Bicyclic heteroaryl compounds and uses thereof

Abstract

The present invention provides bicyclic heteroaryl compounds of formula (I), methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds for the treatment of cancer and other diseases.

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of International Application No. PCT / CN2022 / 075544, filed February 8, 2022, and International Application No. PCT / CN2022 / 132667, filed November 17, 2022, the entire texts of which are incorporated herein by reference. [Background technology]

[0002] The Hippo signaling pathway is involved in suppressing cell proliferation and promoting apoptosis. Because many cancers are characterized by uncontrolled cell division, this signaling pathway is of interest in the search for new therapeutic agents for the treatment of cancer and other hyperproliferative diseases and disorders. Summary of the Invention [Means for solving the problem]

[0003] In one embodiment, described herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0004] [ka]

[0005] however: X 1 is C, C(R 1 ), or N; X 2 is C, C(R 2 ), or N; X 3 is C, C(R 3 ), or N; X 4 is C, C(R 4 ), or N; X 5 is C(R 5 ), C(R 5 )(R5a ), N(R 5b ), or N; X 6 is C(R 6 ), C(R 6 )(R 6a ), N(R 6b ), or N; X 7 is C(R 7 ), C(R 7 )(R 7a ), N(R 7b ), or N; X 8 is C(R 8 ), C(R 8 )(R 8a ), N(R 8b ), or N; X 9 is C(R 9 ) or N; X 10 is C(R 10 ) or N; X 11 is C(R 16 ), C(R 16 )(R 16a ), C(O), N(R 16b ), or N; L 1 and L 2 are independently a bond and R 14a C optionally substituted with one, two or three groups selected from 1-6 Selected from the group consisting of alkylene; R 1 , R 2 , R 3 and R 4 are independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 16 and R 16a are independently hydrogen, halogen, -CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21a ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14b optionally substituted with one, two or three groups selected from R 5b , R 6b , R 7b , R 8b and R 16b are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -C(O)R 23 , -C(O)N(R 20 )(R 21 ), and -S(O)R 23 Selected from the group consisting of: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14c optionally substituted with one, two or three groups selected from R 9 , R 10 and R 11 are independently hydrogen, halogen, and C 1-6 selected from the group consisting of alkyl; R 12 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15a optionally substituted with one, two or three groups selected from R 13 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b optionally substituted with one, two or three groups selected from R 14a , R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: R 15a are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -NH-C 3-9 Cycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22)C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 15b are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 20 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 21 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forming a heterocycloalkyl; R 21a are each independently, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 22 are each independently hydrogen, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 23 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl;

[0006] [ka]

[0007] indicates a single or double bond that satisfies all valences.

[0008] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 9 is C(R 9 In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 9 is hydrogen. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 10 is C(R 10 In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 10 is hydrogen. In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 11 is hydrogen.

[0009] In other aspects, described herein are compounds having the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0010] [ka]

[0011] however: X 1 is C, C(R 1 ), or N; X 2 is C, C(R 2 ), or N; X 3 is C, C(R 3 ), or N; X 4 is C, C(R 4 ), or N; X 5 is C(R 5 ), C(R 5 )(R 5a ), N(R 5b ), or N; X 6 is C(R 6 ), C(R 6 )(R 6a ), N(R 6b ), or N; X 7 is C(R 7 ), C(R 7 )(R 7a ), N(R 7b ), or N; X 8 is C(R 8 ), C(R 8 )(R 8a ), N(R 8b ), or N; X 11 is C(R 16 ), C(R 16 )(R 16a ), C(O), N(R 16b ), or N; Y is N(R 18 ) or O; L 1 and L 2 are independently a bond and R 14a C optionally substituted with one, two or three groups selected from 1-6 Selected from the group consisting of alkylene; R 1 , R 2 , R 3 and R 4 are independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 16 and R 16a are independently hydrogen, halogen, -CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21a ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14b optionally substituted with one, two or three groups selected from R 5b , R 6b , R 7b , R 8b and R 16b are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -C(O)R 23 , -C(O)N(R 20 )(R 21 ), and -S(O)R 23 Selected from the group consisting of: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14c optionally substituted with one, two or three groups selected from R 12a is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 Heteroaryl is R 15a optionally substituted with one, two or three groups selected from R 13 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b optionally substituted with one, two or three groups selected from R 14a , R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: R 15aare each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -NH-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23, -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 15b are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20)(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21) optionally substituted with one, two, or three groups independently selected from 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 17 is hydrogen, halogen, and C 1-6 selected from the group consisting of alkyl; R 18 is hydrogen and C 1-6 selected from the group consisting of alkyl; R 20 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R21 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forming a heterocycloalkyl; R 21a are each independently, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 22 are each independently hydrogen, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 23 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl;

[0012] [ka]

[0013] indicates a single or double bond that satisfies all valences.

[0014] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is N(R 18 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is O. In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, R 17 is hydrogen.

[0015] In some embodiments of the compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, X 11 is N. In some embodiments of the compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, X 11 is C(R 16 In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(H). In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(O). In some embodiments of the compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, X 1 is N and X 2 is C. In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C, and X 2 is N. In some embodiments of the compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, X 3 is C, and X 4 is C. In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N and X4 is C. In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C, and X 4 is N. In some embodiments of the compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, X 5 is C(R 5 ) or N;X 6 is C(R 6 ) or N;X 7 is C(R 7 ) or N;X 8 is C(R 8 ) or N.

[0016] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ia):

[0017] [ka]

[0018] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ib):

[0019] [ka]

[0020] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ic):

[0021] [ka]

[0022] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Id):

[0023] [ka]

[0024] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ie):

[0025] [ka]

[0026] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (If):

[0027] [ka]

[0028] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ig):

[0029] [ka]

[0030] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ih):

[0031] [ka]

[0032] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ii):

[0033] [ka]

[0034] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ij):

[0035] [ka]

[0036] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ik):

[0037] [ka]

[0038] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (II):

[0039] [ka]

[0040] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Im):

[0041] [ka]

[0042] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (In):

[0043] [ka]

[0044] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Io):

[0045] [ka]

[0046] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ip):

[0047] [ka]

[0048] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iq):

[0049] [ka]

[0050] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ir):

[0051] [ka]

[0052] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Is):

[0053] [ka]

[0054] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (It):

[0055] [ka]

[0056] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iu):

[0057] [ka]

[0058] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iv):

[0059] [ka]

[0060] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iw):

[0061] [ka]

[0062] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ix):

[0063] [ka]

[0064] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iy):

[0065] [ka]

[0066] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIa):

[0067] [ka]

[0068] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIb):

[0069] [ka]

[0070] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5is F or Cl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is F.

[0071] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is F or Cl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is F.

[0072] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is halogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is F or Cl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is F.

[0073] In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is F or Cl. In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is F.

[0074] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 2is a bond. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 2 is R 14a C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15bIn some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 6-10 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15bIn some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 3-10In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 2-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15b are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 20 where R 20 is C 1-6 Alkyl and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L is selected from haloalkyl. 1 is R 14a C optionally substituted with one, two or three groups selected from 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 1 is unsubstituted C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 1 is a bond. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 2-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R15a In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-9 is heteroaryl, However, C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 2-9In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently a halogen, -CN, or C1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -NH-C 3-9 Cycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23)2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 20 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 14a , R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: Or, two R's 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 21 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forming a heterocycloalkyl; R 21a are each independently, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 22 are each independently hydrogen, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 23 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 It is optionally substituted with one, two or three groups selected from heteroaryl.

[0075] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from2-9 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently a halogen, -CN, or C 1-6 Alkyl, and C 1-6 haloalkyl.

[0076] In other aspects, described herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0077] In other aspects, described herein are methods of inhibiting the Hippo pathway in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of inhibiting YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof, comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0078] In another aspect, described herein is a method of treating a disease or condition affected by inhibition of YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0079] In other aspects, described herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, the cancer is selected from the group consisting of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, and pancreatic cancer.

[0080] In other aspects, described herein are methods of treating cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0081] In other aspects, described herein are methods of treating fibrosis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the method of treating fibrosis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, the fibrosis is liver fibrosis, kidney fibrosis, and lung fibrosis.

[0082] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0083] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0084] Proper function of the Hippo pathway involves a cytoplasmic kinase cascade, resulting in the phosphorylation, cytoplasmic sequestration, and eventual degradation of two transcriptional coactivators, namely, YAP (Yes-associated protein) and TAZ (Transcription coactivator with PDZ binding motif). The unphosphorylated, activated YAP / TAZ coactivators translocate to the nucleus and bind to and activate the Transcriptional Enhanced Associate Domain (TEAD) transcription factor family (TEAD1-4), which are involved in the development of various types of cancer and hyperproliferative disorders. Therefore, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interactions represents an attractive target for preventing and / or treating cancer, other hyperproliferative disorders, and diseases associated with Hippo pathway dysfunction.

[0085] Specific Terms Unless otherwise stated, the following terms used in this application have the following definitions: The use of the term "comprises," as well as other forms such as "includes," "including," "including," etc., is non-limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0086] As used in the text, C1-C x is C1-C2, C1-C3...C1-Cx For example, a group designated "C1-C4" indicates that the moiety has 1 to 4 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, for example, "C1-C4 alkyl" indicates that the alkyl has 1 to 4 carbon atoms, i.e., the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0087] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight-chain. In some embodiments, an alkyl group has 1 to 10 carbon atoms, i.e., C1-C 10 As used herein, numerical ranges such as "1 to 10" refer to each integer within the range; for example, "1 to 10 carbon atoms" means that the alkyl group is one, two, three, four, five, six, etc., up to and including 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is a C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0088] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups described above can be converted to alkylene by removing a second hydrogen atom from the alkyl. In some embodiments, alkylene is a C1-C6 alkylene. In other embodiments, alkylene is a C1-C4 alkylene. In certain embodiments, alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, alkylene contains 2 carbon atoms (e.g., a C2 alkylene). In other embodiments, alkylene contains 2 to 4 carbon atoms (e.g., a C2-C4 alkylene). Representative alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0089] "Deuteroalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl have been replaced by deuterium.

[0090] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group and can be the same or different. In some embodiments, R is H or alkyl. In some embodiments, an alkenyl is selected from the group consisting of ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0091] The term "alkynyl" refers to a species of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from the group consisting of ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0092] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0093] "Alkylamine" means -N(alkyl) x H y refers to a group where x is 0 and y is 2; alternatively, x is 1 and y is 1; alternatively, x is 2 and y is 0.

[0094] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0095] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, this term distinguishes carbocycles from "heterocyclic" rings or "heterocycles," in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0096] As used herein, the term "aryl" refers to an aromatic ring in which all atoms forming the ring are carbon atoms. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C6-C 10 Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0097] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which all atoms forming the ring (i.e., skeletal atoms) are carbon atoms. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Multicyclic cycloalkyls include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0098] As used herein, the term "halo," or alternatively "halogen," or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0099] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced by a halogen atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0100] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from the group consisting of trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0101] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl is an atom other than carbon, e.g., an atom selected from oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0102] The term "heteroalkylene" refers to a divalent heteroalkyl radical.

[0103] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, a heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compound. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 10 atoms in the ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in the ring system. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, Oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, 3H-indolyl, indolin-2-onyl, iso These include indolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroisoquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be either C-bonded (or C-linked) or N-bonded where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (both C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both of the two rings of a bicyclic heterocycle are aromatic.

[0104] The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0105] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, a heterocycloalkyl is C2-C6 10 In other embodiments, heterocycloalkyl is C4-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0106] The term "oxo" refers to the =O radical.

[0107] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties (when the atoms joined by the bond are considered part of a larger substructure). In one embodiment, when a group described herein is a bond, the referenced group is absent, allowing a bond to form between the remaining specified groups.

[0108] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often a recognizable chemical entity embedded within or attached to a molecule.

[0109] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from the group consisting of D, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from the group consisting of D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, a substituent is substituted with one or two of the foregoing groups. In some embodiments, an optional substituent at an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0110] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means that it does not have lasting adverse effects on the general health of the subject being treated.

[0111] As used herein, the term "modulate" means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0112] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0113] As used herein, terms such as "co-administration" are meant to encompass the administration of more than one selected therapeutic agent to a single patient and are intended to include therapeutic regimens in which the agents are administered via the same or different routes of administration or at the same or different times.

[0114] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the administration of an amount of an agent or compound sufficient to relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound described herein required to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0115] As used herein, the terms "enhance" or "enhancing" mean to increase or prolong either in potency or duration a desired effect. Thus, in reference to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a given system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of other therapeutic agents in a desired system.

[0116] As used herein, the term "pharmaceutical composition" refers to a product resulting from the mixing or combination of multiple active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient simultaneously, in parallel, or sequentially as separate entities, without any specific time constraints, provided that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0117] The terms "kit" and "article of manufacture" are used synonymously.

[0118] The term "subject" or "patient" includes mammals. Examples of mammals include all members of the class Mammalia, including, but not limited to, humans, non-human primates such as chimpanzees, and apes and monkeys; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0119] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating the conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0120] compound The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb) described herein, including pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates thereof, are inhibitors of YAP-TEAD and / or inhibitors of TAZ-TEAD protein-protein interaction. In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb) described herein, including pharmaceutically acceptable salts and solvates thereof, are inhibitors of YAP-TEAD and inhibitors of TAZ-TEAD protein-protein interaction. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb) described herein, including pharmaceutically acceptable salts and solvates thereof, is an inhibitor of YAP-TEAD. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb) described herein, including pharmaceutically acceptable salts and solvates thereof, is an inhibitor of TAZ-TEAD protein-protein interaction.

