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CN-121991056-A - Benzoheterocyclic compounds as KIF18A inhibitors and uses thereof

CN121991056ACN 121991056 ACN121991056 ACN 121991056ACN-121991056-A

Abstract

The invention provides a benzo heterocyclic compound with KIF18A inhibitory activity, a preparation method and a pharmaceutical composition thereof. Also relates to the application of the compound or the pharmaceutical composition as a KIF18A inhibitor in preventing or treating cancers.

Inventors

  • TIAN JINGWEI
  • YE LIANG
  • YANG YIFEI
  • ZHU HAIBO
  • ZHANG JIANZHAO
  • LU JING
  • WANG WENYAN

Assignees

  • 山东全重生物医药科技有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241101

Claims (10)

  1. 1. A compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof: Wherein, the X 1 is selected from-C (R 1a R 1b )-、-N(R 1a ) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; X 2 is selected from-C (R 2a R 2b )-、-N(R 2a ) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; Each occurrence of X 3 is independently selected from-C (R 3a R 3b )-、-N(R 3a ) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; X 4 is selected from CR 5a , or N; X 5 is selected from CR 5b , or N; X 6 is selected from CR 5c , or N; x 7 is selected from CR 5d , or N; optionally, X 5 and X 6 together form a ring A selected from R 1a 、R 1b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2 、-S(O) 2 C 1-6 alkylene OH, or R 1a 、R 1b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; r 2a 、R 2b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2 、-S(O) 2 C 1-6 alkylene OH, or R 2a 、R 2b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; R 3a 、R 3b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2 、-S(O) 2 C 1-6 alkylene OH, or R 3a 、R 3b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; each R 4a 、R 4b is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; Each occurrence of R 5a 、R 5b 、R 5c 、R 5d is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; R 6 is selected from R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6j 、R 6k Each occurrence is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 6a and R 6b 、R 6c and R 6d 、R 6e and R 6f 、R 6g and R 6h 、R 6j and R 6k together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group; R 7 is selected from Each R 7a 、R 7b is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 7a 、R 7b together with the carbon atoms to which it is attached form C 3-6 cycloalkyl; m is selected from 1 or 2.
  2. 2. The compound, pharmaceutically acceptable salt, or stereoisomer thereof, of claim 1, wherein the compound, pharmaceutically acceptable salt, or stereoisomer has the structural formula (III): Wherein, the X 1 is selected from-C (R 1a R 1b ) -, or-S (O) 2 -; X 3a is selected from-C (R 3a R 3b ) -, or-S (O) 2 -; X 3b is selected from a bond, -C (R 3a R 3b )-、-N(R 3a ) -, or-S (O) 2 -; X 5 is selected from CR 5b , or N; X 6 is selected from CR 5c , or N; x 7 is selected from CR 5d , or N; optionally, X 5 and X 6 together form a ring A selected from R 1a 、R 1b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-6 alkylene OH, -NH 2 , or R 1a 、R 1b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; R 2a is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-6 alkylene OH, -NH 2 ; r 3a 、R 3b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-6 alkylene OH, -NH 2 , or R 3a 、R 3b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; Each occurrence of R 5b 、R 5c 、R 5d is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; R 6 is selected from R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6j 、R 6k Each occurrence is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 6a and R 6b 、R 6c and R 6d 、R 6e and R 6f 、R 6g and R 6h 、R 6j and R 6k together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group; R 7 is selected from R 7a 、R 7b is each independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 7a 、R 7b together with the carbon atoms to which it is attached form C 3-6 cycloalkyl.
