WO2019090081A1 – May 9, 2019 – MODULATORS OF THE INTEGRATED STRESS PATHWAY

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Inventors :

MARTIN, Kathleen, Ann - 3450 Sacramento Street, San Francisco, CA 94118; SIDRAUSKI, Carmela - 20434 Walnut Ave, Saratoga, CA 95070; FROST, Jennifer, M. - 635 Yorktown Lane, Gurnee, IL 60031; TONG, Yunsong - 1408 Braxton Road, Libertyville, IL 60048; XU, Xiangdong - 4 River Oaks Circle West, Buffalo Grove, IL 60089; SHI, Lei - 1908 Trevino Terrace, Vernon Hills, IL 60061; CHUNG, Seungwon - 1512 Virginia Avenue, Libertyville, IL 60048; XIONG, Zhaoming - 37 River Oaks Circle Rd, Buffalo Gorve, IL 60089; MURAUSKI, Kathleen - 1807 W. Argyle Street, Apt. 404, Chicago, IL 60640; ZHANG, Qingwei, I. - 1820 S Falcon Drive, Libertyville, IL 60048; BROWN, Brian, S. - 812 Washington St., Evanston, IL 60202; DART, Michael, J. - 844 Yale Lane, Highland Park, IL 60035

Owner :

CALICO LIFE SCIENCES LLC ABBVIE INC.

Application Number :

WOUS18058963

Document Number :

WO2019090081A1

Priority Date :

January 1, 1970

Filing Date :

November 2, 2018

Date of Grant/ Publication :

May 9, 2019

Class :

; C07D207 / 26; C07D209 / 46; C07D207 / 273; C07D233 / 32; C07D239 / 88; C07D239 / 96; C07D263 / 20; C07D265 / 10; C07D401 / 04; C07D401 / 12; C07D403 / 12; C07D405 / 04; C07D413 / 12; A61P3 / 00; A61P19 / 00

Abstract

Provided herein are compounds of Formula (I) or Formula (II), compositions, and methods there of useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.

Claim(s)

