WO2019090085A1 – 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; CHUNG, Seungwon - 1512 Virginia Avenue, Libertyville, IL 60048; ZHANG, Qingwei, I. - 1820 S. Falcon Drive, Libertyville, IL 60048; SHI, Lei - 1908 Trevino Terrace, Vernon Hills, IL 60061; MURAUSKI, Kathleen - 1807 W. Argyle Street, Apt. 404, Chicago, IL 60640; DART, Michael, J. - 844 Yale Lane, Highland Park, IL 60035; RANDOLPH, John, T. - 304 Braodway Avenue, Libertyville, IL 60048

Owner :

CALICO LIFE SCIENCES LLC ABBVIE INC.

Application Number :

WOUS18058969

Document Number :

WO2019090085A1

Priority Date :

January 1, 1970

Filing Date :

November 2, 2018

Date of Grant/ Publication :

May 9, 2019

Class :

; C07C233 / 00; C07C235 / 00; C07C237 / 00; A61P19 / 00; A61P25 / 00; A61P3 / 00; A61P21 / 00; A61P29 / 00; A61P35 / 00; A61K31 / 16; A61K31 / 165; A61K31 / 538; A61K31 / 352; A61K31 / 36; A61K31 / 498; C07D311 / 66; C07D319 / 20; C07D405 / 12; C07D413 / 06; C07D265 / 36; C07D493 / 04; C07D207 / 22; C07D209 / 42; C07D307 / 84

Abstract

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

Claim(s)