  3. 3. The compound of any one of claims 1-2, a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: X 1 is selected from-S (O) 2 -; X 2 is selected from-N (R 2a ) -; x 3 is selected from-C (R 3a R 3b ) -; m is selected from 1, or X 1 is selected from-C (R 1a R 1b ) - -; X 2 is selected from-N (R 2a ) -; X 3 is selected from-S (O) 2 -; m is selected from 1, or X 1 is selected from-S (O) 2 -; X 2 is selected from-N (R 2a ) -; Each occurrence of X 3 is independently selected from-C (R 3a R 3b ) -, or-N (R 3a ) -; Provided that one X 3 of two adjacent X 3 is selected from-N (R 3a ) -, the other X 3 is selected from-C (R 3a R 3b ) -, or two adjacent X 3 are simultaneously selected from-C (R 3a R 3b ) -; m is selected from 2.
  4. 4. The compound of claim 2, a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: X 1 is selected from-S (O) 2 -; x 3a is selected from-C (R 3a R 3b ) -; X 3b is selected from the group consisting of bonds; Or alternatively X 1 is selected from-C (R 1a R 1b ) -; X 3a is selected from-S (O) 2 -; X 3b is selected from the group consisting of bonds; Or alternatively X 1 is selected from-S (O) 2 -; x 3a is selected from-C (R 3a R 3b ) -; X 3b is selected from the group consisting of a bond, -C (R 3a R 3b ) -, or-N (R 3a ) -.
  5. 5. The compound of any one of claims 1-4, a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: X 4 is selected from CR 5a ;X 5 , CR 5b ;X 6 is selected from CR 5c ;X 7 and CR 5d , or X 4 is selected from N, X 5 is selected from CR 5b ;X 6 is selected from CR 5c ;X 7 is selected from CR 5d , or X 4 is selected from CR 5a ;X 5 , X 6 is selected from CR 5c ;X 7 is selected from CR 5d , or X 4 is selected from CR 5a ;X 5 , CR 5b ;X 6 is selected from N, X 7 is selected from CR 5d , or X 4 is selected from CR 5a ;X 5 , CR 5b ;X 6 is selected from CR 5c ;X 7 is selected from N, or X 4 is selected from N, X 5 is selected from N, X 6 is selected from CR 5c ;X 7 is selected from CR 5d , or X 4 is selected from N, X 5 is selected from CR 5b ;X 6 is selected from N, X 7 is selected from CR 5d , or X 4 is selected from N, X 5 is selected from CR 5b ;X 6 is selected from CR 5c ;X 7 is selected from N, or X 4 is selected from CR 5a ;X 5 , X 6 is selected from N, X 7 is selected from CR 5d , or X 4 is selected from CR 5a ;X 5 and N, X 6 is selected from CR 5c ;X 7 and N, or X 4 is selected from CR 5a ;X 5 , CR 5b ;X 6 is selected from N, X 7 is selected from N, or X 4 is selected from CR 5a ;X 5 and CR 5b ;X 6 is selected from CR 5c ;X 7 and N, and at the same time, X 5 and X 6 together form a ring A selected from Or alternatively X 4 is selected from CR 5a ;X 5 and CR 5b ;X 6 is selected from N, X 7 is selected from N, and simultaneously, X 5 and X 6 together form a ring A selected from Or alternatively X 4 is selected from CR 5a ;X 5 and N, X 6 is selected from CR 5c ;X 7 and N, at the same time, X 5 and X 6 together form a ring A selected from
  6. 6. The compound of any one of claims 1-5, a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: r 1a 、R 1b is independently at each occurrence selected from H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-4 hydroxyalkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-3 alkylene OH, -NH 2 , or R 1a 、R 1b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; R 2a 、R 2b is independently at each occurrence selected from H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-4 hydroxyalkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-3 alkylene OH, -NH 2 , or R 2a 、R 2b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; r 3a 、R 3b is independently at each occurrence selected from H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-4 hydroxyalkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -S (O) 2 C 1-3 alkylene OH, -NH 2 , or R 3a 、R 3b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl. Each R 4a 、R 4b is independently selected from H, halogen, C 1-3 alkyl, or C 1-3 haloalkyl; Each occurrence of R 5a 、R 5b 、R 5c 、R 5d is independently selected from H, halogen, C 1-3 alkyl, or C 1-3 haloalkyl; R 6 is selected from R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6j 、R 6k Each occurrence is independently selected from H, halogen, C 1-3 alkyl, or C 1-3 haloalkyl, or R 6a and R 6b 、R 6c and R 6d 、R 6e and R 6f 、R 6g and R 6h 、R 6j and R 6k together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group; R 7 is selected from R 7a 、R 7b is each independently selected from H, halogen, C 1-3 alkyl, or C 1-3 haloalkyl, or R 7a 、R 7b together with the carbon atoms to which it is attached form C 3-6 cycloalkyl.
