11 mL, 0.65 mmol). After 20 min, B-13 (73 mg, 0.26 mmol) was added, and the mixture was stirred at 60 °C for 2 h, concentrated, and purified by preparative HPLC (45-65% MeCN / H 2O (0.1 M HCl)) to give N,N-dimethyl-3-(5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indoline]-1'-carbonyl)benzenesulfonamide (Compound 42, 50 mg).

[0815] The compounds in Table 7.2 were prepared in the same manner as compound 42 from the indicated indoline and carboxylic acid.

[0816] Table 7.2

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825] Preparation of N-(1"-(3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 341)

[0826]

[0827] A-86 (0.55 g, 2.0 mmol), DMF (5.5 mL), Et 3 A mixture of N (0.85 mL, 6.1 mmol), EDCI (1.4 g, 7.1 mmol), and HOBt (0.96 g, 7.1 mmol) was stirred at 20 °C for 0.5 h, and then B-14 (0.25 g, 0.81 mmol) was added. The mixture was stirred at 20 °C for 12 h, and H 2 O (16 mL) and extracted with EtOAc (2 x 16 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 20-55% MeCN / H 2O [formic acid]) to give N-(1"-(3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 341, 30 mg).

[0828] The compounds in Table 7.3 were prepared in the same manner as compound 341 from the indicated indoline and carboxylic acid.

[0829] Table 7.3

[0830]

[0831]

[0832]

[0833]

[0834] Synthesis Example S-009

[0835] Preparation of ethyl (1'-(3-(piperidin-1-ylsulfonyl)benzoyl)spiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (Compound 141)

[0836]

[0837] Compound 142 (0.20 g, 0.39 mmol), dioxane (10 mL), Cs 2 CO 3 (0.38 g, 1.2 mmol), Pd 2 (dba) 3 A mixture of 1,2-dihydro-1,4 ... 2 The mixture was purified by evaporation with 0.2% HCl (0.05% HCl) to afford ethyl (1′-(3-(piperidin-1-ylsulfonyl)benzoyl)spiro[cyclohexane-1,3′-indoline]-5′-yl)carbamate (Compound 141, 21 mg).

[0838] Synthesis Example S-010

[0839] Preparation of N-(1'-(3-(cyclopentyl(hydroxy)methyl)benzoyl)spiro[cyclohexane-1,3'-indolin]-5'-yl)methanesulfonamide (Compound 157)

[0840]

[0841] A degassed mixture of compound 156 (0.10 g, 0.21 mmol), NaBH4 (16 mg, 0.42 mmol), and MeOH (2 mL) was stirred under N 2 The mixture was concentrated and extracted with EtOAc (10 mL). The extract was washed with water (5 mL x 2) and brine (3 mL), and then purified by Na 2 SO 4 Dry, filter, concentrate, and analyze by preparative HPLC (42-72% MeCN / H 2 O [0.1% formic acid]) to afford N-(1′-(3-(cyclopentyl(hydroxy)methyl)benzoyl)spiro[cyclohexane-1,3′-indoline]-5′-yl)methanesulfonamide (Compound 157, 20 mg).

[0842] The compounds in Table 7.4 were prepared in the manner described for the synthesis of compound 157 from the indicated ketones.

[0843] Table 7.4

[0844]

[0845]

[0846] Synthesis Example S-011

[0847] Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide

[0848]

[0849] To bicyclo[1.1.1]pentan-1-amine (16 mg, 196 μmol), CH 2 Cl 2 Et (1.0 mL) was added to the mixture 3 N (82 μg, 0.59 mmol) and C-01 (100 mg, 0.20 mmol). The resulting mixture was stirred at 25 °C for 1 h, then concentrated and heated to 40 °C. 2 The extracts were combined, washed with brine (10 mL), and purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (35-65% MeCN / H 2O [0.1% formic acid]) to give N-(bicyclo[1.1.1]pentan-1-yl)-3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 223, 15 mg).

[0850] The compounds in Table 7.5 were prepared in the same manner as compound 223 from the indicated sulfonyl chlorides and amines.

[0851] Table 7.5

[0852]

[0853]

[0854] Synthesis Example S-012

[0855] Preparation of N-(1"-(5-(cyclopentyl(hydroxy)methyl)thiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 301)

[0856]

[0857] Step 1. To a mixture of 5-formylthiophene-3-carboxylic acid (0.12 mg, 0.74 mmol) and DMF (1.5 mL) were added HATU (0.42 g, 1.1 mmol), and iPr 2 NEt (0.39 mL, 2.2 mmol). After stirring for 30 min, B-14 (0.27 mg, 0.88 mmol) was added, and the mixture was stirred at 80 °C for 1.5 h. 2 O (4 mL) and extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (30 mL) and purified by Na 2 SO 4 Dry, filter, concentrate, and purify by silica gel chromatography (0-100% EtOAc / PE) to give N-(1"-(5-formylthiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.31 g). 1 H NMR (400 MHz, DMSO-d 6)δppm 10.00-9.91(m,1H)8.14(s,1H)8.08-7.96(m,1H)7.26-7.19(m,2H)7.15-7.00 (m,1H)4.08(d,J=6.58Hz,2H)2.98(s,3H)1.27-1.24(m,8H)0.36-0.28(m,4H).