[0121] In some embodiments, described herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0122] [ka]

[0123] however, X 1 is C, C(R 1 ), or N; X 2 is C, C(R 2 ), or N; X 3 is C, C(R 3 ), or N; X 4 is C, C(R 4 ), or N; X 5 is C(R 5 ), C(R 5 )(R 5a ), N(R 5b ), or N; X 6 is C(R 6 ), C(R 6 )(R 6a ), N(R 6b ), or N; X 7 is C(R 7 ), C(R 7 )(R 7a ), N(R 7b ), or N; X 8 is C(R 8 ), C(R 8 )(R 8a ), N(R 8b ), or N; X 9 is C(R 9 ) or N; X 10 is C(R 10 ) or N; X 11 is C(R 16), C(R 16 )(R 16a ), C(O), N(R 16b ), or N; L 1 and L 2 are independently a bond and R 14a C optionally substituted with one, two or three groups selected from 1-6 Selected from the group consisting of alkylene; R 1 , R 2 , R 3 and R 4 are independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 16 and R 16a are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21a ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14b optionally substituted with one, two or three groups selected from R 5b , R 6b , R 7b , R 8b and R 16b are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 20 , -OC(O)N(R 20 )(R21 ), -C(O)R 23 , -C(O)N(R 20 )(R 21 ), and -S(O)R 23 Selected from the group consisting of: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14c optionally substituted with one, two or three groups selected from R 9 , R 10 and R 11 are independently hydrogen, halogen, and C 1-6 selected from the group consisting of alkyl; R 12 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15a optionally substituted with one, two or three groups selected from R 13 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b optionally substituted with one, two or three groups selected from R 14a , R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20)(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: R 15a are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -NH-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 15b are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23, -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R20 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 21 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forming a heterocycloalkyl; R 21a are each independently, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 22 are each independently hydrogen, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 23 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl;

[0124] [ka]

[0125] indicates a single or double bond that satisfies all valences.

[0126] In any and all embodiments, the substituents are selected from among a subset of the listed options. For example, in some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, X 9 is C(R 9 In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 9 is hydrogen. In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 9 is C 1-6 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R9 is -CH3.

[0127] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 10 is C(R 10 In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 10 is hydrogen. In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 10 is C 1-6 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 10 is -CH3.

[0128] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 9 and R 10 is hydrogen.

[0129] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 11 is hydrogen. In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 11 is C 1-6 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 11 is -CH3.

[0130] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 9 , R 10 and R 11 is hydrogen.

[0131] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 11is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(R 16 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(H). In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(O).

[0132] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C(R 1 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C(H).

[0133] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 2 is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C(R 2 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C(H).

[0134] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is N and X 2is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C, and X 2 is N.

[0135] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C(R 3 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C(H).

[0136] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 4 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 4 is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 4 is C(R 4 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 4 is C(H).

[0137] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C, and X 4 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N and X 4 is C. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X3 is C, and X 4 is N.

[0138] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) or N;X 6 is C(R 6 ) or N;X 7 is C(R 7 ) or N;X 8 is C(R 8 ) or N. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is C(R 8 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is N;X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is C(R 8 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is N;X 7 is C(R 7 ) and X 8 is C(R 8 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is N;X 8 is C(R 8In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is N. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is N;X 6 is C(R 6 ) and X 7 is N;X 8 is C(R 8 In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is N;X 7 is C(R 7 ) and X 8 is N.

[0139] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 12 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15a is optionally substituted with one, two or three groups selected from:

[0140] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 12 is C 1-6 Alkyl, C5-6 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl, and C 3-7 heteroaryl, with the proviso that C 1-6 Alkyl, C 5-6 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl, and C 3-7 Heteroaryl is R 15a is optionally substituted with one, two or three groups selected from:

[0141] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15a are independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -NH-C 3-6 Cycloalkyl, C 3-7 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -N(R 20 )(R 21 ), -OC(O)R 23 Selected from the group consisting of: 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -NH-C 3-6 Cycloalkyl, C 3-7 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , and -N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with 1, 2, or 3 groups independently selected from alkoxy.

[0142] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15a are independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NH-C 3-6 Cycloalkyl, C 3-7 Heterocycloalkyl, -OR 20 , and -N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NH-C 3-6 Cycloalkyl, C 3-7 Heterocycloalkyl is substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , and -N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with 1, 2, or 3 groups independently selected from alkoxy.

[0143] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15a are independent, -C 3-7 Heterocycloalkyl, -NH-C 3-6 Cycloalkyl, -OR 20 , and -N(R 20 )(R 21 ), with the proviso that -C 3-7 Heterocycloalkyl and -NH-C 3-6 Cycloalkyl is a halogen, C 1-6 Alkyl, and -OR 20 is optionally substituted with one, two, or three groups independently selected from

[0144] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15a are independently, -OR 20 and -N(R 20 )(R 21 ), and optionally, two R 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen and -OR 20 is optionally substituted with one, two, or three groups independently selected from

[0145] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 13 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b is optionally substituted with one, two or three groups selected from:

[0146] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 13 is C 1-6 Alkyl, C 5-6 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl, and C 3-7 heteroaryl, with the proviso that C 1-6 Alkyl, C 5-6 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl, and C 3-7 Heteroaryl is R 15b is optionally substituted with one, two or three groups selected from:

[0147] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15b are independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, and -OR 20 Selected from the group consisting of: 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and -OR 20 or optionally substituted with one, two, or three groups independently selected from 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with 1, 2, or 3 groups independently selected from alkoxy.

[0148] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15b are independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -CH2-C3-6 Cycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and -OR 20 Selected from the group consisting of: 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 6-10 Aryl, and -CH2-C 6-10 Aryl is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and -OR 20 is optionally substituted with one, two, or three groups independently selected from

[0149] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15b are independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, and -OR 20 Selected from the group consisting of: 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 Cycloalkyl is substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and -OR 20 is optionally substituted with one, two, or three groups independently selected from

[0150] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 15b is C 1-6 Alkyl or -OR 20 is.

[0151] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 20 are each independently hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, with the proviso that C 1-6 Alkyl, C 3-6 Cycloalkyl is substituted with halogen, hydroxy, C 1-6 Alkyl, and C 1-6 Alkoxy, C 1-9 It is optionally substituted with one, two or three groups selected from heteroaryl.

[0152] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 20 are each independently selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , C 3 cycloalkyl, and cyclobutyl, provided that cyclobutyl is optionally substituted with —OCH 3 .

[0153] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 21 are each independently hydrogen and C 1-6 alkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forms a heterocycloalkyl.

[0154] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, R 21 are each independently hydrogen, -CH3, and C 1-6 alkyl; or R 20 and R 21 together with the nitrogen to which they are attached, can be azetidinyl, pyrrolidinyl, morpholino,

[0155] [ka]

[0156] , or piperidinyl, provided that azetidinyl, pyrrolidinyl, morpholino,

[0157] [ka]

[0158] or piperidinyl is optionally substituted by hydroxy or C1-6 alkyl.

[0159] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ia):

[0160] [ka]

[0161] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ib):

[0162] [ka]

[0163] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ic):

[0164] [ka]

[0165] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Id):

[0166] [ka]

[0167] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ie):

[0168] [ka]

[0169] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (If):

[0170] [ka]

[0171] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ig):

[0172] [ka]

[0173] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ih):

[0174] [ka]

[0175] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ii):

[0176] [ka]

[0177] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ij):

[0178] [ka]

[0179] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ik):

[0180] [ka]

[0181] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (II):

[0182] [ka]

[0183] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Im):

[0184] [ka]

[0185] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (In):

[0186] [ka]

[0187] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Io):

[0188] [ka]

[0189] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ip):

[0190] [ka]

[0191] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iq):

[0192] [ka]

[0193] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ir):

[0194] [ka]

[0195] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Is):

[0196] [ka]

[0197] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (It):

[0198] [ka]

[0199] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iu):

[0200] [ka]

[0201] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iv):

[0202] [ka]

[0203] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iw):

[0204] [ka]

[0205] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Ix):

[0206] [ka]

[0207] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Iy):

[0208] [ka]

[0209] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is F or Cl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), (Iv), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is F. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is R 14b C optionally substituted with one, two or three groups selected from 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is unsubstituted C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is -C(O)N(R 20 )(R 21 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (Io), (Ip), (Iq), (Is), (It), or (Iv), or a pharmaceutically acceptable salt or solvate thereof, R 5 is -C(O)NH2.

[0210] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 is unsubstituted C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 is -C(O)N(R 20 )(R 21 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ii), (Ij), (Il), (Im), (In), (Ip), (Iq), (Ir), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 6 is -C(O)NH2.

[0211] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 is unsubstituted C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 is -C(O)N(R 20 )(R 21 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Id), (Ie), (Ig), (Ih), (Ii), (Ik), (Il), (Im), (In), (Io), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 7 is -C(O)NH2.

[0212] In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R8 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 is unsubstituted C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 HA-OR 20 where R 20 are independently hydrogen and C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 is -C(O)N(R 20 )(R 21 In some embodiments of a compound of Formula (I), (Ia), (Ic), (Id), (Ie), (If), (Ih), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 8 is -C(O)NH2.

[0213] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 2 is a bond. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 2 is R 14a C optionally substituted with one, two or three groups selected from 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 2 is unsubstituted C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, L 2 is -CH2-.

[0214] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15bIn some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 6-10 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is one R 15bIn some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C substituted by one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is one R 15b C substituted by a group 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 3-10 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 2-9 It is heterocycloalkyl.

[0215] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 20 where R 20 is C 1-6 Alkyl and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b and R are each halogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b are C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15band R are each -CF. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b are C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b and R are each —CH3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15b are -OR 20 where R 20 is C 1-6 Alkyl and C 1-6 haloalkyl.

[0216] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 1 is R 14a C optionally substituted with one, two or three groups selected from 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 1 is unsubstituted C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, L 1 is a bond.

[0217] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15a In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyrazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, and pyrazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12is unsubstituted pyridyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 2-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is R 15a C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 12 is unsubstituted C 1-6 It is alkyl.

[0218] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently a halogen, -CN, or C1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each halogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each -CF. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are C 1-6In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each —CH3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each -CN. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -N(R 20 )(R 21 )

[0219] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently -NH2, -NH(CH3), -N(CH3)2, -N(CH3)(CH2)2OH, -NH(CH2)2OCH3,

[0220] [ka]

[0221] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each -NH. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each —NH(CH). In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each —N(CH3)2. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15aand R are each —N(CH3)(CH2)2OH. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each -NH(CH2)2OCH3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are respectively

[0222] [ka]

[0223] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are respectively

[0224] [ka]

[0225] is.

[0226] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -OR 20 where R 20 are independently hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, with the proviso that C 1-6 Alkyl and C 3-6 Cycloalkyl is substituted with halogen, hydroxy, C 1-6 Alkyl, and C 1-6 Alkoxy, C 1-9 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -OR 20 where R 20 is independently selected from the group consisting of hydrogen, -CH, -CHCHOH, -CHCHOCH, cyclopropyl, and cyclobutyl, provided that cyclopropyl and cyclobutyl are optionally substituted with -OCH. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15aare each independently selected from the group consisting of -OH, -OCH3, -OCH2CH2OH, and -OCH2CH2OCH3.

[0227] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently, -OR 20 and -N(R 20 )(R 21 ), optionally with the proviso that two R 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen and -OR 20 is optionally substituted with one, two, or three groups independently selected from

[0228] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -N(R 20 )(R 21 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R15a are -N(R 20 )(R 21 ), where R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forms a heterocycloalkyl.

[0229] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -N(R 20 )(R 21 ), where R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forms a heterocycloalkyl, provided that C 2-9 Heterocycloalkyl is hydroxy or C 1-6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), or (Iy), or a pharmaceutically acceptable salt or solvate thereof, R 15a are azetidinyl, pyrrolidinyl, morpholino, and

[0230] [ka]

[0231] or piperidinyl, with the proviso that azetidinyl, pyrrolidinyl, morpholino,

[0232] [ka]

[0233] or piperidinyl optionally substituted with hydroxy.

[0234] In some embodiments, described herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0235] [ka]

[0236] however, X 1 is C, C(R 1 ), or N; X 2 is C, C(R 2 ), or N; X 3 is C, C(R 3 ), or N; X 4 is C, C(R 4 ), or N; X 5 is C(R 5 ), C(R 5 )(R 5a ), N(R 5b ), or N; X 6 is C(R 6 ), C(R 6 )(R 6a ), N(R 6b ), or N; X 7 is C(R 7 ), C(R 7 )(R 7a ), N(R 7b ), or N; X 8 is C(R 8 ), C(R 8 )(R 8a ), N(R 8b ), or N; X 11 is C(R 16 ), C(R 16 )(R 16a ), C(O), N(R 16b ), or N; Y is N(R 18 ) or O; L 1 and L 2 are independently a bond and R 14a C optionally substituted with one, two or three groups selected from 1-6 Selected from the group consisting of alkylene; R 1 , R 2 , R 3 and R 4 are independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 16 and R 16a are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21a ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14b optionally substituted with one, two or three groups selected from R 5b , R 6b , R 7b , R 8b and R 16b are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -C(O)R 23 , -C(O)N(R 20 )(R 21 ), and -S(O)R 23 Selected from the group consisting of: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 14c optionally substituted with one, two or three groups selected from R 12a is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15a optionally substituted with one, two or three groups selected from R 13 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b optionally substituted with one, two or three groups selected from R 14a , R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23)2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23, -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 Optionally substituted with one, two, or three groups independently selected from: R 15a are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -NH-C 3-9 Cycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 15b are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15b combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one, two, or three groups independently selected from alkoxy; R 17 is hydrogen, halogen, and C 1-6 selected from the group consisting of alkyl; R 18 is hydrogen and C 1-6 selected from the group consisting of alkyl; R 20 are each independently hydrogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 21 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 20 and R 21 together with the nitrogen to which they are attached, C 2-9 Forming a heterocycloalkyl; R 21a are each independently, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 22 are each independently hydrogen, C 1-6 Alkyl and C 1-6 selected from the group consisting of haloalkyl; R 23 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl;

[0237] [ka]

[0238] indicates a single or double bond that satisfies all valences.