  7. 7. The compound of any one of claims 1-6, pharmaceutically acceptable salt, or stereoisomer thereof, wherein: R 1a 、R 1b is independently at each occurrence selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-difluoroethyl 2, 2-dichloroethyl, 2-trifluoroethyl, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 CH 2 (OH)CH 2 OH、-CH 2 C(CH 3 ) 2 OH、-CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 3 、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetan-2-yl, oxetan-3-yl, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, cyclothiooxiranyl, thietane-2-yl, thietane-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl 、-S(O) 2 CH 2 OH、-S(O) 2 CH 2 CH 2 OH、-S(O) 2 CH 2 CH 2 CH 2 OH、-NH 2 , or R 1a 、R 1b together with the carbon atom to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2a 、R 2b is independently at each occurrence selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-difluoroethyl 2, 2-dichloroethyl, 2-trifluoroethyl, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 CH 2 (OH)CH 2 OH、-CH 2 C(CH 3 ) 2 OH、-CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 3 、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetan-2-yl, oxetan-3-yl, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, cyclothiooxiranyl, thietane-2-yl, thietane-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl 、-S(O) 2 CH 2 OH、-S(O) 2 CH 2 CH 2 OH、-S(O) 2 CH 2 CH 2 CH 2 OH、-NH 2 , or R 2a 、R 2b together with the carbon atom to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 3a 、R 3b is independently at each occurrence selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-difluoroethyl 2, 2-dichloroethyl, 2-trifluoroethyl, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 CH 2 (OH)CH 2 OH、-CH 2 C(CH 3 ) 2 OH、-CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 3 、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetan-2-yl, oxetan-3-yl, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, cyclothiooxiranyl, thietane-2-yl, thietane-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl 、-S(O) 2 CH 2 OH、-S(O) 2 CH 2 CH 2 OH、-S(O) 2 CH 2 CH 2 CH 2 OH、-NH 2 , or R 3a 、R 3b together with the carbon atom to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 4a 、R 4b is each independently selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl 2-chloroethyl, 2-difluoroethyl, 2-dichloroethyl, 2-trifluoroethyl 2, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl; R 5a 、R 5b 、R 5c 、R 5d is independently at each occurrence selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl 2-fluoroethyl, 2-chloroethyl, 2-difluoroethyl, 2-dichloroethyl, 2-trifluoroethyl 2, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl; R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6j 、R 6k Each occurrence is independently selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl 2-fluoroethyl, 2-chloroethyl, 2-difluoroethyl, 2-dichloroethyl, 2-trifluoroethyl 2, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl, or R 6a and R 6b 、R 6c and R 6d 、R 6e and R 6f 、R 6g and R 6h 、R 6j and R 6k together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 7a 、R 7b is each independently selected from H, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl 2-chloroethyl, 2-difluoroethyl, 2-dichloroethyl, 2-trifluoroethyl 2, 2-trichloroethyl, tetrafluoroethyl, tetrachloroethyl, pentafluoroethyl, pentachloroethyl, or R 7a 、R 7b together with the carbon atom to which it is attached forms cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  8. 8. The compound of any one of claims 1-7, a pharmaceutically acceptable salt, or stereoisomer thereof, selected from the group consisting of:
  9. 9. a pharmaceutical composition comprising a compound according to any one of claims 1-8, a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  10. 10. Use of a compound according to any one of claims 1-8, a pharmaceutically acceptable salt, stereoisomer thereof or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prevention and/or treatment of KIF18A mediated related diseases and/or disorders.