[0858] Step 2. To a mixture of N-(1"-(5-formylthiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.25 g, 0.56 mmol) and THF (3 mL) was added bromo(cyclopentyl)magnesium (1 M, 2.8 mL). The mixture was stirred at -70 °C for 2, slowly poured into ice (5 mL), and extracted with EtOAc (10 ml x 3). The combined extracts were washed with brine (30 mL), purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (C18, 45%-75% MeCN / H 2 O[NH 4 HCO 3 ]) to give N-(1"-(5-(cyclopentyl(hydroxy)methyl)thiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 301, 3.5 mg).

[0859] Preparation of N-(1"-(5-(cyclopentyl(hydroxy)methyl)furan-2-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 352)

[0860]

[0861] Step 1. 5-Formylfuran-2-carboxylic acid (0.20 g, 1.4 mmol), DMF (3 mL), EDCI (0.55 g, 2.9 mmol), HOBt (0.39 g, 2.9 mmol), and iPr 2 Net (0.75 mL, 4.3 mmol) was stirred at 20 ° C for 30 min, and B-14 (0.44 g, 1.4 mmol) in DMF (0.5 mL) was added dropwise at 20 ° C. The mixture was stirred at 20 ° C for 12 h, poured into water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (20 mL) and purified by Na 2 SO 4Drying, concentration and purification by silica gel chromatography (10-50% EtOAc / PE) gave N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.23 g).

[0862] Step 2. To a mixture of N-(1″-(3-formylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.20 g, 0.37 mmol) and THF (3 mL) was added bromo(cyclopentyl)magnesium (1 M, 0.47 mL). The mixture was stirred at -60°C for 0.5 h and poured into saturated NH 4 Cl (5 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (C18, 30-70% MeCN / H 2 O [formic acid]) to give N-(1"-(5-(cyclopentyl(hydroxy)methyl)furan-2-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 352, 7.0 mg).

[0863] Synthesis Example S-013

[0864] Preparation of N-(1″-(3-((3,3-difluoroazetidin-1-yl)sulfonyl)-4-hydroxybenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 303)

[0865]

[0866] Two mixtures of compound 302 (90 and 40 mg, 0.15 and 0.067 mmol), DMF (3 and 1.3 mL), and LiCl (19 and 8.5 mg, 0.45 and 0.20 mmol) were stirred at 160 °C for 4 h. The mixtures were combined and poured into H 2 O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 15-55% MeCN / H 2 O[NH 4 HCO 3]) to afford N-(1″-(3-((3,3-difluoroazetidin-1-yl)sulfonyl)-4-hydroxybenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 303, 10 mg).

[0867] Synthesis Example S-014

[0868] Preparation of N-(1″-(3-(2-(3,3-difluoroazetidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 314)

[0869]

[0870] Step 1. 3-vinylbenzoic acid (0.13 g, 0.89 mmol), DMF (3 mL), B-14 (0.30 mg, 0.98 mmol), HOBt (0.24 mg, 1.8 mmol), EDCI (0.34 g, 1.8 mmol), Et 3 A mixture of N (0.37 mL, 2.7 mmol) was stirred at 20 °C for 2 h, then poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate, and purify by silica gel chromatography (0-40% EtOAc / PE) to give N-(1"-(3-vinylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.30 g).

[0871] Step 2. At 0°C, N-(1"-(3-vinylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.15 g, 0.34 mmol) and CH 2 Cl 2 m-CPBA (0.14 g, 0.60 mmol, 85% purity) was added to the mixture (1 mL). The mixture was stirred at 20°C for 12 h and Na 2 SO 3 (1M, 30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4Dry, concentrate, and purify by silica gel chromatography (0-30% EtOAc / PE) to give N-(1"-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.10 g).

[0872] Step 3. 3,3-difluoroazetidine hydrochloride (39 mg, 0.30 mmol), iPr 2 A mixture of NEt (0.10 mL, 0.60 mmol), EtOH (1 mL), and N-(1″-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (90 mg, 0.20 mmol) was stirred at 80° C. for 12 h. The mixture was concentrated and purified by preparative HPLC (35-65% MeCN / H 2 O [formic acid]) to give N-(1"-(3-(2-(3,3-difluoroazetidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 314, 22 mg).

[0873] Preparation of N-(1"-(3-(2-(4,4-difluoropiperidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 315)

[0874]

[0875] (Compound 315) Prepared by the method described for compound 314 from N-(1"-(3-vinylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide and 3,3-difluoropiperidine hydrochloride.

[0876] Synthesis Example S-015

[0877] Preparation of N-(1"-(3-((piperidin-1-ylimino)methyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 318)

[0878]

[0879] Step 1. 3-Formylbenzoic acid (0.20, 0.10, and 0.10 g, 1.3, 0.65, and 0.65 mmol), THF (10, 5, and 5 mL), EDCI (0.51, 0.25, and 0.25 g, 2.7, 1.4, and 1.4 mmol), HOBt (0.36, 0.18, and 0.18 g, 2.7, 1.4, and 1.4 mmol), Et 3 The three mixtures of N (0.56, 0.28, and 0.28 mL, 4.0, 2.0, and 2.0 mmol) were stirred at 20 °C for 0.5 h, then B-14 (0.41, 0.21, 0.21 g, 1.3, 0.65, and 0.65 mmol) was added to the mixture, and it was stirred at 20 °C for 12 h. The mixtures were combined, poured into water (20 mL), and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (20-100% EtOAc / PE) to give N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.36 g).