We claim: 1. A compound of Fo 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, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl 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 be optionally substituted by R N1 ; L 1 is a bond, Ci-C 6 alkylene, 2-7 membered heteroalkylene, -NR N2 -, or -0-, wherein Ci-C 6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R L1 ; L 2 is a bond, Ci-C 6 alkylene, or 2-7 membered heteroalkylene, 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; R 2 is hydrogen or Ci-C 6 alkyl; W is a 8-10 membered, partially unsaturated, fused bicyclic ring moiety comprising a 5-6 membered heterocyclyl fused to a phenyl or 5-6-membered heteroaryl; wherein the heterocyclyl may be optionally substituted on one or more available saturated carbons with 1-4 R W1 ; and wherein the phenyl or heteroaryl may optionally be substituted on one or more available unsaturated carbons with 1-4 R W2 ; and wherein if the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may optionally be substituted with R N3 ; and wherein W is attached to L 2 through an available saturated carbon or nitrogen atom within the heterocyclyl; 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 ; each R L1 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 L2 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 ; 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, Ci-C 6 alkenyl, – C(0)-Ci-C 6 alkyl, -C(0)-Ci-C 6 cycloalkyl, Ci-C 6 alkyl-C0 2 H, Ci-C 6 alkyl-C0 2 -Ci-C 6 alkyl, – C(0)-Ci-C 3 alkyl-0-Ci-C 3 alkyl-0-Ci-C 3 alkyl, -C(0)-phenyl, -C(0)-heteroaryl, -C(O)- heterocyclyl, -S-Ci-C 6 alkyl, -S(0) 2 -Ci-C 6 alkyl, -S(0) 2 -phenyl, -S(0) 2 -heteroaryl, – C(0)NR B R c and -C(0)OR D ; wherein Ci-C 6 alkyl, Ci-C 6 alkenyl, C(0)-Ci-C 6 alkyl, -C(0)-Ci-C 6 cycloalkyl, Ci-C 6 alkyl-C0 2 H, Ci-C 6 alkyl-C0 2 -Ci-C 6 alkyl, -C(0)-heterocyclyl, -S-Ci-C 6 alkyl and – S(0) 2 -Ci-C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of fluoro, hydroxyl, Ci-C 6 alkoxy, Ci-C 6 alkyl (optionally substituted by one, two or three fluorine atoms) and S(0) w Ci_6 alkyl (wherein w is 0, 1 or 2); and wherein -C(0)-phenyl, -C(0)-heteroaryl, -S(0) 2 -phenyl and -S(0) 2 -heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, Ci-C 6 alkyl (optionally substituted by one, two or three fluorine atoms), Ci-C 6 alkoxy (optionally substituted by one, two or three fluorine atoms), S(0 2 )NR B R c and S0 2 F; 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 W1 is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl (optionally substituted by -C0 2 H), hydroxy-Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl-O-, 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 R CC , – 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 W2 is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-C2-C6 alkyl-O- halo-Ci-C6 alkyl, halo-Ci-C6 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 W2 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 cc is independently selected from the group consisting of Ci-C 6 alkyl-OH, Ci-C 6 alkyl-C0 2 H and Ci-C 6 alkyl-C0 2 -Ci-C 6 alkyl; 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-C6 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 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 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, or 2- azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 R x groups.;
nd of any one of claims 1-5, wherein 8. The compound of any one of claims 1-7, wherein D is substituted with 0 R The compound of any one of claims 1-8, wherein D 10. The compound of any one of claims 1-7, wherein D is substituted with 1 or 2 R ound of any one of claims 1-7 and 10, wherein D 12. The compound of any one of claims 10-11, 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 5: The compound of any one of claims 1-12, wherein L is a bond, 2-7 membered heteroalkylene, -NR -, or -0-, wherein 2-7 membered heteroalkylene is optionally substituted by 1-5 R” 1 .;
claim 6: The compound of any one of claims 1-13, wherein L is a bond, 2-7 membered heteroalkylene, -NR -, or -0-, wherein 2-7 membered heteroalkylene is substituted by 0 R L L 1 l.;
claim 7: 15. The compound of any one of claims 1-14, wherein L 1 is selected from a bond, CH 2 O-*, CH 2 OCH 2 -*, -NCH 3 -, -NH-, or -0-, wherein “-*” indicates the attachment point to A.;
claim 8: 16. The compound of any one of claims 1-15, wherein R 1 is hydrogen or CH 3 .;
claim 9: 17. The compound of any one of claims 1-16, wherein R 2 is hydrogen or CH 3 .;
claim 10: 18. The compound of any one of claims 1-17, wherein A is phenyl or 5-6-membered heteroaryl; wherein 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-C6 alkyl, halo, cyano, -OR A , or G 1 .;
claim 11: 19. The compound of any one of claims 1-18, wherein A is phenyl, pyrazine, or pyridyl, each of which is optionally substituted with 1-2 R Y groups.;