1. A compo Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, cubanyl, cyclohexyl, cyclobutyl, or tetrahydropyranyl wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, cubanyl, cyclohexyl, cyclobutyl, or tetrahydropyranyl is optionally substituted on one or more available carbons with 1-4 R x ; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may optionally be substituted with R N1 ; L 1 is a bond, Ci-C 6 alkylene, 2-7 membered heteroalkylene, or -0-, wherein Ci-C 6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R L1 ; L 2 is Ci-C 6 alkylene, 2-7 membered heteroalkylene, a bond, -NR N2 -, -0-, or -S(0) w – (wherein w is 0, 1 or 2); wherein Ci-C 6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R L2 ; R 1 is hydrogen or Ci-C 6 alkyl; W is a 3-7-membered saturated, or partially unsaturated, monocyclic nitrogen-containing heterocyclyl; wherein the 3-7-membered saturated or partially unsaturated monocyclic heterocyclyl is optionally substituted on one or more available carbons with 1-5 R w ; and wherein if the 3-7-membered saturated or partially unsaturated monocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R N3 ; and wherein W is attached to D through an available nitrogen atom or carbon atom within W; A and Z are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted on one or more available carbons with 1-5 R Y ; and wherein if the 5-6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R N4 ; each R L1 is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, oxo, halo, cyano, -OR A , – NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and – S(0) 2 R D ; each R L2 is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C 6 alkyl, halo-Ci-C 6 alkyl, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and -S(0) 2 R D ; R N1 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C2-C6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R N2 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R N3 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R N4 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; each R w is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and -S(0) 2 R D ; each R x is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and -S(0) 2 R D ; each R Y is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, – C(0)OR D , -S(R E ) m , -S(0)R D , -S(0) 2 R D , and G 1 ; or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl each of which is optionally substituted with 1-5 R x ; each G 1 is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R z ; each R z is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , and -S(0) 2 R D ; R A is, at each occurrence, independently hydrogen, Ci-C 6 alkyl, halo-Ci-C 6 alkyl, – C(0)NR B R c , -C(0)R D , or -C(0)OR D ; each of R B and R c is independently hydrogen or Ci-C 6 alkyl; or R B and R c together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R z ; each R D is independently Ci-C 6 alkyl or halo-Ci-C 6 alkyl; each R E is independently hydrogen, Ci-C 6 alkyl, or halo-Ci-C 6 alkyl; each R F is independently hydrogen, Ci-C 6 alkyl, or halo; and m is 1 when R F is hydrogen or Ci-C 6 alkyl, 3 when R F is Ci-C 6 alkyl, or 5 when R F is halo.;
2. The compound of claim 1, wherein D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a cyclohexyl, a cyclobutyl, or a tetrahydropyranyl each optionally substituted with 1-4 R x;
3. The compound of any one of claims 1-2, wherein D is a bridged bicyclic 5-8 membered cycloalkyl, a bridged bicyclic 5-8 membered heterocyclyl, a cyclohexyl, a cyclobutyl, or a tetrahydropyranyl, each optionally substituted with 1-4 R x .;
4. The compound of any one of claims 1-3, wherein D is bicyclo[l.l.l]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2- azabicyclo[2.2.2]octane, cyclohexyl, cyclobutyl, or tetrahydropyranyl, each of which is optionally substituted with 1-4 R x groups.;
5. The compound of any one of claims 1-4, wherein D is ( x > 0-4 nd of any one of claims 1-5, wherein D is or;
7. The compound of any one of claims 1-6, wherein D is substituted with 0 R;
8. The compound of any one of claims 1-7, wherein D is;
9. The compound of any one of claims 1-6, wherein D is substituted with 1 or 2 R;
11. The compound of any one of claims 9-10, wherein each R is independently selected from the group consisting of oxo, -OR A , -C(0)OH, -C(0)OR D , halo, and hydroxy-C C 6 alkyl.;