[0880] Step 2. A mixture of N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.31 g, 0.73 mmol), EtOAc (3 mL), TFA (81 μg, 1.1 mmol), and piperidin-1-amine (0.47 g, 4.4 mmol) was stirred at 80°C for 12 h. The mixture was concentrated, added to water (30 mL), and extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), purified by NaOH. 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 40-80% MeCN / H 2 O [formic acid]) to give N-(1"-(3-((piperidin-1-ylimino)methyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.17 g).

[0881] Synthesis Example S-016

[0882] Preparation of N-(1"-(3-(1-cyclopentyl-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 331)

[0883]

[0884] To compound 164 (50 mg, 99 μmol) in THF (1 mL) was added MeMgBr (3 M, 99 uL, 0.30 mmol) at 0°C. The mixture was stirred at 20°C for 2 h and poured into H 2 O (3 mL), concentrated, and analyzed by preparative HPLC (40-80% MeCN / H 2 O [formic acid]) to give N-(1"-(3-(1-cyclopentyl-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 331, 6 mg).

[0885] Synthesis Example S-017

[0886] Preparation of N-(tert-butyl)-3-(5"-(1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 332)

[0887]

[0888] Step 1. Compound 9 (0.20 g, 0.38 mmol), tributyl(1-ethoxyvinyl)stannane (0.19 mL, 0.56 mmol), Pd(PPh 3 ) 2 Cl 2 A degassed mixture of oxadiazine (53 mg, 75 μmol), CsF (0.11 g, 0.75 mmol), and dioxane (4 mL) was heated at 130 °C under N 2 Stir for 2 h under H atmosphere. Add KF (0.10 g) into H 2 O (20 mL), and the mixture was stirred at 20 °C for 0.5 h. The mixture was extracted with EtOAc (20 x 2 mL), and the combined extracts were washed with brine (10 mL), 2 SO 4 Dry, filter, concentrate, and purify by silica gel chromatography (0-50% EtOAc / PE) to give 3-(5"-acetyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)-N-(tert-butyl)benzenesulfonamide (0.11 g).

[0889] Step 1. To a mixture of 3-(5″-acetyldispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)-N-(tert-butyl)benzenesulfonamide (0.11 g, 0.22 mmol) and MeOH (10 mL) was slowly added NaBH at 0°C. 4 (25 mg, 0.67 mmol). The mixture was stirred at 0°C for 3 h and poured into saturated NH 4 Cl (20 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 45-75% MeCN / H 2 O [formic acid]) to give N-(tert-butyl)-3-(5"-(1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 332, 25 mg).

[0890] Synthesis Example S-018

[0891] Preparation of N-(1"-(3-((cyclobutylmethyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 335)

[0892]

[0893] Compound 334 (0.20 g, 0.39 mmol), HOAc (2 mL), and 30% H 2 O 2 The mixture of (0.11 mL, 1.2 mmol) was stirred at 20 °C for 2 h. The mixture was mixed with saturated Na 2 SO 3 (20 mL) and H 2 O (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 35-65% MeCN / H 2 O [formic acid]) to afford N-(1″-(3-((cyclobutylmethyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (compound 335, 76 mg, 35.40% yield, 99.00% purity) as a white solid.

[0894] Synthesis Example S-019

[0895] Preparation of N-(tert-butyl)-3-(5"-(2,2,2-trifluoro-1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 338)

[0896]

[0897] Step 1. Compound 9 (0.50 g, 0.94 mmol) and KBF 3 (vinyl) (0.63 g, 4.7 mmol), K 2 CO 3 (0.65 g, 4.7 mmol), PdCl 2 A degassed mixture of 1,2-dimethoxy-1,4-dimethoxy-2-nitropropene (0.12 g, 0.66 mmol), and DMSO (5 mL) was heated at 100 °C under N 2 Stir for 3 h under H 2 O (20 mL), with CH 2 Cl 2 The resulting mixture was extracted with 1% ethyl acetate (2 x 20 mL) and the combined extracts were washed with brine (10 mL), purified by Na 2 SO 4 Drying, concentration and purification by silica gel chromatography (30-50% EtOAc / PE) gave N-(tert-butyl)-3-(5"-vinyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.32 mg).

[0898] Step 2. At 0°C, N-(tert-butyl)-3-(5"-vinyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.32 g, 0.67 mmol), CH 2 Cl 2 A mixture of 2-nitropropene (10 mL), ... and MeOH (10 mL) was added with O 3 (32 mg, 669 umol, 1.0 eq) for 0.5 h. The solution was washed with O 2 (21 mg, 669 umol, 1.0 eq) was purged for 0.5 h and then reacted with PPh 3 (0.35 g, 1.3 mmol) were stirred for 1 h, and H 2 O (20 mL) and washed with CH 2 Cl 2 The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4Dry, concentrate, and purify by silica gel chromatography (30-50% EtOAc / PE) to give N-(tert-butyl)-3-(5"-formyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.25 g).