[0239] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is N(R 18 In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is N(H). In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is N(R 18 ) and R 18 is C 1-6 In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is alkyl. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is N(CH). In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y is O.

[0240] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R 17 is hydrogen. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R 17 is C 1-6 In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R 17 is -CH3.

[0241] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(R 16 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(H). In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 11 is C(O).

[0242] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C(R 1 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C(H).

[0243] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 2is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 2 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C(R 2 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C(H).

[0244] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is N and X 2 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 1 is C, and X 2 is N.

[0245] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C(R 3 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C(H).

[0246] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 4 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 4 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X4 is C(R 4 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 4 is C(H).

[0247] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C, and X 4 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N and X 4 is C. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C, and X 4 is N.

[0248] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) or N;X 6 is C(R 6 ) or N;X 7 is C(R 7 ) or N;X 8 is C(R 8 ) or N. In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is C(R 8 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is N;X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is C(R8 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is N;X 7 is C(R 7 ) and X 8 is C(R 8 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is N;X 8 is C(R 8 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is C(R 6 ) and X 7 is C(R 7 ) and X 8 is N. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is N;X 6 is C(R 6 ) and X 7 is N;X 8 is C(R 8 In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, X 5 is C(R 5 ) and X 6 is N;X 7 is C(R 7 ) and X 8 is N.

[0249] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIa):

[0250] [ka]

[0251] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIb):

[0252] [ka]

[0253] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is hydrogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 is halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 is F or Cl. In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is F. In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 is unsubstituted C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 5 HA-OR 20 where R 20 are independently hydrogen and C 1-6In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is -C(O)N(R 20 )(R 21 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 5 is -C(O)NH2.

[0254] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R6 is hydrogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 is halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 is unsubstituted C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 6 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is -C(O)N(R 20 )(R 21 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 6 is -C(O)NH2.

[0255] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R 21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is hydrogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 is halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 is unsubstituted C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 7 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is -C(O)N(R 20 )(R 21 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 7 is -C(O)NH2.

[0256] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 8 are hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 20 , -C(O)OR 20 , -C(O)R 23 , -C(O)N(R 20 )(R 21 ), -S(O)R 23 , and -S(O)N(R 20 )(R21 )-, with the proviso that C 1-6 Alkyl is R 14b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 are hydrogen, halogen, -CN, C 1-6 Alkyl, -OR 20 , and -C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl is R 14b and optionally substituted with one, two, or three groups selected from R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is hydrogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 8 is halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 8 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is R 14b C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 8 is R 14b C substituted by one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R8 is unsubstituted C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 8 HA-OR 20 where R 20 are independently hydrogen and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is -C(O)N(R 20 )(R 21 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 8 is -C(O)NH2.

[0257] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 13 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 14a, R 14b and R 14c are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23, -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 20 , -SR 20 , -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , -CH2S(O)2N(R 20 )(R 21 ), with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 20 , -SR 20, -SF5, -N(R 20 )(R 21 ), -C(O)OR 20 , -OC(O)N(R 20 )(R 21 ), -N(R 22 )C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)OR 23 , -N(R 22 )S(O)2R 23 , -C(O)R 23 , -S(O)R 23 , -OC(O)R 23 , -C(O)N(R 20 )(R 21 ), -C(O)C(O)N(R 20 )(R 21 ), -N(R 22 )C(O)R 23 , -S(O)2R 23 , -S(O)2N(R 20 )(R 21 )-, -N=S(=O)(R 23 )2, -S(=O)(=NH)N(R 20 )(R 21 ), -S(=O)(=NH)C(R 20 )(R 21 ), -S(=O)(=NR 23 )R 23 , -CH2C(O)N(R 20 )(R 21 ), -CHN(R 22 )C(O)R 23 , -CH2S(O)2R 23 , and -CH2S(O)2N(R 20 )(R 21 ) optionally substituted with one, two, or three groups independently selected from 15a combine to form C 3-6 Cycloalkyl or C 2-9 Forms a heterocycloalkyl, provided that C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl is substituted with halogen, oxo, C 1-6 Alkyl, C 1-6Haloalkyl, and C 1-6 Optionally substituted with 1, 2, or 3 groups independently selected from alkoxy.

[0258] In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 2 is a bond. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, L 2 is R 14a C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L is alkylene. 2 is unsubstituted C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L is alkylene. 2 is -CH2-.

[0259] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 13 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R15b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, with the proviso that C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is R 15b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 6-10 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 13 is R 15b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is one R 15b In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15bC optionally substituted with one, two or three groups selected from 1-9 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C substituted by one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C substituted by one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is one R 15b C substituted by a group 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is one R 15b C substituted by a group 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 3-10 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 13 is R 15b C optionally substituted with one, two or three groups selected from 2-9 It is heterocycloalkyl.

[0260] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15bare each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 20 where R 20 is C 1-6 Alkyl and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15b and R are each halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15b are C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15b and R are each -CF. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15b are C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15b and R are each —CH. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15b are -OR 20 where R 20 is C 1-6 Alkyl and C 1-6 haloalkyl.

[0261] In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 1 is R 14a C optionally substituted with one, two or three groups selected from 1-6In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L is alkylene. 1 is unsubstituted C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L is alkylene. 1 In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, L 1 is a bond.

[0262] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and imidazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyrazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-9 Heteroaryl, provided that C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, and pyrazolyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is unsubstituted pyridyl. In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12ais unsubstituted pyrimidinyl. In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is unsubstituted pyrazolyl. In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 2-9 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is unsubstituted C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is R 15a C optionally substituted with one, two or three groups selected from 2-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 12a is unsubstituted C 2-6 It is alkyl.

[0263] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15aare each independently a halogen, -CN, or C 1-6 Alkyl, and C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each halogen. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15a are C 1-6 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a and R are each -CF. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15a are C 1-6 In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15a and R are each —CH. In some embodiments of the compounds of Formula (II), (IIa), or (IIb), or pharmaceutically acceptable salts or solvates thereof, R 15a and R are each —CN. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -N(R 20 )(R 21 In some embodiments of the compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R 15a are -NH2, respectively.

[0264] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0265] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is selected from the following:

[0266] [ka]

[0267] [ka]

[0268] [ka]

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same activity are also included in the scope of the present disclosure.In addition, the compounds described herein can exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.Solvated forms of the compounds described herein are also considered to be disclosed herein.

[0277] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that may be administered to an individual without destroying the biological activity or properties of the compound and that is relatively non-toxic, i.e., without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0278] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that comprises the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, "Handbook of Pharmaceutical Salts: Properties, Selection and Use," Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than non-ionic species, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be equilibrated with a neutral form, thereby regulating their passage across biological membranes.

[0279] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compounds described herein (i.e., in free base form) are basic and are reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D). ; glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0280] In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salts.

[0281] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt."

[0282] In some embodiments, the compounds described herein are acidic and react with bases. In such cases, the acidic protons of the compounds described herein are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine and lysine. Inorganic bases that can be used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0283] It should be understood that a reference to a pharmaceutically acceptable salt also includes solvent addition forms. In some embodiments, solvates contain a stoichiometric or non-stoichiometric amount of a solvent and are formed during the process of isolating or purifying a compound using a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be easily prepared or formed by the processes described herein. Furthermore, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0284] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds that have the same type of activity.

[0285] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Introducing appropriate substituents into the organic radicals can reduce, minimize, or eliminate these metabolic pathways. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, for example, halogen, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0286] In other embodiments, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0287] The compounds described herein include isotopically labeled compounds, which are identical to the compounds described in the various formulas and structures disclosed herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, e.g. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium provides several therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life and reduced dosage. In some embodiments, one or more hydrogen atoms of the compounds described herein are replaced by deuterium.

[0288] In some embodiments, the compounds described herein contain one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds described herein include all diastereomers, enantiomers, atropisomers, epimers, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entegegen (E), and zusanmen (Z) isomers, and the appropriate mixtures thereof.

[0289] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization or chromatography, or a combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0290] Compound synthesis The compounds described herein are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0291] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, pharmacology, etc. are employed.

[0292] The compounds are described, for example, in March's Advanced Organic Chemistry, 6 thThe starting materials are prepared using standard organic chemistry techniques, such as those described in the "Synthetic Transformations" series, Vol. 1, No. 1, pp. 111-115, 1997. Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein can be employed, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions. The starting materials are commercially available or readily prepared.

[0198] Suitable reference and technical books detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to literature describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable reference and technical books that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to literature describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC「Comprehensive Organic Transformations: A Guide to Functional Group Preparations」 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. 「Advanced Organic Chemistry: Reactions, Mechanisms, and Structure」4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) 「Modern Carbonyl Chemistry」(2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. 「Patai's 1992 Guide to the Chemistry of Functional Groups」 (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. 「Organic Chemistry」 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C. 「Intermediate Organic Chemistry」 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 「Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia」 (1999) John Wiley & Sons, ISBN:3-527-29645-X, 8 volumes in total; 「Organic Reactions」 (1942-2000) John Wiley & Sons, over 55 volumes in total; 「Chemistry of Functional Groups」 John Wiley & Sons, 73 volumes in total can be cited.

[0293] In some embodiments, the compounds are prepared as described in the Examples.

[0294] method In some embodiments, described herein is a method of inhibiting the Hippo pathway in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0295] In some embodiments, described herein are methods of inhibiting YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of inhibiting YAP-TEAD and TAZ-TEAD interactions in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0296] In some embodiments, described herein is a method of inhibiting YAP-TEAD in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of inhibiting TAZ-TEAD interaction in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0297] In some embodiments, described herein is a method of treating a disease or condition affected by inhibition of YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a disease or condition affected by inhibition of YAP-TEAD and TAZ-TEAD interactions in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a disease or condition affected by inhibition of YAP-TEAD in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, described herein is a method of treating a disease or condition affected by inhibition of TAZ-TEAD interaction in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0298] In some embodiments, described herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Ix), (Iy), (Iw), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon cancer, and pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is medulloblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer.

[0299] In some embodiments, described herein are methods of treating hyperproliferative diseases and disorders in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0300] In some embodiments, described herein is a method of treating cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0301] In some embodiments, described herein are methods of treating fibrosis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating fibrosis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein the fibrosis is liver fibrosis, kidney fibrosis, or lung fibrosis.

[0302] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the selected route of administration. Overviews of the pharmaceutical compositions described herein are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0303] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

[0304] The administration of the compounds and compositions described herein can be affected by any method that allows the compound to be delivered to the site of action.These methods include, but are not limited to, enteral route (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral route (including injection or infusion, intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (including epidermal, transdermal, enema, eye drops, ear drops, nasal, vaginal) administration, and the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0305] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0306] Orally usable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, inert diluent, or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored and formulated to provide sustained or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee cores are coated with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0307] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions can be provided in unit dosage or multi-dose containers, e.g., sealed ampoules or vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, or tablets of the type described above.

[0308] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the target recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0309] Pharmaceutical compositions can also be formulated into depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, as poorly soluble salts.

[0310] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, patches, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose, acacia, tragacanth, or the like.

[0311] The pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0312] The pharmaceutical compositions can be administered locally, i.e., by non-systemic administration. This includes applying the compounds of the present invention to the epidermis or buccal cavity, and injecting such compounds into the ear, eye, or nose, without the compounds significantly entering the bloodstream. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0313] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, and pastes, as well as drops suitable for administration to the eye, ear, or nose. For topical administration, the active ingredient may be present in an amount of 0.001% to 10% w / w, for example 1% to 2% w / w, based on the weight of the formulation.

[0314] Pharmaceutical compositions for administration by inhalation are conveniently delivered by insufflation, nebulizer pressurized packs, or other convenient means of delivering an aerosol spray. Pressurized packs may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered with the aid of an inhaler or insufflator.

[0315] In some embodiments, the compounds described herein are formulated to achieve the compound's delivery to specific regions of the gastrointestinal tract.For example, the compounds described herein are formulated for oral delivery using bioadhesive polymers, pH-sensitive coatings, time-dependent biodegradable polymers, microflora-activating systems, etc., to effectively deliver the compound to specific regions of the gastrointestinal tract.

[0316] In some embodiments, the compounds described herein are formulated to provide controlled release of the compound. Controlled release refers to releasing the compound described herein from a dosage form incorporating the compound described herein according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, sustained release, pulsed release, delayed release profiles, etc. In contrast to immediate release compositions, controlled release compositions allow for the delivery of a drug to a subject over an extended period of time according to a predetermined profile. Such release rates can provide a therapeutically effective level of the drug for an extended period of time while minimizing side effects, compared to conventional immediate release dosage forms, thereby extending the duration of the pharmacological response. Such extended response provides many advantages that cannot be obtained with comparable short-acting immediate release formulations.

[0317] Approaches for delivering intact therapeutic compounds to specific regions of the gastrointestinal tract (such as the colon) include:

[0318] (i) Polymer coating: By coating drug molecules with a suitable polymer that degrades only in the colon, the intact molecule can be delivered to the colon without being absorbed in the upper part of the intestine.

[0319] (ii) Coating with pH-sensitive polymers: The majority of intestinal and colon-targeted delivery systems are based on coating tablets or pellets, which are then filled into conventional hard gelatin capsules. The most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

[0320] (iii) coating with biodegradable polymers; (iv) embedding into a matrix; (v) embedding in biodegradable matrices and hydrogels; (vi) embedding in a pH-sensitive matrix; (vii) timed release systems; (viii) redox-sensitive polymers; (ix) bioadhesive systems; (x) coating with particulates; (xi) osmotically controlled drug delivery; Another approach to colon-targeted drug delivery and controlled-release systems involves embedding drugs in polymer matrices to entrap and release the drug in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-based systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure drug release in the colon.

[0321] Additional pharmaceutical approaches are known for targeted delivery of therapeutic agents to specific regions of the gastrointestinal tract. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Sci. 2003 Jan-Apr;6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems. Crit Rev Ther Drug Carrier Syst. 2007;24(2):147-202. Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan;3(1):111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug; 16(4): 731-741.