12. The compound of any one of claims 1-11, wherein L 1 is 2-7 membered heteroalkylene optionally substituted by 1-5 R L1 ; and L 2 is Ci-Ce alkylene optionally substituted by 1-5 R L2 , 2-7 membered heteroalkylene optionally substituted by 1-5 R L2 , a bond, -NR N2 -, or -0-.;
13. The compound of any one of claims 1-12, wherein L 1 is 2-7 membered heteroalkylene optionally substituted by 0 R L1 ; and L 2 is Ci-C 6 alkylene optionally substituted by 0 R L2 , 2-7 membered heteroalkylene optionally substituted by 0 R L2 , a bond, -NR N2 -, or -0-. 14. The compound of any one of claims 1-13, wherein L 1 is a bond, CH2O-*, CH2CH2O-* OCH2-* or CH2OCH2-* ; and L 2 is selected from a bond, CH 2 0-*, -OCH 2 -*, -CH 2 – -NH-, – NCH 3 -, or -0-, wherein “-*” indicates the attachment point to A or Z, respectively.;
15. The compound of any one of claims 1-14, wherein R 1 is hydrogen or C¾.;
16. The compound of any one of claims 1-15, wherein each of A and Z is independently phenyl or 5-6-membered heteroaryl; wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 R Y , and each R Y is independently Ci-C 6 alkyl, halo-Ci-C 6 alkyl, halo-Ci-C6 alkoxy, halo, cyano, -OR A , or G 1 .;
17. The compound of any one of claims 1-16, wherein each of A and Z is independently phenyl, pyridyl, isoxazolyl,pyrazinyl, thiazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 R Y groups.;
claim 15: 18. The compound of any one of claims 1-17, wherein each of A and Z is independently selected from the roup consisting of:;
claim 16: 19. The compound of any one of claims 1-18, wherein A is phenyl or pyridyl, each of which is optionally substituted with 1-2 R Y groups.;
claim 17: 20. The compound of any one of claims 1-19, wherein A is selected from the group consistin of:;
claim 18: 21. The compound of any one of claims 1-20, wherein Z is phenyl, pyridyl, isoxazolyl, thiazolyl, pyrazinyl or pyrazolyl, each of which is optionally substituted with 1-3 R Y groups.;
claim 19: 22. The compound of any one of claims 1-21, wherein Z is selected from the group consistin of: wherein R is hydrogen or CH 3 .;
claim 20: 23. The compound of any one of claims 1-22, wherein each R Y is independently hydrogen, chloro, fluoro, CF 3 , CHF 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCF 3 , OCH(CH 3 ) 2 , or CN.;
claim 21: 24. The compound of any one of claims 1-23, wherein W is a pyrrolidinone, imidazolidinone, dihydroimidazolidinone, oxazolidinone, oxazolidinedione, oxazolone, dihydropyrrolone, piperazine, piperazinone, oxazinanone, or dihydrooxazole moiety, each of which is optionally substituted with 1-4 R w groups.;
claim 22: 25. The compound of any one of claims 1-24, wherein W is a pyrrolidin-2-one, imidazolidin- 2-one, oxazolidin-2-one, oxazol-2-one, l ,5-dihydropyrrol-2-one, piperazine, piperazinone, 1 ,3- oxazinan-2-one, 4,5-dihydrooxazole, l,3-dihydro-2H-imidazol-2-one, oxazolidine-2,4-dione, moiety, each of which is optionally substituted with 1-4 R w groups, and each R w is independently Ci-C 6 alkyl, halo-Ci-C6 alkyl, halo, oxo, cyano, or -OR A .;
claim 23: 26. The compound of any one of claims 1-25, wherein W is selected from the group consisting of: is hydrogen or C¾.;
claim 24: 27. The compound of any one of claims 1-26, wherein the compound of Formula (I) is a compound of Formula (I- a): Formula (I- a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is bicyclo[l.l.l]pentanyl, bicyclo[2.2.2]octanyl, cyclohexyl, cyclobutyl or tetrahydropyranyl, each of which is optionally substituted with 1-4 R x groups; L 1 is CH 2 O-* or CH 2 OCH 2 -*, wherein “-*” indicates the attachment point to A; L 2 is selected from a bond, CH 2 0-*, -OCH 2 -*, -CH 2 – -NH-, -NCH 3 – or -0-, wherein “-*” indicates the attachment point to Z; W is a pyrrolidinone, imidazolidinone, dihydroimidazolidinone, oxazolidinone, oxazolidinedione, oxazolone, dihydropyrrolone, piperazine, piperazinone, oxazinanone, or dihydrooxazole moiety, each of which is optionally substituted with 1-4 R w groups. and wherein the imidazolidinone may be optionally substituted on an available nitrogen with hydrogen or CH 3 ; A is phenyl or pyridyl, each of which is optionally substituted with 1-5 R Y groups;