[0899] Step 3. To a mixture of N-(tert-butyl)-3-(5"-formyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.15 g, 0.31 mmol) and DMF (2 mL) was added TMSCF at 50°C. 3 (89 mg, 0.62 mmol) and CsF (95 mg, 0.62 mmol). The mixture was stirred at 50 °C for 12 h, concentrated, and added to H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 35-75% MeCN / H 2 O [formic acid]) to give N-(tert-butyl)-3-(5"-(2,2,2-trifluoro-1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 338, 11 mg).

[0900] Synthesis Example S-20

[0901] Preparation of N-(1″-(3-((3,3-difluoroazetidin-1-yl)methyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 345)

[0902]

[0903] Step 1. Compound 344 (0.28 g, 0.64 mmol), CH 2 Cl 2 A mixture of 2-nitropropene (5 mL), and PCC (0.27 g, 1.3 mmol) was stirred at 20 °C for 2 h and washed with CH 2 Cl 2 (10 mL) and diluted with H 2 O (5 mL), saturated NaHCO 3 The mixture was washed with aqueous solution (5 mL), brine (5 mL), and then with Na 2 SO 4Dry, concentrate, and purify by flash silica gel chromatography (0-50% EtOAc / PE) to give N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.18 g).

[0904] Step 2. A mixture of N-(1″-(3-formylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolino]-5″-yl)methanesulfonamide (0.10 g, 0.23 mmol), MeOH (1 mL), THF (1 mL), 3,3-difluoroazetidine hydrochloride (44 mg, 0.34 mmol), and HOAc (26 μL, 0.46 mmol) was stirred at 20° C. for 2 h, and NaBH 3 CN (43 mg, 0.68 mmol), and the mixture was stirred at 20 °C for 10 h. At 0 °C, the mixture was treated with H 2 O (5 mL) and washed with CH 2 Cl 2 The combined extracts were washed with H 2 O (10 mL) and brine (10 mL), and 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (C18, 25-65% MeCN / H 2 O [formic acid]) to afford N-(1"-(3-((3,3-difluoroazetidin-1-yl)methyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 345, 6 mg).

[0905] Synthesis Example S-21

[0906] Preparation of 2-methyl-N-(3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)phenyl)propane-2-sulfonamide (Compound 355)

[0907]

[0908] Step 1. B-14 (0.20 g, 0.65 mmol), CH 2 Cl 2 (4mL), iPr 2A mixture of NEt (0.34 mL, 2.0 mmol) and 3-bromobenzoyl chloride (0.10 mL, 0.78 mmol) was stirred at 20 °C for 1 h, then concentrated and poured into water (5 mL). The resulting mixture was extracted with EtOAc (10 mL x 2), and the combined extracts were washed with brine (10 mL), purified by Na 2 SO 4 Dry, concentrate, and purify by silica gel chromatography (10-100% EtOAc / PE) to give N-(1"-(3-bromobenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.21 g).

[0909] Step 2. N-(1"-(3-bromobenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.10 g, 0.20 mmol), 2-methylpropane-2-sulfonamide (0.11 g, 0.82 mmol), CuI (78 mg, 0.41 mmol), N1,N2-dimethylcyclohexane-1,2-diamine dihydrochloride (88 mg, 0.41 mmol), K 3 PO 4 A degassed mixture of 1,2-dimethoxy-1,4-dimethoxy-2-nitropropene (0.13 g, 0.61 mmol), and DMF (2 mL) was heated at 160 °C under N 2 The mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 2), and the combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 35-65% MeCN / H 2 O[NH 4 CO 3 ]) to give 2-methyl-N-(3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)phenyl)propane-2-sulfonamide (Compound 355, 16 mg).

[0910] Synthesis Example S-22

[0911] Preparation of N-(1"-(3-(1-hydroxy-3,3-dimethylbutyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 357)

[0912]

[0913] To N-(1"-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (50 mg, 0.11 mmol), CuCl 2 To a mixture of t-BuMgCl (1 M, 0.44 mL) was added dropwise t-BuMgCl (1 M, 0.44 mL) (15 mg, 0.11 mmol), LiCl (5 mg, 0.11 mmol), and THF (1 mL). The mixture was stirred at 20 °C for 2 h and poured into saturated NH 4 Cl aqueous solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate and analyze by preparative HPLC (C18, 45-85% MeCN / H 2 O [formic acid]) to give N-(1"-(3-(1-hydroxy-3,3-dimethylbutyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (8.0 mg).

[0914] Synthesis Example S-23

[0915] Preparation of N-(tert-butyl)-3-(5"-((2-fluoroethyl)sulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 365)

[0916]

[0917] At 0°C, compound 148 (50 mg, 87 μmol) was dissolved in CH 2 Cl 2 DAST (23 μL, 0.18 mmol) was added to the mixture in 4% paraformaldehyde (1.5 mL). The mixture was stirred at 20 °C under N 2 Stir for 1 h, pour in H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, concentrate, and analyze by preparative HPLC (C18, 45-75% MeCN / H 2 O [formic acid]) to give N-(tert-butyl)-3-(5"-((2-fluoroethyl)sulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 365, 13 mg).