[0322] It should be understood that the compounds and compositions described herein may include, in addition to the ingredients specifically mentioned above, other agents conventional in the art for the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0323] Administration and Treatment Regimen In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from inhibition of the YAP-TEAD and / or TAZ-TEAD interaction. A method of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0324] In certain embodiments, compositions containing the compounds described herein are administered for prophylaxis and / or treatment. In certain therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this application will vary depending on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to medication, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0325] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or prophylactically effective dose." For this application, the precise amount will vary depending on the patient's health, weight, and other factors. When used in a patient, the amount effective for this application will vary depending on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health, response to the medication, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated but is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0326] In certain embodiments, if the patient's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including throughout the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the discretion of the physician.

[0327] In certain embodiments, if a patient's condition improves, the administered drug dosage is temporarily reduced or temporarily suspended for a predetermined period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the drug holiday is, for example, 10% to 100%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0328] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, if symptoms recur, the patient will require intermittent treatment on a long-term basis.

[0329] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0330] In general, however, dosages used in adult human treatment are typically in the range of 0.01 mg to 5000 mg per day. In one aspect, dosages used in adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0331] In one embodiment, a suitable daily dosage of a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active ingredient in a dosage form will be lower or higher than the ranges set forth herein, depending on many variables related to the particular treatment regime. In various embodiments, the daily dosage and unit dosage amount will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0332] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals and are evaluated using LDs. 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dosage ranges and / or therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is sufficient to achieve an ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0333] In any of the foregoing aspects, an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof according to further embodiments is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered topically to a mammal; and / or (f) administered non-systemically or topically to a mammal.

[0334] In any of the foregoing aspects, further embodiments comprising a single administration of an effective amount of the compound include further embodiments in which (i) the compound is administered once daily; or (ii) the compound is administered multiple times at daily intervals to the mammal.

[0335] In any of the foregoing aspects, further embodiments involving multiple administrations of an effective amount of the compound include: (i) the compound is administered continuously or intermittently in a single dose; (ii) the time between multiple doses is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and administration of the compound is resumed after the drug holiday period. In one embodiment, the length of the drug holiday is between 2 days and 1 year.

[0336] In certain embodiments, it is suitable to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0337] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when used in combination with other therapeutic agents, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is enhanced by administering one of the compounds described herein with other agents (including treatment regimens) that also have therapeutic benefit.

[0338] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0339] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be an additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0340] In certain embodiments, different therapeutically effective dosages of the compounds described herein are utilized in formulating pharmaceutical compositions and / or treatment regimens when the compounds described herein are administered in combination with one or more additional agents, such as additional therapeutically effective drugs or adjuvants. The therapeutically effective dosages of drugs and other agents used in combination treatment regimens are optionally determined by the same means as those described herein for the active ingredients themselves. Additionally, the prophylactic / therapeutic methods described herein include the use of metronomic dosing, i.e., administering more frequently and at lower doses to minimize toxic side effects. In some embodiments, combination treatment regimens include treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated before, during, or after treatment with a second agent described herein and continued until any time during or after treatment with the second agent has ended. Also included are treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination therapy also includes scheduled treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0341] It should be understood that the dosage regimen for treating, preventing or ameliorating the condition for which relief is sought will vary depending on various factors (for example, the disease, disorder or condition suffered by the subject; the age, weight, sex, diet and condition of the subject).Therefore, in some embodiments, the dosage regimen actually adopted will vary, and in some embodiments, will deviate from the dosage regimen provided herein.

[0342] In the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of combination drug employed, the particular drug employed, the disease or condition being treated, etc. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0343] In combination therapy, the therapeutic agents (one of which is one of the compounds described herein) can be administered in any order or simultaneously. Simultaneous administration can, for example, mean that the therapeutic agents are provided in a single, unified form or in multiple forms (e.g., as a single tablet or as two separate tablets).

[0344] The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to a subject with a propensity to develop a condition or disease to prevent the onset of the disease or condition. In other embodiments, the compounds and compositions are administered to a subject as soon as possible after the onset of symptoms. In specific embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, for the duration necessary to treat the disease. In some embodiments, the duration of treatment may vary, and the duration of treatment may be tailored to the specific needs of each subject. For example, in specific embodiments, the compounds described herein or formulations containing the compounds are administered for at least two weeks, from about one month to about five years. [Example]

[0345] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0346] As used in the preceding and throughout the description of the invention, the following abbreviations, unless otherwise specified, shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH acetic acid Ac Acetyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Bn Benzyl BOC or Boc tert-butylcarbamate t-Bu tert-butyl Cy Cyclohexyl DBA or dba dibenzylidene acetone DCE Dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIPEA or DIEA Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMSO dimethyl sulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq equivalent Et Ethyl Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HMPA Hexamethylphosphoramide HPLC High Performance Liquid Chromatography KHMDS Potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide LAH Lithium aluminum hydride LCMS Liquid Chromatography / Mass Spectrometry Me methyl MeOH Methanol MS mass spectrometry Ms. Mesir NBS N-Bromosuccinimide NMM N-methylmorpholine NMP N-methylpyrrolidin-2-one NMR nuclear magnetic resonance PCC Pyridinium Chlorochromate Ph phenyl PPTS Pyridinium p-toluenesulfonate iPr / i-Pr iso-propyl TBS tert-butyldimethylsilyl RP-HPLC Reversed-phase high-pressure liquid chromatography TFA trifluoroacetic acid TEA Triethylamine THF tetrahydrofuran TLC thin layer chromatography Chemical Examples

[0347] [ka]

[0348] Step 1: To a solution of 7-fluoro-1H-indazole (3 g, 22.04 mmol) and dicyclohexyl(methyl)amine (5.17 g, 26.45 mmol) in THF (50 mL) was added 1-chloro-5,5-dimethyl-2-oxa-5-silahexane (4.41 g, 26.45 mmol) at 25 °C. The yellow solution was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (50 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi flash (6% EtOAc in heptane) to give compound A8-1 (5.8 g, 21.77 mmol, 98.81%) as a yellow oil. LC-MS (ESI) m / z: 267.1 [M+H] + . Step 2: To a mixture of compound A8-1 (5.8 g, 21.77 mmol) and 4-iodo-2-methoxypyridine (5.37 g, 22.86 mmol) in water (100 mL), Pd(PPh3)4 (2.52 g, 2.18 mmol), 1,10-phenanthroline (0.78 g, 4.36 mmol), and silver carbonate (9.01 g, 32.66 mmol) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 18 h. The mixture was cooled to room temperature and diluted with water (60 mL) and EtOAc (60 mL). The mixture was filtered, and the filtrate was extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (6% EtOAc in heptane) to give compound A8-2 (6.5 g, 17.4 mmol, 79.95%) as a colorless oil. LC-MS (ESI) m / z: 374.1 [M+H] + . Step 3: To a solution of compound A8-2 (5 g, 13.39 mmol) in MeOH (50 mL), HCl / dioxane (20 mL, 4.0 M) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure. After adjusting the pH of the residue to 8 with saturated aqueous sodium bicarbonate, the mixture was extracted with EtOAc (100 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound A8-3 (3.2 g, 13.05 mmol, 97.46%) as a white solid. LC-MS (ESI) m / z: 244.1 [M+H] + . Step 4: To a solution of compound A8-3 (800 mg, 3.29 mmol) in DMF (10 mL) was added 1-iodo-4-(trifluoromethyl)benzene (890 mg, 3.45 mmol), CuI (375 mg, 1.97 mmol), N,N'-dimethylethylenediamine (347 mg, 3.95 mmol), and K3PO4 (1.39 g, 6.58 mmol). The mixture was stirred at 130 °C under a N2 atmosphere for 14 h. The mixture was diluted with water (60 mL) and EtOAc (60 mL). The mixture was filtered, and the filtrate was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (16% EtOAc in heptane) to give compound A8-4 (950 mg, 2.45 mmol, 74.57%) as a white solid. LC-MS (ESI) m / z: 388.1 [M+H] + .

[0349] Step 5: To a solution of compound A8-4 (950 mg, 2.45 mmol) in DMF (8 mL), p-toluenesulfonic acid monohydrate (2.33 g, 12.25 mmol) and LiCl (519 mg, 12.25 mmol) were added. The mixture was stirred at 120 °C for 1 h. The mixture was cooled to room temperature, and water (60 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the solid was washed twice with water. The solid was dried to give compound A8 (900 mg, 2.41 mmol, 98.30%) as a white solid. LC-MS (ESI) m / z: 374.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.04 - 7.95 (m, 5H), 7.55 (d, J = 6.8 Hz, 1H), 7.52 - 7.46 (m,1H), 7.45 - 7.39 (m, 1H), 6.96 (d, J = 1.2 Hz, 1H), 6.81 (dd, J = 6.8, 1.7 Hz, 1H). The intermediates listed below were synthesized according to the procedure in A8.

[0350] [Table 1-1]

[0351] [Table 1-2]

[0352] [Table 1-3]

[0353] [Table 1-4]

[0354] [Table 1-5]

[0355] [ka]

[0356] Step 1. To a solution of compound A1-3 (100 mg, 0.381 mmol, prepared by the method described in Scheme 1) in DMF (4 mL) was added NaH (46 mg, 1.14 mmol, 60% in mineral oil) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (109 mg, 0.457 mmol), and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (15 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-25% EtOAc / PE) to give compound AA1-1 (85 mg, 58.1%) as a colorless oil. LC-MS (ESI) m / z: 385.1 [M+H] + . Step 2. To a solution of compound AA1-1 (85 mg, 0.221 mmol) in DMF (3 mL), LiCl (47 mg, 1.11 mmol) and p-toluenesulfonic acid monohydrate (148 mg, 0.781 mmol) were added, and the mixture was stirred at 120 °C for 1 h. The mixture was diluted with water (15 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound AA1 (80 mg, 97.7%) as a white solid. LC-MS (ESI) m / z: 371.1 [M+H] + .

[0357] [ka]

[0358] Step 1: To a solution of 2-chloropyrimidine-4-carboxylic acid (10 g, 63.08 mmol) and TEA (7.02 g, 69.38 mmol) in THF (100 mL) was slowly added isobutyl chloroformate (9.48 g, 69.38 mmol). The mixture was stirred at 25 °C for 1 h. The resulting precipitate was filtered, and to the resulting clear solution was slowly added a solution of NaBH (4.77 g, 126.15 mmol) in water (20 mL). The reaction mixture was stirred at 25 °C for 30 min. Then, water (100 mL) was added to the mixture, which was then extracted with EtOAc (40 mL*3). The combined organic fractions were washed with brine (60 mL) and dried over anhydrous NaSO. After evaporation of the solvent under reduced pressure, the residue was purified by Combiflash (40% EtOAc / heptane) to give compound A25-1 (2 g, 13.86 mmol, 21.93%) as a white solid. LC-MS: m / z=144.9 [M+H] + . Step 2: To a solution of compound A25-1 (1.8 g, 12.452 mmol) and PPh3 (3.27 g, 12.45 mmol) in DCM (40 mL) was added NCS (1.66 g, 12.45 mmol) slowly at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 10% EtOAc / heptane) to give compound A25-2 (1.8 g, 11.04 mmol, 88.69%) as a colorless oil. LC-MS: m / z=163.0 [M+H] + . Step 3: To a solution of compound A8 (500 mg, 1.34 mmol) in DMF (10 mL) was added compound A25-2 (327 mg, 2.00 mmol) and K2CO3 (370 mg, 2.68 mmol). The mixture was stirred at 40 °C for 15 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 4% MeOH in DCM) to give compound A25 (470 mg, 0.94 mmol, 70.20%) as a white solid. LC-MS: m / z=500.1 [M+H] + . The intermediates listed below were synthesized according to the procedure of A25:

[0359] [Table 2]

[0360] [ka]

[0361] Step 1: To a solution of B13-1 (1 g, 4.11 mmol), DMAP (0.05 g, 0.41 mmol), and EtN (0.86 mL, 6.17 mmol) in THF (20 mL) was added BocO (1.06 mL, 4.94 mmol). The yellow solution was stirred at 25 °C for 12 h. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-20% EtOAc / petroleum ether) to give B13-2 (1.35 g, 3.93 mmol, 95.62%) as a yellow oil. LC-MS (ESI) m / z: 345.1 [M+H] + Step 2: To a suspension of B13-2 (100 mg, 0.29 mmol), (2-methoxypyridin-4-yl)boranediol (66.66 mg, 0.44 mmol), and KPO (123.35 mg, 0.58 mmol) in dioxane (2 mL) and HO (0.2 mL), Pd(dppf)Cl.CHCl (23.73 mg, 0.03 mmol) was added. The red suspension was stirred under nitrogen protection at 100 °C for 12 h. TLC indicated completion of the reaction. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-50% EtOAc / petroleum ether) to give B13-3 (45 mg, 0.20 mmol, 68.65%) as a yellow solid. LC-MS (ESI) m / z: 226.1 [M+H] + Step 3: A suspension of B13-3 (45 mg, 0.20 mmol), 4-iodo-1-(trifluoromethyl)benzene (0.04 mL, 0.30 mmol), CuI (22.83 mg, 0.12 mmol), N,N'-dimethylethylenediamine (21.13 mg, 0.240 mmol), and KPO (84.81 mg, 0.40 mmol) in DMF (2 mL) was stirred at 130 °C for 12 h under nitrogen protection. TLC showed the reaction was complete. The mixture was extracted with EtOAc (15 mL*3) and water (20 mL), and the combined organic layers were washed with brine (20 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-7% EtOAc / petroleum ether) to give B13-4 (60 mg, 0.162 mmol, 81.31%) as a yellow solid. LC-MS (ESI) m / z: 370.1 [M+H] + Step 4: B13 was synthesized according to Step 5 of A8. LC-MS (ESI) m / z: 356.1 [M+H] +

[0362] [ka]

[0363] Step 1. To a solution of imidazo[1,5-a]pyridine (236 mg, 1.998 mmol) and 4-iodo-1-(trifluoromethyl)benzene (543 mg, 2.00 mmol) in toluene (2.5 mL), Pd(OAc) (22.4 mg, 0.100 mmol), PPh (52.4 mg, 0.20 mmol), and t-BuNOAc (1.20 g, 3.99 mmol) were added, and the mixture was stirred at 100 °C for 16 h under a N atmosphere. The mixture was diluted with water (30 mL), and the mixture was extracted with EtOAc (20 mL × 4). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-20% EtOAc / PE) to give compound B15-1 (300 mg, 57.3%) as a yellow solid. LC-MS (ESI) m / z: 263.1 [M+H] + . Step 2. To a solution of compound B15-1 (250 mg, 0.953 mmol) in DMA (7.5 mL) was added Pd(phen)(PF) (30 mg, 0.040 mmol), 4-iodo-2-methoxypyridine (291 mg, 1.24 mmol), and CsCO (621 mg, 1.91 mmol), and the mixture was stirred at 150 °C for 15 h in a sealed tube under a N atmosphere. The mixture was diluted with water (50 mL), and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-20% EtOAc / PE) to give compound B15-2 (300 mg, 85.20%) as a brown solid. LC-MS (ESI) m / z: 370.1 [M+H] + . Step 3. To a solution of compound B15-2 (100 mg, 0.271 mmol) in DMF (3 mL) was added LiCl (57.4 mg, 1.35 mmol) and p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol), and the mixture was stirred at 130 °C for 1 h under a N atmosphere. The mixture was diluted with water (20 mL), and the mixture was extracted with EtOAc (30 mL × 3). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give intermediate B15 (80 mg, 83.2%) as a yellow solid. LC-MS (ESI) m / z: 356.1 [M+H] + .