Z is phenyl, pyridyl, isoxazolyl, thiazolyl, pyrazinyl or pyrazolyl, each of which is optionally substituted on one or more available carbons with 1-5 R Y groups; and wherein pyrazolyl may be optionally substituted on an available nitrogen with hydrogen or CH 3 ; each R w is independently fluoro, chloro, oxo, OH, OCH 3 , CHF 2 , OCF 3 CF 3 , CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 ; each R x is independently fluoro, oxo, OH, OCH 3 , C(0)OH, or C(0)OCH 3 ; each R Y is independently chloro, fluoro, CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , or CN; or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 R x ; and R 1 is hydrogen. 28. The compound of any one of claims 1-27, wherein the compound of Formula (I) is a compound of Formula (I-b) Formula (I-b) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein each of A, W, Z, L 1 , and L 2 is defined as for Formula (I).;
claim 25: 29. The compound of any one of claims 1-28, wherein the compound of Formula (I) is a compound of Formula (T Formula (I-c) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 26: 30. The compound of any one of claims 1-29, wherein the compound of Formula (I) is a compound of Formula -d) : Formula (I-d) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 27: 31. The compound of any one of claims 1-28, wherein the compound of Formula (I) is a compound of Formula (I-e-1), Formula (I-e-2), Formula (I-e-3), Formula (I-e-4), Formula (I-e- 5), Formula (I-e-6), Formula (I-e-7), Formula (I-e-8), Formula (I-e-9), Formula (I-e- 10), Formula (I-e-11), Formula (I-e-12), Formula (I-e-13), Formula (I-e-14), or Formula (I-e-15): Formula (I-e-1) Formula (I-e-2) Formula (I-e-3) Formula (I-e-4) Formula (I-e-5) Formula (I-e-6) Formula (I-e-7) Formula (I-e-8) Formula (I-e-9) Formula (I-e-11) Formula (I-e-14) 15 Formula (I-e-15) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 28: 32. The compound of any one of claims 1-27, wherein the compound of Formula (I) is a compound of Formula (I-f): Formula (I-f) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, stereoisomer thereof.;
claim 29: 33. The compound of any one of claims 1-27 and 32, wherein the compound of Formula (I) is a compound of Formul Formula (I-g) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 30: 34. The compound of any one of claims 1-27 and 32-33, wherein the compound of Formula (I) is a compound of Formula (Th): Formula (I-h) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. 35. The compound of any one of claims 1-27 and 32-34, wherein the compound of Formula (I) is a compound of Formula (Ti-1), Formula (Ti-2), Formula (Ti-3), Formula (Ti-4), Formula (I-i-5), Formula (Ti-6), Formula (Ti-7), Formula (Ti-8), Formula (Ti-9), Formula (I-i-10), Formula (I-i-11), Formula (I-i-12), Formula (I-i-13), Formula (I-i-14), or Formula (I-i-15): Formula (Ti-1) Formula (Ti-2) Formula (Ti-3) Formula (Ti-4) Formula (I-i-5) Formula (I-i-6) Formula (I-i-7) Formula (I-i-8) Formula (I-i-9) Formula (I-i Formula (I- Formula (I-i- 12) Formula (I-i- 13) Formula (I- Formula (I-i- 15) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 31: 36. The compound of any one of claims 1-27, wherein the compound of Formula (I) compound of Formula (I-j): Formula (I-j) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 32: 37. The compound of any one of claims 1-27 and 36, wherein the compound of Formula (I) is a compound of Formul Formula (I-k) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 33: 38. The compound of any one of claims 1-27 and 36-37, wherein the compound of Formula (I) is a compound of Formula (1-1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 34: 39. The compound of any one of claims 1-27 and 36-38, wherein the compound of Formula (I) is a compound of Formula (I-m-1), Formula (I-m-2), Formula (I-m-3), Formula (I-m-4), Formula (I-m-5), Formula (I-m-6), Formula (I-m-7), Formula (I-m-8), Formula (I-m-9), Formula (I-m-10), Formula (I-m-11), Formula (I-m-12), Formula (I-m-13), Formula (I-m-14), or Formula (I-m-15): Formula (I-m-1) Formula (I-m-2) Formula (I-m-3) Formula (I-m-4) Formula (I-m-5) Formula (I-m-6) Formula (I-m-7) Formula (I-m-8) Formula (I-m-9) Formula (I-m-10) Formula (I-m-11) Formula (I-m-12) Formula (I-m-13) Formula (I-m-14) Formula (I-m-15) Formula (I-m-16) Formula (I-m-17) Formula (I-m-18) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, stereoisomer thereof. A compound of Formula II): Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is bicyclo[l.l.l]pentane, bicyclo[2.2.2]octane, cyclohexyl, cyclobutyl, or tetrahydropyranyl each of which is optionally substituted with 1-4 R x groups; L 1 is a bond, Ci-C 6 alkylene, 2-7 membered heteroalkylene, or -0-, wherein Ci-C 6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R L1 ; R 1 is hydrogen or Ci-C 6 alkyl; A is phenyl or 5-6-membered heteroaryl, wherein phenyl or 5-6-membered heteroaryl is optionally substituted on one or more available carbons with 