[0918] Table 7c describes the chromatographic separation of isomers for specific examples.

[0919] Table 7c.

[0920]

[0921]

[0922]

[0923]

[0924] Table 8.

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961] Bioassay

[0962] Inhibition of KIF18A microtubule-dependent ATPase activity:

[0963] Test compounds were plated in 384-well plates in a 3x dilution scheme. Assay buffer: HO 2 80 mM PIPES (pH 6.9), 1 mM MgCl 2, 75mM KCl, 1mM EGTA, 1mM DTT, 0.01% BSA, 0.005% Tween-20, 1μM paclitaxel. To 50nL of compound in DMSO, 2.5μL of enzyme mix [4nM hKIF18A(1-374) in assay buffer] was added. After incubation at room temperature for 30min, 2.5μL of microtube mix [0.2mg / mL preformed microtubes in assay buffer, 2.0mM ATP] was added, the plate was centrifuged for 30s, and then incubated at 28°C for 60min. 5μL of ADP-Glo ​​MaxR1, centrifuge the plate for 30 seconds, and incubate the mixture at room temperature for 4 hours. Add 10 μL ADP-Glo ​​Max R2, the plate was centrifuged for 30 s and incubated at room temperature for 60 min. Luminescence was measured using an Envision plate reader, and the % inhibition for each well was calculated as: ([maximum - minimum] - [test value - minimum]) / [maximum - minimum]. Via a four-parameter variable slope model, IC 50 Values ​​were calculated based on concentration compared to % inhibition data.

[0964] Table 9 indicates that the compounds provided herein are potent inhibitors of KIF18a. In comparison, the data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) was 17 nM.

[0965] Binding dynamics of the KIF18a-microtubule complex

[0966] Compound binding kinetic parameters (k 缔合 and k 解离 ) was determined by global progress curve analysis (GPCA). 2 KIF18A (0.25 nM) was incubated with serial dilutions of compounds for up to 24 hr in an assay buffer containing 1 μM paclitaxel, 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA, and 0.005% Tween-20. ADP product levels were measured by The time / dose-dependent progression curves were then globally fitted to a Michaelis-Menten kinetic model with 1-step slow binding inhibition to derive the association rate k缔合 and the dissociation rate k 解离 Value both (Zhang, R., Wong, K. (2017): "High performance enzymekinetics of turnover, activation and inhibition for translational drug discovery", Expert Opinion on Drug Discovery, 2017 January; 12(1):17-37.doi:10.1080 / 17460441.2017.1245721).

[0967] The results of the binding kinetics assays are summarized in Table 10. The data in Table 10 indicate that compounds provided herein can be used with either a small dissociation rate, or a very long dissociation half-life (ln(2) / k 解离 ) to achieve subnanomolar potency. For comparison, the data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) are: k 缔合 =0.059nM -1 h -1 ;k 解离 =0.21h -1 ; Dissociation t 1 / 2 =4.1h; K I =3.4nM.

[0968] Cell viability of KIF18a-sensitive cell lines

[0969] 24 hours before compound treatment, cell lines were seeded as follows: HCC15 (Korean Cell Line Bank) 600 cells / well, 95 μL RPMI-1640 medium supplemented with 100 units / ml penicillin, 100 units / ml streptomycin, and 10% FBS; NIH:OVCAR-3 (ATCC), 1000 cells / well, 95 μL RPMI-1640 medium supplemented with 100 units / ml penicillin, 100 units / ml streptomycin, 0.01 mg / mL bovine insulin, and 20% FBS; JIMT-1 (Addexbio) 1000 cells / well, 95 μL DMEM medium supplemented with 100 units / ml penicillin, 100 units / ml streptomycin, and 10% FBS.

[0970] Test compounds were added to the cells in a 20x dilution scheme by adding 5 μL of serially diluted compounds to the plate and incubated at 37°C, 5% CO 2 The treated cells were incubated for an additional 7 days in an incubator. DMSO was used as a negative control (0% effect), and wells without cells were used as positive controls (100% effect). The cells were incubated for seven days, and cell viability was measured by Promega Cell The luminescence units were converted to ATP concentrations using an ATP standard curve (10 points, 2-fold dilution from 5 uM). The inhibition percentage for each well was calculated as: ([maximum value - minimum value] - [test value - minimum value]) / [maximum value - minimum value]. Using a four-parameter variable slope model, IC 50 Values ​​were calculated based on concentration compared to % inhibition data. The results of the bioassays are summarized in Table 10.

[0971] Table 11 indicates that for KIF18a sensitive cancer cell lines, compounds as provided herein effectively inhibit cell growth or induce cell killing. In comparison, the data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) are: HCC-15, 0.066 μM; JIMT-1 0.13 μM; NIH: OVCAR3, 0.10 μM.