[0364] [ka]

[0365] Step 1: To a solution of 5-fluoro-1H-indazole (545 mg, 4.00 mmol) in DMF (10 mL) and water (0.5 mL) was added KOH (1.31 g, 6.00 mmol) followed by I (1.52 g, 6.00 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction was quenched with aqueous NaSO and 3 N aqueous hydrochloric acid and diluted with water. The mixture was extracted twice with MTBE. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give compound B28-1 (1.05 g, 100%) as a yellow solid. LC-MS (ESI) m / z: 262.7 [M+H] + . Step 2: To a mixture of compound B28-1 (262 mg, 1.00 mmol) in dioxane (4 mL) and water (1 mL), 2-methoxypyridine-4-boronic acid (306 mg, 2.00 mmol), SPhos-Pd-G3 (23 mg, 0.03 mmol), SPhos (12 mg, 0.03 mmol), and K3PO4.3HO (533 mg, 2.00 mmol) were added at 20 °C. The mixture was stirred at 100 °C for 16 h under nitrogen protection. The reaction mixture was diluted with water and 3N aqueous HCl (1.5 mL) and extracted twice with MTBE. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was absorbed onto silica gel and purified by CombiFlash (26% EtOAc in heptane) to give compound B28-2 (119 mg, 49%) as a white solid. LC-MS (ESI) m / z: 243.9 [M+H] + . Step 3: To a solution of compound B28-2 (119 mg, 0.489 mmol) in dry DMF (2.5 mL) was added CuI (55.9 mg, 0.294 mmol) and DMEDA (52 mg, 63 μL, 0.587 mmol), followed by KPO (208 mg, 0.978 mmol). The mixture was heated at 130 °C for 16 h under nitrogen protection. The reaction was diluted with a large amount of HO and aqueous NH (6 mL) and stirred for 20 min. The mixture was filtered, and the filter cake was washed with HO. The filter cake was dried at 60 °C to give compound B28-3 (169 mg, 89%) as a pale yellow solid. LC-MS (ESI) m / z: 387.9 [M+H] + . Step 4: To a solution of compound B28-3 (169 mg, 0.436 mmol) in DMF (4 mL) was added LiCl (93 mg, 2.18 mmol) and TsOH.HO (415 mg, 2.18 mmol). The mixture was stirred at 120 °C for 12 h. The solution was diluted with water and stirred for 20 min. The mixture was filtered, and the filter cake was washed with water. The solid was dried at 50 °C to give intermediate B28 (150 mg, 92%) as a pale yellow solid. LC-MS (ESI) m / z: 373.9 [M+H] + . The intermediates listed below were synthesized according to the procedure of B28:

[0366] [Table 3]

[0367] [ka]

[0368] Step 1: To a solution of 4-(trifluoromethyl)phenyl isocyanate (1.12 g, 6.00 mmol) in DCE (30 mL) was added 2-iodoaniline (1.31 g, 6.00 mmol) at 20 °C. The mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with DCM. The solid was collected to give compound B30-1 (2.15 g, 88%) as a white solid. LC-MS (ESI) m / z: 356.1 [M+H] + . Step 2: To a solution of B30-1 (2.38 g, 5.85 mmol) in dry DMSO (20 mL) was added CuI (223 mg, 1.17 mmol) and DBU (1.78 g, 11.7 mmol) at 20 °C. The mixture was heated at 120 °C under nitrogen by microwave irradiation for 0.5 h. The mixture was cooled to room temperature, poured into HO and 3N aqueous HCl, and stirred for 5 min. The mixture was filtered, and the filter cake was washed with water. The solid was dried at 60 °C to give compound B30-2 (1.36 g, 83%) as a pale yellow solid. LC-MS (ESI) m / z: 356.1 [M+H] + . Step 3: To a mixture of B30-2 (584 mg, 2.10 mmol), 2-methoxypyridine-4-boronic acid (385 mg, 2.52 mmol), and copper(II) acetate (499 mg, 2.73 mmol) in DCM (14 mL) was added TEA (638 mg, 6.30 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was diluted with aqueous NH and water and extracted twice with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by CombiFlash (20% EtOAc in heptane) to give compound B30-3 (491 mg, 60%) as a colorless solid. LC-MS (ESI) m / z: 356.1 [M+H] + . Step 4: To a solution of B30-3 (453 mg, 1.18 mmol) in DMF (10 mL) was added LiCl (150 mg, 3.53 mmol) and TsOH.HO (671 mg, 3.53 mmol). The mixture was stirred at 20 °C for 17 h. The solution was diluted with water and stirred for 20 min. The mixture was filtered, and the filter cake was washed with water. The solid was dried at 60 °C to give intermediate B30 (436 mg, 100%) as a white solid. LC-MS (ESI) m / z: 371.9 [M+H] +

[0369] [ka]

[0370] Step 1: To a solution of 2-aminomethylpyrimidine (546 mg, 5.00 mmol) in THF (15 mL) and water (15 mL) was added Na2CO3 (1.06 g, 10.0 mmol) followed by 4-(trifluoromethyl)benzoyl chloride (1.04 g, 5.00 mmol) at 20 °C. The mixture was stirred for 1 h. The mixture was diluted with water and extracted twice with MTBE. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound B16-1 (1.34 g, 95%) as a pale yellow solid. LC-MS (ESI) m / z: 281.9 [M+H] + Step 2: To a solution of compound B16-1 (703 mg, 2.50 mmol) in DCE (15 mL) was added POCl (4.66 mL, 50 mmol). The mixture was heated at 90 °C for 16 h. The solution was cooled to room temperature and slowly poured into water, then neutralized to pH = 8 with solid NaCO. The mixture was extracted twice with EA. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by Combiflash (60% EtOAc in heptane) to give compound B16-2 (419 mg, 64%) as a yellow solid. LC-MS (ESI) m / z: 263.9 [M+H] + Step 3: To a solution of compound B16-2 (360 mg, 1.37 mmol) in MeCN (10 mL) was added NIS (461.6 mg, 2.05 mmol). The solution was stirred at 20 °C for 1 h. The reaction was quenched with aqueous NaSO and diluted with water. The mixture was extracted twice with EA. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residual oil was absorbed onto silica gel and purified by Combiflash (30% EtOAc in heptane) to give compound B16-3 (43 mg, 83%) as a yellow solid. LC-MS (ESI) m / z: 389.9 [M+H] + Step 4: B16 was synthesized according to Step 4 of B30. LC-MS (ESI) m / z: 357.1 [M+H] + The intermediates listed below were synthesized according to the procedure of B16:

[0371] [Table 4]

[0372] [ka]

[0373] Step 1: To a solution of 3-iodo-1H-pyrazolo[3,4-b]pyridine (10 g, 40.8 mmol) in DMF (100 mL) was added NaH (3.27 g, 81.6 mmol) under a N atmosphere at 0 °C. 2-(Trimethylsilyl)ethoxymethyl chloride (7.48 g, 44.9 mmol) was added to the mixture, and the mixture was stirred at 25 °C overnight. The mixture was diluted with water (300 mL). The mixture was extracted with EtOAc (200 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 10% EA in heptane) to give compound B31-1 (12.0 g, 78.4%) as a white solid. LC-MS (ESI) m / z: 376.0 [M+H] + . Step 2: To a solution of compound B31-1 (7.0 g, 18.7 mmol) in dioxane (75 mL), (2-methoxypyridin-4-yl)boranediol (3.42 g, 22.4 mmol), K2CO3 (5.16 g, 37.3 mmol), Pd(dppf)Cl2-CHCl2 (1.52 g, 1.87 mmol), and water (15 mL) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 16 h. The mixture was filtered and washed with EA. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (12% EA in heptane) to give compound B31-2 (6.5 g, 97.8%) as a yellow oil. LC-MS (ESI) m / z: 357.2 [M+H] + . Step 3: To a solution of compound B31-2 (490 mg, 1.37 mmol) in DMF (10 mL), LiCl (291 mg, 6.87 mmol) and p-toluenesulfonic acid (1.18 g, 6.87 mmol) were added, and the mixture was stirred at 120 °C for 2 h. The mixture was diluted with water (30 mL). Then, the mixture was extracted with EtOAc (40 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-10% MeOH / DCM) to give compound B31-3 (380 mg, 80.7%) as a white solid. LC-MS (ESI) m / z: 343.2 [M+H] + Step 4: To a solution of compound B31-3 (350 mg, 1.02 mmol) and 4-(chloromethyl)-2-{[(4-methoxyphenyl)methyl](methyl)amino}pyrimidine (284 mg, 1.02 mmol) in DMF (10 mL), K2CO3 (282 mg, 2.04 mmol) was added, and the mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (40 mL). The mixture was extracted with EtOAc (40 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-100% EtOAc / PE) to give compound B31-4 (520 mg, 87.2%) as a colorless oil. LC-MS (ESI) m / z: 584.3 [M+H] + Step 5: A solution of compound B31-4 (500 mg, 0.857 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 8 with saturated aqueous NaHCO3. The mixture was then extracted with DCM (30 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-10% MeOH / DCM) to give compound B31 (340 mg, 82.1%) as a yellow oil. LC-MS (ESI) m / z: 484.2 [M+H] + .

[0374] [ka]

[0375] Step 1: To a solution of compound A8-2 (2.30 g, 6.16 mmol) in DMF (50 mL), LiCl (1.31 g, 30.8 mmol) and p-toluenesulfonic acid (5.30 g, 30.8 mmol) were added, and the reaction mixture was stirred at 120 °C for 2 h. The mixture was diluted with water (100 mL). The resulting suspension was filtered, and the filter cake was dried to give compound B32-1 (1.10 g, 77.9%) as a white solid. LC-MS (ESI) m / z: 230.1 [M+H] + . Step 2: To a solution of compound B32-1 (800 mg, 3.49 mmol) in DMF (90 mL), K2CO3 (965 mg, 6.98 mmol) and 1-chloro-5,5-dimethyl-2-oxa-5-silahexane (582 mg, 3.49 mmol) were added, and the mixture was stirred at 40 °C for 1 h. The mixture was diluted with water (160 mL). The mixture was extracted with EtOAc (100 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-10% MeOH / DCM) to give compound B32-2 (900 mg, 71.7%) as a white solid. LC-MS (ESI) m / z: 360.1 [M+H] + . Step 3: To a suspension of compound B32-2 (900 mg, 2.50 mmol) in DMF (20 mL), 4-(chloromethyl)-2-{[(4-methoxyphenyl)methyl](methyl)amino}pyrimidine (765 mg, 2.75 mmol) and K2CO3 (692 mg, 5.01 mmol) were added, and the mixture was stirred at 40 °C for 2 h. The mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (60 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-100% EtOAc / PE) to give compound B32-3 (1.20 g, 79.8%) as a yellow oil. LC-MS (ESI) m / z: 601.3 [M+H] + Step 4: To a solution of compound B32-3 (1.20 g, 2.00 mmol) in MeOH (20 mL) was added HCl / dioxane (20 mL) (4.0 M), and the mixture was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 8 with saturated aqueous NaHCO . The mixture was extracted with EtOAc (40 mL × 2). The combined layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL), and the resulting suspension was filtered to give compound B32 (710 mg, 75.6%) as a white solid. LC-MS (ESI) m / z: 471.2 [M+H] +

[0376] [ka]

[0377] Step 1: To a stirred solution of methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and TEA (0.8 mL, 5.80 mmol) in DMF (20 mL), cyclopropanamine (0.3 mL, 4.35 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction was poured into water and extracted with DCM. The organic layers were combined and dried over Na2SO4. The dried solution was filtered, and the filtrate was concentrated in vacuo to give a pale yellow solid, which was purified by flash chromatography (gradient elution, 0–80% EtOAc in hexanes) to give compound D1-1 (300 mg, 53.59%) as a yellow solid. LC-MS (ESI) m / z: 194.1 [M+H] + . Step 2: To a solution of compound D1-1 (200 mg, 1.04 mmol) in EtOH (4 mL), NaBH4 (78 mg, 2.07 mmol) was added, and the mixture was stirred at 20 °C for 12 h. MeOH (5 mL) was added, and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-5% MeOH / DCM) to give compound D1-2 (150 mg, 87.7%) as a colorless oil. LC-MS (ESI) m / z: 166.1 [M+H] + . Step 3: To a solution of compound D1-2 (120 mg, 0.726 mmol) in DCM (5 mL) was added PPh3 (229 mg, 0.872 mmol) and NCS (116 mg, 0.872 mmol) in portions at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was evaporated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-10% EtOAc / DCM) to give compound D1 (40 mg, 30.0%) as a colorless oil. LC-MS (ESI) m / z: 184.1 [M+H] + .