Description

Benzoheterocyclic compounds as KIF18A inhibitors and uses thereof Technical Field The present invention relates to a class of benzoheterocyclic compounds having KIF18A inhibitory activity, and their use as KIF18A inhibitors and for the treatment of cancer. Background Chromosome Instability (CIN) is one of the characteristics of tumor cells, which is caused by sustained errors in dynamics controlling chromosome segregation microtubules during mitosis, thereby impairing mitotic spindle function, resulting in changes in chromosome number and structure. About 90% of tumors exhibit chromosomal abnormalities and aneuploidy, with 30% -40% of tumors polyploiding. KIF18A belongs to the Kinesin-8 subfamily, which belongs to the positive-end directed motor domain, consisting of an N-terminal motor domain, a class-specific neck region, a central coiled-coil domain, and a C-terminal tail domain. KIF18A can move in the positive direction by means of energy released by hydrolyzed ATP in cells and uses microtubules as rails, and plays a key role in mitotic spindle assembly and regulation of chromosome alignment by controlling correct chromosome location and spindle tension in the metaphase of mitosis. KIF18A is overexpressed in various types of tumors, including, but not limited to, colon, breast, lung, pancreas, prostate, bladder, head, neck, cervical and ovarian cancers. KIF18A is a key regulator of processes such as chromosome abnormality or mitosis stage chromosome localization, spindle length, activation of spindle assembly check points, microtubule length regulation, etc. of tumor cells, but is not necessary in the normal diploid cell mitosis process. During CIN tumor cell division, the loss of KIF18A can prolong the mitotic time or activate spindle check points, arrest mitosis in the G2/M phase, and simultaneously lead to chromosome mismatch, post-chromosome lag and micronucleus formation, nuclear membrane rupture, chromosome oscillation amplitude increase and the like, induce mitosis disasters, and thus tumor cell death. Whereas inhibition of KIF18A activity did not affect normal diploid cell division proliferation. Research shows that the KIF18A inhibitor can activate mitosis check points, selectively kill cancer cells with unstable chromosomes, and form synthetic death with CIN tumor cells, thus having wide prospect as a potential tumor treatment strategy. There is currently no drug on the market that treats many conditions including cancer by the KIF18A inhibition pathway. Therefore, a new KIF18A inhibitor compound can be developed to meet the huge market demand. Disclosure of Invention In one aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof: Wherein, the X 1 is selected from-C (R 1aR1b)-、-N(R1a) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; X 2 is selected from-C (R 2aR2b)-、-N(R2a) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; Each occurrence of X 3 is independently selected from-C (R 3aR3b)-、-N(R3a) -, -O-, -C (=O) -, -S (O) -, or-S (O) 2 -; X 4 is selected from CR 5a, or N; X 5 is selected from CR 5b, or N; X 6 is selected from CR 5c, or N; x 7 is selected from CR 5d, or N; optionally, X 5 and X 6 together form a ring A selected from R 1a、R1b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2、-S(O)2C1-6 alkylene OH, or R 1a、R1b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; r 2a、R2b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2、-S(O)2C1-6 alkylene OH, or R 2a、R2b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; R 3a、R3b is independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, -NH 2、-S(O)2C1-6 alkylene OH, or R 3a、R3b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl; each R 4a、R4b is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; Each occurrence of R 5a、R5b、R5c、R5d is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; R 6 is selected from R6a、R6b、R6c、R6d、R6e、R6f、R6g、R6h、R6j、R6k Each occurrence is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 6a and R 6b、R6c and R 6d、R6e and R 6f、R6g and R 6h、R6j and R 6k together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group; R 7 is selected from Each R 7a、R7b is independently selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or R 7a、R7b together with the carbon atoms to which it is attached form C 3-6 cycloalkyl; m is selected from 1 or 2. In some embodiment