1-5 R Y ; and wherein if the 5-6- membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R N4 ; T 5 is nitrogen or C(R T ); T 6 is nitrogen or C(R T ); T 7 is nitrogen or C(R T ); T 8 is nitrogen or C(R T ); wherein no more than two of T 5 , T 6 , T 7 , and T 8 may be nitrogen; V 2 is selected from the group consisting of * -C(R V21 R V22 )- # , * -C(R V21 R V22 )- C(R V23 R V24 )- # , -C(R V21 R V22 )-C(R V23 R V24 )-C(R V23 R V24 )- # , -C(R V21 R V22 )-C(R V21 R V22 )-0- # , -C(R V21 R V22 )-C(R V21 R V22 )-NR N4 – # , -C(R V21 R V22 )-NR N4 – # , -C(0)-C(R V23 R V24 )- # , -C(O)- C(R V23 R V24 ) _ C(R V23 R V24 ) _# 5 *_ C(0) _ NR N4_# *_ C(0) _# AND *_ C(0 )-0- # , wherein and “- # ” indicate the attachment points of V 2 as indicated in Formula (II); 2 * + * U21 U22 + U is selected from the group consisting of a bond, -C(O) – , and -C(R R ) – , wherein ” * -” and “- + indicate the attachment points of U 2 as indicated in Formula (II); wherein if V 2 is * -C(R V21 R V22 )- # , U 2 is not a bond; U21 U22 R and are each independently selected from the group consisting of hydrogen, Ci- C 6 alkyl, hydro y-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C 6 alkyl, – OH, -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , C 2 -C 6 alkyl-C(0)OH, and C 2 -C 6 alkyl- C(0)OR D ; R V21 and R V22 are each independently selected from the group consisting of hydrogen, C – Ce alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, – OH, -C(0)NR B R c , -C(0)R D , -C(0)OH, and -C(0)OR D ; and V23 RV24 R v ^ and ^ are each independently selected from the group consisting of hydrogen, Ci- C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , – S(0)R D , and -S(0) 2 R D ; each R L1 is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, oxo, halo, cyano, -OR A , – NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and – S(0) 2 R D ; R N4 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; each R T is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C 6 alkyl, halo-Ci-C 6 alkyl, halo-Ci-C 6 alkoxy, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, – C(0)OR D , -S(R F ) m , -S(0)R D , and -S(0) 2 R D ; or 2 R T groups on adjacent atoms, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R x ; each R x is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and -S(0) 2 R D ; each R Y is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, – C(0)OR D , -S(R F ) m , -S(0)R D , -S(0) 2 R D , and G 1 ; or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R x ; each G 1 is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R z ; each R z is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , and -S(0) 2 R D ; R A is, at each occurrence, independently hydrogen, Ci-C 6 alkyl, halo-Ci-C 6 alkyl, – C(0)NR B R c , -C(0)R D , or -C(0)OR D ; each of R B and R c is independently hydrogen or Ci-C 6 alkyl; or R B and R c together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R z ; each R D is independently Ci-C 6 alkyl or halo-Ci-C 6 alkyl; each R E is independently hydrogen, Ci-C 6 alkyl, or halo-Ci-C 6 alkyl; each R F is independently hydrogen, Ci-C 6 alkyl, or halo; and m is 1 when R F is hydrogen or Ci-C 6 alkyl, 3 when R F is Ci-C 6 alkyl, or 5 when R F is halo.;
claim 35: 41. The compound of claim 40, wherein the compound is represented by:;
claim 36: 42. The compound of any one of claims 40-41, wherein V 2 is selected from the group consisting of -C(R V21 R V22 )- # , -C(R V21 R V22 )-C(R V23 R V24 )- # , -C(0)-C(R V23 R V24 )- # , and – C(R V21 R V22 )-C(R V23 R V24 )-C(R V23 R V24 )- # ; wherein and “-* ” indicate the attachment points of V 2 as indicated in Formula (II). V21 V22;
claim 37: 43. The compound of any one of claims 40-42, wherein each of R and R is independently selected from the group consisting of hydrogen, -OH, and C1-C3 alkyl. V 1 V22;
claim 38: 44. The compound of any one of claims 40-43, wherein each of R and R is hydrogen or -OH;
claim 39: 45. The compound of any one of claims 40-45, wherein each of R and R is independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, cyano, and -NR B R C .;
claim 40: 46. The compound of any one of claims 40-45, wherein each of R and R is hydrogen. 47. The compound of any one of claims 40-46, wherein U 2 is selected from the group consisting of a bond, * -C(0) – + , * -CH 2 – + , and * -CH(CH 2 C0 2 H) – + , wherein and “- +” indicate the attachment points of U 2 as indicated in Formula (II); and V 2 is selected from the group consisting of * -CH 2 – # , * -CH 2 -CH 2 – # , * -C(0)-CH 2 – # , * -C(0)-NH- # , * -CH 2 -NH- # , and -CH 2 -CH 2 -CH 2 – ; wherein ” -” and “- indicate the attachment points of V as indicated in Formula (II). 48. The compound of any one of claims 40-47, wherein the moiety is selected from the group consisting of:;