[0378] [ka]

[0379] Step 1: To a solution of ethyl 1H-pyrazole-3-carboxylate (1.0 g, 7.14 mmol) in DMF (20 mL), 1-iodo-4,4,5,5-tetramethyl-3-oxa-4-silahexane (2.45 g, 8.56 mmol) and CsCO (4.65 g, 14.3 mmol) were added, and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (40 mL). The mixture was extracted with PE / EtOAc (1 / 1, 50 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0–10% EtOAc / heptane) to give compound D2-1 (1.05 g, 49.30%) as a colorless oil. LC-MS (ESI) m / z: 299.2 [M+H] + . Step 2: To a solution of compound D2-1 (500 mg, 1.68 mmol) in DCM (5 mL) was added diisobutylaluminum hydride (10.1 mL, 10.1 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h and at 20 °C for 0.5 h. The reaction was quenched with aqueous sodium potassium tartrate (5 mL, 2.0 M) and stirred at 20 °C for 30 min. The mixture was extracted with DCM (10 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-50% EtOAc / heptane) to give compound D2 (300 mg, 69.8%) as a colorless oil. LC-MS (ESI) m / z: 257.2 [M+H] + .

[0380] [ka]

[0381] Step 1: To a solution of 2-chloropyrimidine-4-carboxylic acid (2 g, 12.62 mmol) and EtN (1.93 mL, 13.88 mmol) in THF (40 mL) was slowly added isobutyl chloroformate (1.81 mL, 13.88 mmol). The reaction mixture was stirred at 25 °C for 1 h. The resulting precipitate was filtered, and to the resulting clear solution, a solution of NaBH (0.95 g, 25.23 mmol) in water (8 mL) was slowly added. The reaction mixture was stirred at 25 °C for 30 min. Water (100 mL) was then added, and the product was extracted with EtOAc (40 mL * 3). The combined organic fractions were washed with brine (60 mL) and dried over NaSO. After evaporation of the solvent under reduced pressure, the residue was purified by CombiFlash to give compound D3-1 (860 mg, 5.95 mmol, 47.16%) as a white solid. LC-MS (ESI) m / z: 144.9 [M+H] + . Step 2: To a solution of compound D3-1 (860 mg, 5.95 mmol) and 1H-imidazole (0.60 mL, 8.92 mmol) in DCM (20 mL) was added chlorodimethyl(2-methylprop-2-yl)silane (1.55 mL, 8.92 mmol) at 25 °C. The white suspension was stirred at 25 °C for 1 h. TLC showed the reaction was complete. The mixture was extracted with water (40 mL) and DCM (30 mL * 2), and the combined organic layer was washed with brine (30 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-10% EtOAc / petroleum ether) to give compound D3-2 (1.36 g, 5.256 mmol, 88.33%) as a yellow oil. LC-MS (ESI) m / z: 259.1 [M+H] + . Step 3: A suspension of compound D3-2 (500 mg, 1.93 mmol), Zn(CN)2 (136.10 mg, 1.16 mmol), and Pd(PPh3)4 (223.24 mg, 0.19 mmol) in anhydrous DMF (10 mL) was stirred at 100 °C for 16 h. TLC showed the reaction was complete. The mixture was filtered. The filtrate was diluted with EtOAc (20 mL*3) and water (60 mL). The combined organic layer was washed with brine (60 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-10% EtOAc / petroleum ether) to give compound D3-3 (300 mg, 1.20 mmol, 62.27%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ 8.82 (d, J = 5.2 Hz, 1H), 7.75 (dt, J = 5.2, 1.0 Hz, 1H), 4.81 (s, 2H), 0.96 (s, 9H), 0.14 (s, 6H). Step 4: To a solution of compound D3-3 (340 mg, 1.36 mmol) in MeOH (2 mL) was added HCl / dioxane (0.5 mL) at 25 °C. The yellow solution was stirred at 25 °C for 2 h. TLC showed the reaction was complete. The mixture was adjusted to pH = 8 with saturated NaHCO3 and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-30% EtOAc / petroleum ether) to give compound D3-4 (170 mg, 1.26 mmol, 92.28%) as a yellow oil. Step 5: To a solution of compound D3-4 (120 mg, 0.89 mmol) and PPh3 (349.38 mg, 1.33 mmol) in DCM (2 mL) was added NCS (177.87 mg, 1.33 mmol) at 25 °C. The yellow solution was stirred at 25 °C for 2 h. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-20% EtOAc / petroleum ether) to give compound D3-5 (130 mg, 0.85 mmol, 95.33%) as a yellow oil. LC-MS (ESI) m / z: 154.1 [M+H]+ . Step 6: To a solution of compound D3-5 (110 mg, 0.72 mmol) in MeOH (3 mL) was added BF3.OEt2 (3 mL) at 25 °C. The brown solution was stirred at 80 °C for 48 h. The starting material remained and the desired MS peak was detected. The mixture was adjusted to pH = 8 with saturated NaHCO3 and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-30% EtOAc / petroleum ether) to give compound D3 (35 mg, 0.19 mmol, 26.19%) as a yellow oil. LC-MS (ESI) m / z: 187.1 [M+H] + .

[0382] [ka]

[0383] Step 1: A suspension of 4-chloro-2-methylpyrimidine (100 mg, 0.78 mmol), NBS (207.67 mg, 1.17 mmol), and AIBN (63.87 mg, 0.39 mmol) in CCl4 (5 mL) was stirred at 80 °C for 3 days. The desired MS peak was detected, and the starting material remained. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-10% EtOAc / heptane) to give compound D4 (30 mg, 0.15 mmol, 18.59%) as a colorless oil. LC-MS (ESI) m / z: 209.1 [M+H] + .

[0384] [ka]

[0385] Step 1: To a solution of 1-methyl-6-oxo-1,2-diazine-3-carboxylic acid (200 mg, 1.30 mmol) and EtN (0.20 mL, 1.43 mmol) in THF (4 mL) was slowly added isobutyl chloroformate (0.19 mL, 1.43 mmol). The reaction mixture was stirred at 25 °C for 1 h. The resulting precipitate was filtered, and to the resulting clear solution was slowly added a solution of NaBH (98.18 mg, 2.60 mmol) in water (1 mL). The reaction mixture was stirred at 25 °C for 30 min. Water (15 mL) was then added, and the product was extracted with EtOAc (10 mL*3). The combined organic fractions were washed with brine (20 mL) and dried over NaSO. After evaporating the solvent under reduced pressure, the residue was purified by Combiflash to give compound D5-1 (140 mg, 1.00 mmol, 77.78%) as a white solid. LC-MS (ESI) m / z: 140.9 [M+H] + . Step 2: A solution of compound D5-1 (70 mg, 0.50 mmol), tetrabromomethane (331.30 mg, 1.00 mmol), and PPh3 (262.03 mg, 1.00 mmol) in DCM (2 mL) was stirred at 40 °C for 2 h. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-25% EtOAc / petroleum ether) to give compound D5 (60 mg, 0.30 mmol, 59.16%) as a white solid. LC-MS (ESI) m / z: 205.1 [M+H] + . Example 1: Synthesis of Compound 1

[0386] [ka]

[0387] To a solution of compound A2 (50 mg, 0.134 mmol) in DMF (4 mL) was added NaH (10.74 mg, 0.269 mmol, 60% in mineral oil), and the mixture was stirred at 20 °C for 10 min. 2-[(1R)-1-bromoethyl]pyridine (37 mg, 0.201 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 3 h. The mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-100% EtOAc / PE) to give compound 1 (32 mg, 43.5% yield) as an off-white solid. LC-MS (ESI) m / z: 478.1 [M+H] + . 1 H-NMR(400 MHz, CDCl3) δ 8.74 (dd, J = 4.4, 1.6 Hz, 1H), 8.65 - 8.58 (m, 1H), 8.07 (dd, J = 8.8, 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.73 - 7.60 (m, 2H), 7.47 - 7.37 (m, 4H), 7.32 (dd, J = 7.2, 2.0 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.55 (q, J = 7.2 Hz, 1H), 1.84 (d, J = 7.2 Hz, 3H). The compounds listed below were synthesized according to the procedure for Compound 1:

[0388] [Table 5-1]

[0389] [Table 5-2]

[0390] [Table 5-3]

[0391] [Table 5-4]

[0392] [Table 5-5]

[0393] [Table 5-6]

[0394] [Table 5-7]

[0395] [Table 5-8]

[0396] [Table 5-9]

[0397] [Table 5-10]

[0398] [Table 5-11]

[0399] Example 2: Synthesis of Compound 27

[0400] [ka]

[0401] To a solution of compound A1 (50 mg, 0.141 mmol), tetrahydropyran-4-ol (21.6 mg, 0.211 mmol), and PPh3 (55.5 mg, 0.211 mmol) in anhydrous THF (1 mL) was added ethyl [(1E)-(ethoxycarbonyl)diazenyl]methanoate (0.033 mL, 0.211 mmol) at 25 °C. The yellow solution was stirred at 25 °C for 15 min. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-50% EtOAc / PE) and preparative HPLC (HCOOH) to give compound 27 (5 mg, 8.07%) as a white solid. 1 H-NMR (400 MHz, DMSO_d6) δ 8.22 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.2 Hz, 1H), 7.64 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 7.2, 2.0 Hz, 1H), 4.98 (tt, J = 12.0, 4.0 Hz, 1H), 4.01 (dd, J = 11.2, 4.2 Hz, 2H), 3.50 (td, J = 11.6, 2.0 Hz, 2H), 1.95 (qd, J = 12.0, 4.4 Hz, 2H), 1.82 - 1.71 (m, 2H). LC-MS (ESI) m / z: 440.1 [M+H] + .

[0402] [Table 6-1]

[0403] [Table 6-2]

[0404] [Table 6-3]

[0405] [Table 6-4]

[0406] Example 3: Synthesis of Compounds 21, 23, 24 and 25

[0407] [ka]

[0408] Step 1: To a suspension of compound 22 (200 mg, 0.386 mmol) in THF (3 mL) and HO (3 mL) was added LiOH.HO (80.98 mg, 1.930 mmol). The yellow solution was stirred at 25 °C for 12 h. The mixture was adjusted to pH = 4 with citric acid and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine, dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-10% MeOH / DCM) to give compound 21 (170 mg, 87.4%) as a yellow solid. LC-MS (ESI) m / z: 505.1 [M+H] + . 1H-NMR (400 MHz, DMSO_d6) δ 8.69 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.22 - 8.10 (m, 3H), 8.07 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 7.2 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 7.6, 4.8 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 7.2, 2.0 Hz, 1H), 6.25 (q, J = 7.2 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H). Step 2: To a suspension of compound 21 (120 mg, 0.238 mmol), DMAP (145.30 mg, 1.189 mmol), and NH₄Cl (0.025 mL, 0.714 mmol) in DMF (2 mL) was added EDCI (91.20 mg, 0.476 mmol). The brown suspension was stirred at 25 °C for 12 h. The mixture was poured into water (50 mL) and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (20 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-7% MeOH / DCM) to give compound 23 (100 mg, 83.5%) as a yellow solid. LC-MS(ESI) m / z: 504.1 [M+H]+. 1H-NMR (400 MHz, DMSO_d6) δ 8.73 (d, J = 1.2 Hz, 1H), 8.59 (dt, J = 4.8, 1.6 Hz, 1H), 8.42 (s, 1H), 8.16 - 8.12 (m, 3H), 8.07 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.2 Hz, 1H), 7.83 (td, J = 7.6, 2.0 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 7.2, 2.0 Hz, 1H), 6.27 (q, J = 7.2 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H). Step 3: To a solution of compound 23 (30 mg, 0.060 mmol) and TEA (0.037 mL, 0.268 mmol) in anhydrous THF (1 mL) was added TFAA (0.017 mL, 0.119 mmol) at 25 °C. The green solution was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-70% EtOAc / PE) to give compound 25 (15 mg, 51.85%) as a yellow solid. LC-MS (ESI) m / z: 486.1 [M+H] + . 1H-NMR (400 MHz, DMSO_d6) δ 8.89 (s, 1H), 8.63 - 8.55 (m, 1H), 8.14 (dd, J = 10.8, 8.4 Hz, 3H), 8.02 (d, J = 8.4 Hz, 2H), 7.96 (dd, J = 8.8, 1.6 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.83 (td, J = 7.6, 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.39 - 7.28 (m, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 7.2, 2.0 Hz, 1H), 6.25 (q, J = 7.2 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H). Step 4: To a solution of compound 22 (20 mg, 0.039 mmol) in THF (1 mL) was added LiBH (0.84 mg, 0.039 mmol) at 25 °C. The colorless solution was stirred at 25 °C for 1 h. The mixture was quenched with saturated NH Cl (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine, dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-4% MeOH / DCM) to give compound 24 (13 mg, 68.7%) as a white solid. LC-MS (ESI) m / z: 491.1 [M+H] + . 1H-NMR (400 MHz, DMSO_d6) δ 8.57 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.13 - 8.10 (m, 2H), 7.99 (dd, J = 8.8, 7.2 Hz, 3H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (td, J = 7.6, 2.0 Hz, 1H), 7.58 (dd, J = 8.8, 1.6 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.33 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 7.2, 2.0 Hz, 1H), 6.52 (s, 1H), 6.24 (q, J = 7.2 Hz, 1H), 5.39 (t, J = 5.6 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 1.77 (d, J = 7.2 Hz, 3H). The compounds listed below were synthesized according to the procedure for Compound 25:

[0409] [Table 7]