[0972] Table 9. Summary of biochemical assay data

[0973]

[0974]

[0975]

[0976]

[0977] Table 10. Summary of kinetic assay data

[0978]

[0979]

[0980] a) Association rate from binding kinetics assay. b) Dissociation rate from binding kinetics assay. c) Dissociation half-life ln(2) / k 解离 d) Determination of k from binding kinetics 解离 / k 缔合 Determined K I

[0981] Table 11: Summary of cell assay data

[0982]

[0983]

[0984] Assessment of in vivo activity

[0985] at 37 °C in 5% CO in air 2 OVCAR-3 (ATCC) tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 20% fetal bovine serum, 0.01 mg / mL bovine insulin, and 1% Anti-Anti at 37°C in an atmosphere of 5% CO in air. 2 HCC15 (DSMZ) tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Anti-Anti in an atmosphere of 4% paraformaldehyde.

[0986] Tumor cells were subcultured twice a week. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation.

[0987] Tumor cells (10 x 10 6 ) were subcutaneously inoculated into the right flank of each mouse. When the average tumor volume reached 110-175 mm 3 At 14:00, animals were randomly divided into groups of 10 animals each and treatment was initiated. OVCAR-3 cells were implanted into Balb / C nude mice, and HCC15 cells were implanted into SCID Beige mice.

[0988] Compounds were orally administered once or twice daily (12 h). Tumor growth inhibition (TGI) was calculated using the following formula: TGI (%) = [1-(T N -T 0 ) / (V N -V 0 )]×100;T N is the mean tumor volume of the treatment group at the indicated time point, T 0 is the average tumor volume of the treatment group on day 0 of treatment, V N is the mean tumor volume of the vehicle control group at the indicated time points, and V 0 The mean tumor volume of the vehicle group on treatment day 0. The p value was calculated based on tumor size by one-way ANOVA using GraphPad Prism 9.4.0, compared with the vehicle group accordingly. **** indicates p<0.0001.

[0989] Tumor volumes of vehicle- and compound-treated mice as a function of time after initiation of treatment and the results of treatment with selected compounds for SCID Beige mice or nude mice implanted with HCC15 or OVCAR-3 are shown in Figures 1A-1E The calculated TGI for the treatments with selected compounds are shown in Table 12.

[0990] Table 12

[0991]

[0992]

[0993] In summary, the present invention includes but is not limited to the following items:

[0994] 1. A compound of formula (I):

[0995]

[0996] or a pharmaceutically acceptable salt thereof, wherein:

[0997] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[0998] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[0999] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1000] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[1001] m is 0, 1, 2, 3 or 4;

[1002] Y 1 N or CR C1 ;

[1003] Y 2 N or CR C2 ;

[1004] Y3 N or CR C3 ;

[1005] Y 4 N or CR C4 ;

[1006] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[1007] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[1008] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1009] 2. A compound of formula (I-2):

[1010]

[1011] or a pharmaceutically acceptable salt thereof, wherein:

[1012] Ring A is C6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[1013] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1014] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1015] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[1016] m is 0, 1, 2, 3 or 4;

[1017] Y 1 N or CR C1 ;

[1018] Y 2 N or CR C2 ;

[1019] Y 3 N or CR C3 ;

[1020] Y 4 N or CR C4 ;

[1021] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[1022] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[1023] R c1 -R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1024] 3. A compound of formula (I-1):

[1025]

[1026] or a pharmaceutically acceptable salt thereof, wherein:

[1027] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ;

[1028] R a1 -R a20 are independently hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1029] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1030] Each R B The groups are independently halogen, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[1031] m is 0, 1, 2, 3 or 4;

[1032] Y 1 N or CR C1 ;

[1033] Y 2 N or CR C2 ;

[1034] Y 3 N or CR C3 ;

[1035] Y 4 N or CR C4 ;

[1036] where Y1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[1037] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[1038] R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1039] 4. A compound as described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane- [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1'-(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[1040] 5. A compound of formula (I-3):

[1041]

[1042] or a pharmaceutically acceptable salt thereof, wherein:

[1043] Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CRa17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups;

[1044] R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1045] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1046] m is 2;

[1047] Two R's B The group is attached to the same carbon atom on ring B and together with the carbon atom to which it is attached forms C 3-7 Cycloalkyl;

[1048] Y 1 N or CR C1 ;

[1049] Y 2 N or CRC2 ;

[1050] Y 3 N or CR C3 ;

[1051] Y 4 N or CR C4 ;

[1052] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[1053] R C1 -R C4 are independently hydrogen, halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[1054] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1055] 6. A compound as described in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted C 6-14 Aryl.

[1056] 7. The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted phenyl group.