claim 41: 50. The compound of claim 49, wherein each R is independently selected from the group consisting of oxo, -OH , -C(0)OH, -C(0)OR D , halo, and hydroxy-Ci-C 6 alkyl.;
claim 42: 51. The compound of any one of claims 40-50, wherein L 1 is CH 2 O-* or CH 2 OCH 2 -*; wherein “-*” indicates the attachment point to A. The compound of any one of claims 40-51, wherein R 1 is hydrogen or CH 3;
claim 43: 53. The compound of any one of claims 40-52, wherein A is selected from the group consisting of:;
claim 44: 54. The compound of any one of claims 40-53, wherein each R Y is independently hydrogen, chloro, fluoro, CF 3 , CH 3 , CHF 2, OCF 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , or CN.;
claim 45: 55. The compound of any one of claims 40-54, wherein each R T is independently selected from the group consisting of hydrogen, chloro, fluoro, CHF 2 , CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCHF 2 , OCF 3 , OCH 2 CF 3, OCH(CH 3 ) 2 , and CN.;
claim 46: 56. The compound of any one of claims 40-55, wherein the compound of Formula (II) is a compound of Formula (ITa): Formula (ITa) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: R 1 is hydrogen or CH 3; each R Y is independently hydrogen, chloro, fluoro, CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , or CN; and each R T is independently selected from the group consisting of hydrogen, chloro, fluoro, CHF 2 , CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCHF 2 , OCF 3 , OCH 2 CF 3, OCH(CH 3 ) 2 , and CN.;
claim 47: 57. The compound of any one of claims 1-56, wherein the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 48: 58. A pharmaceutically acceptable composition comprising a compound of any one of claims 1-57 and a pharmaceutically acceptable carrier.;
claim 49: 59. A composition for use in treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject, wherein the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof as described in any one of claims 1-57.;
claim 50: 60. The composition of claim 59, wherein the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain injury.;
claim 51: 61. The composition of any one of claims 59 or 60, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo myelination, Alzheimer’s disease, amyotrophic lateral sclerosis, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington’s disease, dementia, kuru, multiple sclerosis, Parkinson’s disease, or a prion disease. 62. The composition of any one of claims 59-61, wherein the neurodegenerative disease comprises vanishing white matter disease.;
claim 52: 63. The composition of claim 59, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or a cancer of the secretory cells.;
claim 53: 64. The composition of claim 59, wherein the inflammatory disease comprises postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulonephritis, auto- immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves’ ophthalmopathy, inflammatory bowel disease, Addison’s disease, vitiligo, asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.;
claim 54: 65. The composition of claim 59, wherein the musculoskeletal disease comprises muscular dystrophy, multiple sclerosis, amyotropic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscle atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Freidrich’s ataxia, a muscle wasting disorder, an inclusion body myopathy, motor neuron disease, or paralysis. 66. The composition of claim 59, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. 67. The composition of claim 59, wherein the mitochondrial disease is associated with or is a result of mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations.;
claim 55: 68. The composition of claim 59 or 67, wherein the mitochondrial disease is a mitochondrial myopathy.;
claim 56: 69. The composition of any one of claims 59 and 67-68, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber’s hereditary optic neuropathy (LHON), and Pearson syndrome.;
claim 57: 70. The composition of claim 59, wherein the autoimmune disease is selected from the group consisting of Achalasia, Addison’s disease, Adult Still’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes),

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