[0410] Example 4: Synthesis of Compound 45

[0411] [ka]

[0412] Step 1: To a stirred mixture of compound B7 (50 mg, 0.140 mmol) and compound D2 (44 mg, 0.154 mmol) in DMF (1 mL), PPh3 (55 mg, 0.210 mmol) and diethyl azodicarboxylate (37 mg, 0.210 mmol) were added, and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (10 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-50% EtOAc / DCM) to give compound 45-1 (80 mg, impure) as a colorless oil. LC-MS (ESI) m / z: 595.2 [M+H] + . Step 2: To a solution of compound 45-1 (80 mg, 0.135 mmol) in MeOH (2 mL), HCl / dioxane (1 mL, 4.0 M) was added, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO (10 mL), and the resulting mixture was extracted with DCM (20 mL). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-10% MeOH / DCM) to give compound 45 (28 mg, 43.3%) as a white solid. LC-MS (ESI) m / z: 481.2 [M+H] + . 1H-NMR (400 MHz, CDCl3) δ 8.83 - 8.77 (m, 1H), 8.73 (d, J = 8.1 Hz, 2H), 8.37 (ddd, J = 10.3, 5.5, 1.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.76 - 7.68 (m, 1H), 7.55 - 7.42 (m, 2H), 7.11 (dh, J = 7.8, 2.6 Hz, 2H), 6.41 (td, J = 6.5, 5.9, 2.6 Hz, 1H), 5.26 (s, 2H), 4.34 - 4.20 (m, 2H), 4.09 - 3.94 (m, 2H). Example 5: Synthesis of Compound 57

[0413] [ka]

[0414] Step 1: To a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (20 mg, 0.083 mmol) and compound B32 (40 mg, 0.083 mmol) in DMF (1 mL) was added CuI (9 mg, 0.050 mmol), N,N'-dimethylethylenediamine (9 mg, 0.099 mmol), and KPO (35 mg, 0.165 mmol). The mixture was stirred at 130 °C under a N atmosphere for 12 h. The mixture was diluted with water (5 mL). The mixture was extracted with EtOAc (5 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-100% EtOAc / PE) to give compound B57-1 (40 mg, 79.1%) as a white solid. LC-MS (ESI) m / z: 612.2 [M+H] + . Step 2: A solution of compound 57-1 (40 mg, 0.065 mmol) in TFA (1 mL) was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 8 with saturated aqueous NaHCO3. The mixture was then extracted with DCM (10 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (with formic acid as an additive) to give compound 57 (13 mg, 40.5%) as a white solid. LC-MS (ESI) m / z: 492.2 [M+H] + . 1 H-NMR (400 MHz, DMSO_d6) δ 8.81 (dd, J = 8.2, 1.5 Hz, 1H), 8.67 (dd, J = 4.5, 1.5 Hz, 1H), 8.26 - 8.17 (m, 1H), 7.97 - 7.87 (m, 2H), 7.86 - 7.77 (m, 2H), 7.49 (dd, J = 8.2, 4.5 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.12 - 7.03 (m, 1H), 7.00 (dd, J = 7.1, 2.0 Hz, 1H), 6.36 - 6.27 (m, 1H), 5.06 (s, 2H), 2.74 (d, J = 4.7 Hz, 3H), 2.28 (s, 3H). The compounds listed below were synthesized according to the procedure for Compound 57:

[0415] [Table 8]

[0416] Example 6: Synthesis of Compound 71

[0417] [ka]

[0418] Step 1: To a solution of compound 68 (70 mg, 0.15 mmol) and LiCl (31.07 mg, 0.73 mmol) in DMF (2 mL) was added p-TsOH (139.44 mg, 0.73 mmol) at 20 °C. The yellow suspension was stirred at 120 °C for 2 h. TLC showed the reaction was complete. The mixture was cooled to room temperature, poured into water (15 mL), and stirred for 30 min. The white suspension was filtered. The filter cake was triturated with MTBE (20 mL) and filtered. The filter cake was dried under vacuum to give compound 71 (60 mg, 0.13 mmol, 88.31%) as a white solid. LC-MS (ESI) m / z: 464.1 [M+H] + . 1 H-NMR (400 MHz, DMSO_d6) δ 12.86 (s, 1H), 8.28 - 8.23 ​​(m, 1H), 8.15 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.66 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 7.2, 2.0 Hz, 1H), 6.24 (s, 1H), 5.08 (s, 2H). The compounds listed below were synthesized according to the procedure for Compound 71:

[0419] [Table 9]

[0420] Example 7: Synthesis of Compound 72

[0421] [ka]

[0422] Step 1: To a solution of methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and EtN (1.21 mL, 8.69 mmol) in THF (4 mL), 2,2,3,3-tetramethyl-7-aza-4-oxa-3-silaoctane (548.68 mg, 2.90 mmol) was added dropwise at 25 °C. The yellow solution was stirred at 25 °C for 12 h. The desired MS peak was detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-10% EtOAc / petroleum ether) to give compound 72-1 (900 mg, 2.77 mmol, 95.44%) as a yellow oil. LC-MS (ESI) m / z: 326.1 [M+H] + . Step 2: To a solution of compound 72-1 (600 mg, 1.84 mmol) in EtOH (10 mL) was added NaBH4 (139.45 mg, 3.67 mmol) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The reaction was quenched with MeOH and stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-20% EtOAc / petroleum ether) to give compound 72-2 (300 mg, 1.01 mmol, 54.71%) as a colorless oil. LC-MS (ESI) m / z: 298.1 [M+H]+. Step 3: To a solution of compound 72-2 (60 mg, 0.20 mmol) and DIPEA (0.07 mL, 0.40 mmol) in DCM (1 mL) was added MsCl (0.02 mL, 0.22 mmol) at 25 °C. The yellow solution was stirred at 25 °C for 0.5 h. TLC showed the reaction was complete. The mixture was extracted with DCM (5 mL * 3) and water (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 72-3 (76 mg, 0.20 mmol, 100%) as a yellow oil, which was used directly in the next step. LC-MS (ESI) m / z: 376.1 [M+H] + . Step 4: A suspension of compound B1 (50 mg, 0.14 mmol), compound 72-3 (52.70 mg, 0.14 mmol), and Cs2CO3 (91.44 mg, 0.28 mmol) in DMF (2 mL) was stirred at 80 °C for 12 h. TLC showed the reaction was complete. The mixture was extracted with EtOAc (10 mL*3) and water (20 mL), and the combined organic layers were washed with brine (20 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-5% MeOH / DCM) to give compound 72-4 (50 mg, 0.08 mmol, 56.04%) as a yellow solid. LC-MS (ESI) m / z: 636.1 [M+H] + . Step 5: A solution of compound 72-4 (50 mg, 0.08 mmol) in HCl / dioxane (0.5 mL) and MeOH (2 mL) was stirred at 25 °C for 1 h. The desired MS peak was detected by LCMS. The mixture was adjusted to pH = 8 with saturated NaHCO3 and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (15 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-7% MeOH / DCM) to give compound 72 (20 mg, 0.04 mmol, 48.76%) as a yellow solid. LC-MS (ESI) m / z: 522.1 [M+H] + . 1 H-NMR (400 MHz, DMSO_d6) δ 8.84 - 8.78 (m, 2H), 8.68 (d, J = 8.8 Hz, 2H), 8.27 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.17 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H), 5.10 (s, 2H), 4.60 (brs, 1H), 3.62 - 3.42 (m, 4H), 3.07 (s, 3H). The compounds listed below were synthesized according to the procedure for Compound 72:

[0423] [Table 10-1]

[0424] [Table 10-2]

[0425] Example 8: Synthesis of Compound 77

[0426] [ka]

[0427] Step 1: A suspension of compound B1 (35 mg, 0.1 mmol), compound D3 (21.99 mg, 0.12 mmol), and K2CO3 (27.15 mg, 0.20 mmol) in DMF (1 mL) was stirred at 40 °C for 12 h. The desired MS peak was detected by LCMS. The mixture was extracted with DCM / MeOH (10 / 1, 10 mL*3) and water (15 mL), washed with brine (15 mL), dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (0-25% EtOAc / DCM) to give compound 77-1 (30 mg, 0.06 mmol, 60.30%) as a yellow solid. LC-MS (ESI) m / z: 505.1 [MH] - . Step 2: A suspension of compound 77-1 (20 mg, 0.04 mmol) and NaBH4 (4.5 mg, 0.12 mmol) in EtOH (2 mL) was stirred at 25 °C for 12 h. The desired MS peak was detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by Combiflash (0-6% MeOH / DCM) and further purified by preparative HPLC (HCOOH) to give compound 77 (3 mg, 0.006 mmol, 15.88%) as a white solid. LC-MS (ESI) m / z: 479.1 [M+H]+ . 1 H-NMR (400 MHz, DMSO_d6) δ 8.86 - 8.79 (m, 2H), 8.74-8.68 (m, 3H), 8.04-7.99 (m, 3H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.18 - 7.08 (m, 2H), 5.28-5.25 (m, 3H), 4.57 (d, J = 6.0 Hz, 2H). Example 9: Synthesis of Compound 128

[0428] [ka]

[0429] A solution of compound A25 (370 mg, 0.74 mmol) in methylamine ethanol (5 mL) was stirred at 25° C. for 8 hours. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% MeOH in DCM) to give compound 128 (345 mg, 0.70 mmol, 94.26%) as a white solid. 1 H-NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.03 - 7.97 (m, 4H), 7.92 (d, J = 7.0 Hz, 1H), 7.53 - 7.40 (m, 2H), 7.08 (d, J = 1.7 Hz, 2H), 6.95 (dd, J =7.1, 1.8 Hz, 1H), 6.33 (d, J = 4.6 Hz, 1H), 5.07 (s, 2H), 2.74 (d, J = 4.2 Hz, 3H). LCMS: m / z 495.1 [M+H] + . The compounds listed below were synthesized according to the procedure for Compound 128:

[0430] [Table 11-1]

[0431] [Table 11-2]

[0432] [Table 11-3]

[0433] [Table 11-4]

[0434] [Table 11-5]

[0435] [Table 11-6]

[0436] [Table 11-7]

[0437] [Table 11-8]

[0438] [Table 11-9]

[0439] Example 10: Synthesis of Compound 131

[0440] [ka]

[0441] Step 1: To a solution of 1-(2-chloropyrimidin-4-yl)ethan-1-one (900 mg, 5.75 mmol) in THF (5 mL) was added water (5 mL) and NaBH (326 mg, 8.62 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 20% EtOAc in heptane) to give compound 131-1 (350 mg, 2.21 mmol, 38.39%) as a colorless oil. LCMS: m / z 159.0 [M+H] + . Step 2: A solution of compound 131-1 (350 mg, 2.22 mmol) in methylamine ethanol (5 mL) was stirred at 25 °C for 14 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 35% EtOAc in heptane) to give compound 131-2 (300 mg, 88.5% yield) as a colorless oil. LCMS: m / z 154.1 [M+H] + . Step 3: To a solution of compound 131-2 (70 mg, 0.46 mmol) in DCM (3 mL) was added methanesulfonic anhydride (103 mg, 0.59 mmol) and TEA (92 mg, 0.91 mmol). The mixture was stirred at 23 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was used directly in the next step. LCMS: m / z 232.1 [M+H] + . Step 4: To a solution of compound B1 (75 mg, 0.21 mmol) in DMF (3 mL) was added sodium hydride (15 mg, 0.63 mmol) under a N2 atmosphere at 25 °C. The mixture was stirred at 25 °C for 0.5 h. Compound 131-3 (49 mg, 0.21 mmol) was added to the mixture, and the mixture was stirred at 50 °C for 18 h. The mixture was quenched with aqueous ammonium chloride solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 4% MeOH in DCM) to give compound 131-4 (50 mg, 0.102 mmol, 48.33%) as a white solid. LCMS: m / z 492.1 [M+H] + . Compound 131-4 (50 mg) was separated by SFC to give compound 130 (15 mg, 30% yield) and compound 131 (17 mg, 34% yield). (Compound 130) 1 H-NMR (400 MHz, MeOD) δ 8.70 (dd, J = 4.5, 1.5 Hz, 1H), 8.66 (d, J = 8.6 Hz, 2H), 8.58 (dd, J = 8.2, 1.5 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.45 (dd, J = 8.2, 4.5 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.58 (d, J = 5.2 Hz, 1H), 6.09 (q, J = 7.2 Hz, 1H), 2.88 (s, 3H), 1.81 (d, J = 7.2 Hz, 3H). LCMS: m / z 492.1 [M+H] + . (Compound 131) 1H-NMR (400 MHz, MeOD) δ 8.73 - 8.71 (m, 3H), 8.60 (dd, J = 8.2, 1.5 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.87 (s, 2H), 7.47 (dd, J = 8.2, 4.5 Hz, 1H), 7.24 (s, 2H), 6.58 (d, J = 5.2 Hz, 1H), 6.09 (q, J = 7.1 Hz, 1H), 2.88 (s, 3H), 1.82 (d, J = 7.2 Hz, 3H). LCMS: m / z 492.1 [M+H] + . The compounds listed below were synthesized according to the procedure for Compound 131:

[0442] [Table 12]

[0443] Example 11: Synthesis of Compound 152

[0444] [ka]