[1057] 8. A compound of formula (Ia1):

[1058]

[1059] or a pharmaceutically acceptable salt thereof, wherein:

[1060] R a14 and R a15 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1061] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1062] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[1063] m is 0, 1, 2, 3 or 4;

[1064] RC2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 or C optionally substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 alkyl;

[1065] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1066] 9. The compound as described in item 8, or a pharmaceutically acceptable salt thereof, wherein R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6alkyl; and R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1067] 10. The compound according to item 8 or item 9, or a pharmaceutically acceptable salt thereof, wherein R C2 For-NR c5 S(O) 2 R c6 , and R c5 and R c6 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1068] 11. A compound of formula (Ia2):

[1069]

[1070] or a pharmaceutically acceptable salt thereof, wherein:

[1071] R a16 For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1072] Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent RB The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl;

[1073] m is 0, 1, 2, 3 or 4;

[1074] R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl;

[1075] R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1076] 12. The compound according to item 11, or a pharmaceutically acceptable salt thereof, wherein R C2 Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 Rc8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 Alkyl, and R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1077] 13. The compound according to item 11 or item 12, or a pharmaceutically acceptable salt thereof, wherein R C2 For-NR c5 S(O) 2 R c6 , and R c5 and R c6 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

[1078] 14. The compound of any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted 5- to 10-membered heteroaryl group.

[1079] 15. A compound as described in item 14, or a pharmaceutically acceptable salt thereof, wherein ring A is indolyl, indazolyl, pyridyl, thienyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolyl, each of which is optionally substituted.

[1080] 16. A compound as described in any one of items 1-15, or a pharmaceutically acceptable salt thereof, wherein R a1 is hydrogen or C 1-6 Alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a4 is hydrogen or C 1-6 Alkyl; R a5 is hydrogen or C 1-6 Alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or optionally C 1-6alkyl-substituted 5- to 12-membered heteroaryl; R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a10 C 3-10 Cycloalkyl; R a11 C 3-10 Cycloalkyl; R a12 is hydrogen or C 1-6 Alkyl; R a13 C 3-10 Cycloalkyl; R a16 C 3-10 cycloalkyl or 3 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected from C 1-6 Substituted by a substituent consisting of an alkyl group or a halogen group; R a17 and R a18 are independently hydrogen or C 1-6 Alkyl; R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 Cycloalkyl; R a21 C 3-10 cycloalkyl; and R a22 C 3-10 Cycloalkyl.

[1081] 17. A compound as described in any one of items 1-16, or a pharmaceutically acceptable salt thereof, wherein R a14 and R a15 are each independently hydrogen; C optionally substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 alkyl), and halogen; C 2-6 C optionally substituted by one or more substituents independently selected from the group consisting of 3-10 Cycloalkyl: C 2-6 Alkenyl, C 3-10 Cycloalkyl, halogen, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from -OH, -O(C 1-6 alkyl), and halogen substituted C 1-6 Alkyl, where R 1a1 and R1a2 are independently hydrogen or C 1-6 Alkyl; C 3-10 Cycloalkenyl; or optionally substituted by one or more C 1-6 Alkyl-substituted 3- to 12-membered heterocycloalkyl.

[1082] 18. A compound as described in any one of items 1-17, or a pharmaceutically acceptable salt thereof, wherein R a14 is hydrogen and R a15 It is tert-butyl.

[1083] 19. A compound as described in any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, -OH, methyl, amino,

[1084]

[1085]

[1086] 20. A compound as described in any one of items 1-13 and 16-19, or a pharmaceutically acceptable salt thereof, wherein ring A is Substituted phenyl.

[1087] 21. A compound as described in any one of items 1-20, or a pharmaceutically acceptable salt thereof, wherein ring B is C 5-7 Cycloalkyl.

[1088] 22. The compound as described in any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 7-membered heterocycloalkyl group.

[1089] 23. A compound as described in any one of items 1-20, or a pharmaceutically acceptable salt thereof, wherein ring B is wherein * indicates the point of attachment to the rest of formula (I).

[1090] 24. A compound as described in any one of items 1-20, or a pharmaceutically acceptable salt thereof, wherein the for wherein * indicates the point of attachment to the rest of formula (I).

[1091] 25. The compound of item 21, or a pharmaceutically acceptable salt thereof, wherein the for

[1092] 26. A compound as described in any one of items 1-25, or a pharmaceutically acceptable salt thereof, wherein Y1 CR C1 ; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[1093] 27. The compound of item 26, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .

[1094] 28. The compound of item 26 or item 27, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 , and R C4 Each is hydrogen.

[1095] 29. A compound as described in any one of items 1-25, or a pharmaceutically acceptable salt thereof, wherein Y 1 N; Y 2 CR C2 ; Y 3 CR C3 ; and Y 4 CR C4 .

[1096] 30. A compound as described in any one of items 1-25, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR C1 ; Y 2 N; Y 3 CR C3 ; and Y 4 CR C4 .

[1097] 31. A compound as described in any one of items 1-29, or a pharmaceutically acceptable salt thereof, wherein R C2 For cyano, -OH, -CH 2 OH, bromine, -NO 2 ,

[1098] 32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R C2 for

[1099] 33. A compound of formula (II):

[1100]

[1101] or a pharmaceutically acceptable salt thereof, wherein:

[1102] Ring A is

[1103] (i) Where Z 1 , Z 2 , Z 3 and Z 4 are independently hydrogen or R D , where R D Halogen, -OH, -NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O) 2 NR a14 R a15 、-S(O) 2 R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 、-P(O)(R a23 )(R a24 ), -C=NR a25 , or C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and optionally substituted by one or more halo or C 1-3 alkyl-substituted 3- to 10-membered heterocycloalkyl,