[0445] Step 1: A solution of compound B32 (400 mg, 0.850 mmol) in TFA (8 mL) was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 8 with saturated aqueous NaHCO3. EtOAc (10 mL) was added to the mixture, and the suspension was filtered. The filter cake was dried to give compound 152-1 (290 mg, 97.4%) as a white solid. LCMS: m / z 351.1 [M+H] + . Step 2: To a solution of compound 145-1 (50 mg, 0.143 mmol) and 3-(4-bromophenyl)oxetane (33.5 mg, 0.157 mmol) in DMF (3 mL), CuI (16.3 mg, 0.086 mmol), N,N'-dimethylethylenediamine (15.1 mg, 0.171 mmol), and KPO (60.6 mg, 0.285 mmol) were added, and the mixture was stirred at 120 °C under a N atmosphere for 12 h. The mixture was diluted with water (6 mL). The mixture was extracted with EtOAc (8 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (with formic acid as an additive) to give compound 152 (31 mg, 45.0%) as an off-white solid. LCMS: m / z 483.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.16 (m, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.72 (dd, J = 8.6, 2.9 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.47 - 7.33 (m, 2H), 7.16 - 7.01 (m, 4H), 6.94 (dd, J = 7.1, 2.0 Hz, 1H), 6.32 (d, J = 5.0 Hz, 1H), 5.05 (s, 2H), 5.00 (dd, J = 8.3, 5.9 Hz, 2H), 4.69 (t, J = 6.3 Hz, 2H), 4.45 - 4.31 (m, 1H), 2.74 (d, J = 4.7 Hz, 3H). Example 12: Synthesis of Compound 156

[0446] [ka]

[0447] Step 1: To a solution of compound B32 (100 mg, 0.213 mmol) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (56.8 mg, 0.234 mmol) in dioxane (4 mL), CuI (24.3 mg, 0.128 mmol), N,N'-dimethylethylenediamine (22.5 mg, 0.255 mmol), and KPO (90.2 mg, 0.425 mmol) were added, and the mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (15 mL × 2). The combined layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution, 0-67% EtOAc / PE) to give compound 156-1 (40 mg, 46.9% purity, 14.0% yield) as a yellow solid. LCMS: m / z 633.2 [M+H] + . Step 2: A solution of compound 146-1 (40 mg, 0.032 mmol) in TFA (3 mL) was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (10 mL × 2). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (with formic acid as an additive) to give compound 156 (4 mg, 26.3%) as a white solid. LCMS: m / z 513.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 - 8.18 (m, 1H), 8.18 - 8.03 (m, 3H), 7.98 - 7.84 ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 1】 however: X １ is C, C(R １ ), or N; X ２ is C, C(R ２ ), or N; X ３ is C, C(R ３ ), or N; X ４ is C, C(R ４ ), or N; X ５ is C(R ５ ), C(R ５ ) (R ５ａ ), N(R ５ｂ ), or N; X ６ is C(R ６ ), C(R ６ ) (R ６ａ ), N(R ６ｂ ), or N; X ７ is C(R ７ ), C(R ７ ) (R ７ａ ), N(R ７ｂ ), or N; X ８ is C(R ８ ), C(R ８ ) (R ８ａ ), N(R ８ｂ ), or N; X ９ is C(R ９ ) or N; X １０ is C(R １０ ) or N; X １１ is C(R １６ ), C(R １６ ) (R １６ａ ), C(O), N(R １６ｂ ), or N; L １ and L ２ are independently a bond and R １４ａ C optionally substituted with one, two or three groups selected from １－６ Selected from the group consisting of alkylene; R １ , R ２ , R ３ and R ４ are independently hydrogen and C １－６ selected from the group consisting of alkyl; R ５ , R ５ａ , R ６ , R ６ａ , R ７ , R ７ａ , R ８ , R ８ａ , R １６ and R １６ａ are independently hydrogen, halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, —OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ａ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , and -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) selected from the group consisting of C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is R １４ｂ optionally substituted with one, two or three groups selected from R ５ｂ , R ６ｂ , R ７ｂ , R ８ｂ and R １６ｂ are independently hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -C(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), and -S(O) ２ R ２３ and wherein C is selected from the group consisting of １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is R １４ｃ optionally substituted with one, two or three groups selected from R ９ , R １０ and R １１ are independently hydrogen, halogen, and C １－６ selected from the group consisting of alkyl; R １２ is C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, with the proviso that C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is R １５ａ optionally substituted with one, two or three groups selected from R １３ is C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, with the proviso that C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is R １５ｂ optionally substituted with one, two or three groups selected from R １４ａ , R １４ｂ and R １４ｃ are each independently a halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, —CH ２ -C １－９ Heteroaryl, —OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) selected from the group consisting of C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, —CH ２ -C １－９ Heteroaryl, and C １－９ Heteroaryl is a group selected from halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ 、-N(R ２２ )S(O) ２ R ２３ 、-C(O)R ２３ 、-S(O)R ２３ 、-OC(O)R ２３ 、-C(O)N(R ２０ )(R ２１ )、-C(O)C(O)N(R ２０ )(R ２１ )、-N(R ２２ )C(O)R ２３ 、-S(O) ２ R ２３ 、-S(O) ２ N(R ２０ )(R ２１ )-、-N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , and -CH ２ S (O) ２ N (R ２０ ) (R ２１ Optionally substituted with 1, 2, or 3 groups independently selected from: R １５ａ are each independently a halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－６ Cycloalkyl, —NH—C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, —CH ２ -C １－９ Heteroaryl, —OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) selected from the group consisting of C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, —CH ２ -C １－９ Heteroaryl, and C １－９ Heteroaryl is a group selected from halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , and -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) optionally substituted with one, two, or three groups independently selected from １５ａ are combined to form C ３－６ Cycloalkyl or C ２－９ Forms a heterocycloalkyl, provided that C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl includes halogen, oxo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one, two, or three groups independently selected from alkoxy; R 15b are each independently a halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, —CH ２ -C １－９ Heteroaryl, —OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) selected from the group consisting of C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, —CH ２ -C １－９ Heteroaryl, and C １－９ Heteroaryl is a group selected from halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２０ , -SR ２０ , -SF ５ , -N(R ２０ ) (R ２１ ), —C(O)OR ２０ , -OC(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)N(R ２０ ) (R ２１ ), -N(R ２２ )C(O)OR ２３ , -N(R ２２ ) S (O) ２ R ２３ , -C(O)R ２３ , -S(O)R ２３ , -OC(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -C(O)C(O)N(R ２０ ) (R ２１ ), -N(R ２２ ) C(O)R ２３ , -S(O) ２ R ２３ , -S(O) ２ N (R ２０ ) (R ２１ )-, -N=S(=O)(R ２３ ) ２ , -S(=O)(=NH)N(R ２０ ) (R ２１ ), -S(=O)(=NH)C(R ２０ ) (R ２１ ), -S(=O)(=NR ２３ ) R ２３ , -CH ２ C(O)N(R ２０ ) (R ２１ ), -CH ２ N (R ２２ ) C(O)R ２３ , -CH ２ S (O) ２ R ２３ , and -CH ２ S (O) ２ N (R ２０ ) (R ２１ ) optionally substituted with one, two, or three groups independently selected from １５ｂ are combined to form C ３－６ Cycloalkyl or C ２－９ Forms a heterocycloalkyl, provided that C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl includes halogen, oxo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one, two, or three groups independently selected from alkoxy; R ２０ are each independently hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, with the proviso that C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is a group selected from halogen, —CN, hydroxy, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ optionally substituted with one, two, or three groups selected from heteroaryl; R ２１ are each independently hydrogen, C １－６ Alkyl, and C １－６ haloalkyl; or R ２０ and R ２１ together with the nitrogen to which they are attached, C ２－９ forming a heterocycloalkyl; R ２１ａ are each independently, C １－６ Alkyl and C １－６ selected from the group consisting of haloalkyl; R ２２ are each independently hydrogen, C １－６ Alkyl and C １－６ selected from the group consisting of haloalkyl; R ２３ are each independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, with the proviso that C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is a group selected from halogen, —CN, hydroxy, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ optionally substituted with one, two, or three groups selected from heteroaryl; 【Chemistry 2】 indicates a single or double bond that satisfies all valences.

2. X ９ is C(R ９ 2. The compound of claim 1, wherein R is C(H) or C(H), or a pharmaceutically acceptable salt or solvate thereof.

3. X １０ is C(R １０ 2. The compound of claim 1, wherein R is C(H) or C(H), or a pharmaceutically acceptable salt or solvate thereof.

4. X １１ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein is N, C(H) or C(O).

5. X 1 is N and X 2 is C; X 1 is C and X 2 is N; X 3 is C and X 4 is C; X 3 is N and X 4 is C; X 3 is C and X 4 is N; X ５ is C(R ５ ) or N; X ６ is C(R ６ ) or N; X ７ is C(R ７ ) or N; X ８ is C(R ８ 2. The compound of claim 1, wherein R is N, or a pharmaceutically acceptable salt or solvate thereof.

6. Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), Formula (Im), Formula (In), Formula (Iq), Formula (Ir), Formula (It), Formula (Iu), Formula (Iv), Formula (Iw), Formula (Ix) or Formula (Iy) 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 2. The compound of claim 1, characterized in that it has the structure: or a pharmaceutically acceptable salt or solvate thereof.

7. R ５ is hydrogen, halogen, -CN, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２０ , -C(O)OR ２０ , -C(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -S(O) ２ R ２３ , and -S(O) ２ N (R ２０ ) (R ２１ )-, with the proviso that C １－６ Alkyl is R １４ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with one, two or three groups selected from:

8. R ５ The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen, F or Cl.

9. R ６ is hydrogen, halogen, -CN, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２０ , -C(O)OR ２０ , -C(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -S(O) ２ R ２３ , and -S(O) ２ N (R ２０ ) (R ２１ )-, with the proviso that C １－６ Alkyl is R １４ｂ and R 6 is selected from the group consisting of hydrogen, halogen, —CN, C 1-6 alkyl, —OR 20 , and —C(O)N(R 20 )(R 21 ), with the proviso that C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 14b , with the proviso that R 20 is independently selected from hydrogen and C 1-6 alkyl, or R 6 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

10. R ７ is hydrogen, halogen, -CN, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２０ , -C(O)OR ２０ , -C(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -S(O) ２ R ２３ , and -S(O) ２ N (R ２０ ) (R ２１ )-, with the proviso that C １－６ Alkyl is R １４ｂ or R 7 is hydrogen; R 7 is selected from the group consisting of hydrogen, halogen, —CN, C 1-6 alkyl, —OR 20 , and —C(O)N(R 20 )(R 21 ), where C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 14b , where R 20 is independently selected from hydrogen and C 1-6 alkyl; or R 7 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

11. R ８ is hydrogen, halogen, -CN, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２０ , -C(O)OR ２０ , -C(O)R ２３ , -C(O)N(R ２０ ) (R ２１ ), -S(O) ２ R ２３ , and -S(O) ２ N (R ２０ ) (R ２１ )-, with the proviso that C １－６ Alkyl is R １４ｂ and R 8 is selected from the group consisting of hydrogen, halogen, —CN, C 1-6 alkyl, —OR 20 , and —C(O)N(R 20 )(R 21 ), wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 14b , wherein R 20 is independently selected from hydrogen and C 1-6 alkyl, or R 8 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

12. L ２ is a bond or R １４ａ C optionally substituted with one, two or three groups selected from １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is alkylene.

13. R １３ is C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, with the proviso that C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is R １５ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with one, two or three groups selected from:

14. R １３ is C ６－１０ 13 is C 3-10 cycloalkyl optionally substituted with one, two or three groups selected from R 15b ; R 13 is C 2-9 heterocycloalkyl optionally substituted with one, two or three groups selected from R 15b ; or R 13 is C 1-9 heteroaryl optionally substituted with one, two or three groups selected from R 15b , wherein C 1-9 heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl, or a pharmaceutically acceptable salt or solvate thereof.

15. R １５ｂ are each independently a halogen, C １－６ Alkyl, C １－６ haloalkyl, and —OR ２０ where R ２０ is C １－６ Alkyl and C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from haloalkyl.

16. L １ is a bond or R １４ａ C optionally substituted with one, two or three groups selected from １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is alkylene.

17. R １２ is R １５ａ C optionally substituted with one, two or three groups selected from １－９ The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is heteroaryl or C 2-9 heterocycloalkyl optionally substituted by one, two or three groups selected from R 15a .

18. R １２ is R １５ａ C optionally substituted with one, two or three groups selected from １－９ heteroaryl, provided that C １－９ 18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, indazolyl, and imidazolyl.

19. R １５ａ are each independently -C ３－７ Heterocycloalkyl, —NH—C ３－６ cycloalkyl, —OR ２０ , and -N(R ２０ ) (R ２１ ) selected from the group consisting of: ３－７ Heterocycloalkyl and —NH—C ３－６ Cycloalkyl is halogen, C １－６ alkyl, and —OR ２０ each R 15a is independently selected from the group consisting of halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —OR 20 , and —N(R 20 )(R 21 ); or each R 15a is independently selected from the group consisting of —OR 20 and —N(R 20 )(R 21 ), or each R 15a is independently selected from the group consisting of —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —N(CH 3 )(CH 2 ) 2 OH, —NH(CH 2 ) 2 OCH 3 , 【Chemistry 25】 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is selected from the group consisting of: -OH, -OCH 3 , -OCH 2 CH 2 OH, and -OCH 2 CH 2 OCH 3 .

20. R ２０ and R ２１ together with the nitrogen to which they are attached, can be azetidinyl, pyrrolidinyl, morpholino, 【Chemistry 26】 , or piperidinyl, provided that azetidinyl, pyrrolidinyl, morpholino, 【Chemistry 27】 or piperidinyl is hydroxy or C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by alkyl.

21. A compound selected from the following: 【Chemistry 28-1】 【Chemistry 28-2】 【Chemistry 28-3】 【Chemistry 28-4】 【Chemistry 28-5】 【Chemistry 28-6】 【Chemistry 28-7】 【Chemistry 28-8】 [Chemistry 28-9] 【Chemistry 28-10】 or a pharmaceutically acceptable salt or solvate thereof.

22. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

23. A method for preparing a medicament for inhibiting the Hippo pathway in a subject in need thereof; a medicament for inhibiting the YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof; a medicament for treating a disease or condition affected by inhibition of the YAP-TEAD and / or TAZ-TEAD interaction in a subject in need thereof; or a medicament for treating cancer, cardiovascular disease, or fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

24. 24. The method of claim 23, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, and pancreatic cancer; and the fibrosis is liver fibrosis, renal fibrosis, and pulmonary fibrosis.

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