[1104] The condition is

[1105] (1) When Z 4 When Z is hydrogen, 1 and Z 3 At least one of them is R D ;and

[1106] (2) When Z 4 For R D When Z 1 For R D ,or

[1107] (ii) in

[1108] is a single bond or a double bond,

[1109] Z 5 is CH, N, O, S, or NX, wherein X is H or C 1-6 alkyl;

[1110] Z 6 For-NR a26 C(O)NR a27 R a28 、-NR a29 C(O)OR a30 、-N=S(O)R a31 R a32 、-S(O)R a33 、-S(O)(NR a34 )R a35 、-S(O) 2 NR a36 R a37 、-S(O) 2 R a38 、-SR a39 , 3- to 10-membered heterocycloalkyl, -C(O)R a40 , or -CH(Z 7 )(Z 8 ), where Z 7 is hydrogen or -OH, and Z 8 C 1-6 Alkyl, C optionally substituted by one or more halogen groups 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl group optionally substituted by one or more halo groups, and

[1111] Ring C is optionally substituted with one or more R E A 5- to 6-membered heteroaryl group substituted with a substituent, wherein each R E The substituents are independently selected from halo, -OH, and C 1-6 Alkyl group, or two R E The substituents together with the atoms to which they are attached form a C 5-6 Cycloalkyl, C 5-6 cycloalkenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl;

[1112] R a4 -R a40 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halo, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl;

[1113] Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon;

[1114] Each R B The groups are independently halogen or C optionally substituted by one or more halogen groups. 1-6 Alkyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The groups together form =CR 1a3 R 1a4 Group, where R 1a3 and R 1a4 are independently hydrogen or C 1-6 alkyl;

[1115] m is 0, 1, 2, 3 or 4;

[1116] Y 1 N or CR C1 ;

[1117] Y 2 N or CR C2 ;

[1118] Y 3 N or CR C3 ;

[1119] Y4 N or CR C4 ;

[1120] where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N;

[1121] R C1 -R C4 are independently hydrogen or R F , where R F Halogen, cyano, -OH, -NO 2 、-C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O) 2 R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O) 2 R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 、-OS(O) 2 R c19 , or C substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 Alkyl, and

[1122] R c1 -R c19 are independently hyd...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O)2NR a14 R a15 、-S(O)2R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups; R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halogen, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 Each is independently hydrogen, halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

2. A compound of formula (I-2): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O)2NR a14 R a15 、-S(O)2R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups; R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halogen, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 Each is independently hydrogen, halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 、-NR c14 C(O)OR c15 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; R c1 -R c15 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

3. A compound of formula (I-1): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O)2NR a14 R a15 、-S(O)2R a16 , and-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 ; R a1 -R a20 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halogen, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halogen, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 Each is independently hydrogen, halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is not 4'-fluoro-1'-[3-(piperidin-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea -1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1'-(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

5. A compound of formula (I-3): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-14 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R a13 、-S(O)2NR a14 R a15 、-S(O)2R a16 、-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 、-SR a21 、-C(O)R a22 , and C substituted by one or more substituents independently selected from the group consisting of 1-6 Alkyl: -OH, cyano, C 3-10 Cycloalkyl, and 3 to 10 membered heterocycloalkyl optionally substituted by one or more halo groups; R a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halogen, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; Two R's B The group is attached to the same carbon atom on ring B and together with the carbon atom to which it is attached forms C 3-7 Cycloalkyl; Y 1 N or CR C1 ; Y 2 N or CR C2 ; Y 3 N or CR C3 ; Y 4 N or CR C4 ; where Y 1 , Y 2 , Y 3 and Y 4 No more than three of them are N; R C1 -R C4 Each is independently hydrogen, halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted C 6-14 Aryl. 7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted phenyl group.

8. A compound of formula (Ia1): or a pharmaceutically acceptable salt thereof, wherein: R a14 and R a15 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-14 aryl, or 5 to 12 membered heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(C 1-6 Alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and optionally one or more independently selected from halogen, -OH, and -O(C 1-6 alkyl) group substituted with a substituent 1-6 Alkyl, where R 1a1 and R 1a2 are independently hydrogen or C 1-6 alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl, wherein one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl, or C 2-6 alkenyl; or two adjacent R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; or two geminal R B The group together with the carbon atom to which it is attached forms a C 3-10 Cycloalkyl; m is 0, 1, 2, 3 or 4; R C2 Halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 、-NR c14 C(O)OR c15 、-NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted by one or more substituents independently selected from the group consisting of halogen and -OH 1-6 alkyl; R c1 -R c18 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R C2 Halogen, cyano, -OH, -NO2, -C(O)NR c1 R c2 、-NR c3 R c4 、-NR c5 S(O)2R c6 、-P(O)R c7 R c8 、-N=S(O)R c9 R c10 、-S(O)(NR c11 )R c12 、-S(O)2R c13 , or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; and R c1 -R c13 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

10. The compound according to claim 8 or claim 9, or a pharmaceutically acceptable salt thereof, wherein R C2 For-NR c5 S(O)2R c6 , and R c5 and R c6 are independently hydrogen, C 3-10 Cycloalkyl, or C optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl.

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