claim 12: 20. The compound of any one of claims 1-19, wherein A is selected from the group consistin of: 21. The compound of any one of claims 1-20, wherein each R Y is independently selected from the group consisting of hydrogen, chloro, fluoro, CHF 2 , CF 3 , CH 3 , CH 2 CH 3 , CH(C]¾) 2 , OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH 3 ) 2 , and CN.;
claim 13: 22. The compound of any one of claims 1-19, wherein L 2 is a bond or Ci-C 6 alkylene, wherein Ci-C 6 alkylene is optionally substituted by 1-5 R L2 .;
claim 14: 23. The compound of any one of claims 1-22, wherein L 2 is a bond or Ci-C 6 alkylene, wherein Ci-C 6 alkylene is optionally substituted by 0 R L2 .;
claim 15: 24. The compound of any one of claims 1-23, wherein L 2 is selected from a bond or CH 2 -*, wherein “-*” indicates the attachment point to W.;
claim 16: The compound of any one of claims 1-24, wherein L 2 is a bond.;
claim 17: The compound of any one of claims 1-25, wherein W is represented by Formula (W-a): Formula (W-a) wherein: T 1 is nitrogen or C(R W2 ) T 2 is nitrogen or C(R W2 ) T 3 is nitrogen or C(R W2 ) T^ is nitrogen or C(R W2 ); wherein no more than two of T 1 , T 2 , T 3 , and T 4 may be nitrogen; U 1 is selected from the group consisting of a bond, -0-, -NR N3 -, and -S(0) w – (wherein w is 0, 1, or 2); V 1 is selected from the group consisting of + -0- # , + -C(R V11 R V12 ) – # , + -C(R V11 R V12 ) – C(0)- # , + -C(R vl l R vl2 )-C(R vl3 R vl4 )- # , + -C(R vl5 R vl6 )-0- # , + -C(R vl5 R vl6 )-NR N3 – # , + -C(0)- NR N3 – # , + -NR N3 – # , + -0-C(R vl5 R vl6 )- # , + -NR N3 ^C(R vl5 R vl6 )- # , + -NR N3 ^C(0)- # , + -C(0)-0- # , +-0-C(0)- # , + -C(R vl5 R vl6 )-S(0) w – # , and + -S(0) w -C(R vl5 R vl6 )- # (wherein w is 0, 1, or 2); wherein the ” + -” and “-* indicate the attachment points of V 1 as indicated in Formula (W-a); wherein if V 1 is + -0- # , + -NR N3 – # , or + -C(R V11 R V12 ) – # ; U 1 is not a bond; R vl l and R V12 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, ccyyaannoo,, –OORR AA ,, –NNRR BB RR CC ,, –NNRR BB RR CCCC ,, -—NNRR BB CC((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 ; RR Vv1l33 aanndd RR VV1144 aarree eeaacchh iinnddeeppeennddeenntt]ly selected from the group consisting of hydrogen, C – C 6 alkyl, hydroxy-Ci-C 6 alkyl, halo-Ci-C 6 alkyl, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B R CC ,— 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 vl5 and R V16 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-C6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OH, and -C(0)OR D ; and R W1 is selected from the group consisting of hydrogen and Ci-C 6 alkyl.;
claim 18: 27. The compound of claim 26, wherein W is represented by Formula (W-a-1), Formula (W- a-2), Formula (W-a-3), Formula (W-a-4 or Formula (W-a-5): Formula (W-a-1), Formula (W-a-2), Formula (W-a-3), Formula (W-a-4), or Formula (W-a-5).;
claim 19: 28. The compound of claim 27, wherein W is re resented by Formula (W-a-1): Formula (W-a-1).;
claim 20: 29. The compound of any one of claims 26-28, wherein U 1 is selected from the group consisting of a bond, -0-, and -NR N3 -; and V 1 is selected from the group consisting of + -0- # , + -C(R V11 R V12 ) – # , + -C(R V11 R V12 )-C(R V13 R V14 ) – # , + -C(R vl5 R vl6 )-0- # , + -C(R V11 R V12 ) -C(0)- # , ÷_0-C(R vl5 R vl6 )- # , + -C(R vl5 R vl6 )-NR N3 – # , and + -C(0)-NR N3 – # ; wherein ” + -” and “- #” indicate the attachment points of V 1 as indicated in Formula (W-a); and wherein if V 1 is + -0- # or + -C(R V11 R V12 ) – # , U 1 is not a bond. 30. The compound of any one of claims 26-28, wherein each of R vn , R V12 , R V13 , and R V14 is independently selected from the group consisting of hydrogen, halo, C1-C 3 alkyl, cyano, -OR A , – NR B R C and -NR B R CC .;
claim 21: 31. The compound of any one of claims 26-30, wherein each of R vn , R V12 , R V13 , and R V14 is independently selected from the group consisting of hydrogen, hydroxyl and -NR R .;
claim 22: 32. The compound of any one of claims 26-31 , wherein each of R V15 and R V16 is independently selected from the group consisting of hydrogen and C1-C 3 alkyl. 33. The compound of any one of claims 26-32, wherein each of R V15 and R V16 is hydrogen.;
claim 23: 34. The compound of any one of claims 26-32, wherein U 1 is selected from the group consisting of a bond, -0-, -NH- and -NCH 3 -; and V 1 is selected from the group consisting of + -0- # , + -CH 2 – # , + -CH 2 -CH 2 – # , + -CH 2 -C(0)- # , + -CH 2 -0- # , + -0-CH 2 – # , + -CH 2 -NH- # , + -CH 2 – NCH 3 – # , + -C(0)-NH- # , and + -C(0)-NCH 3 – # , and wherein ” + -” and indicate the attachment points of V 1 as indicated in Formula (W-a).;
claim 24: 35. The compound of any one of claims 26-34, wherein R W1 is selected from the group consisting of hydrogen, hydroxyl, CH 3, NH(CH 2 ) 2 OH, NH(CH 2 ) 2 C0 2 H and NH(CH 2 ) 2 C0 2 CH 3 .;
claim 25: 36. The compound of any one of claims 26-35, wherein W is a benzo[J|[l,3]dioxole, 3,4- dihydro-2H-benzo[Z?] [l ,4]oxazine, chromane, chroman-4-one, 2H-benzo[Z?][l,4]oxazin-3(4H)- one, 2,3-dihydrobenzo[Z?][l,4]dioxine, indoline, or 2,3-dihydrobenzofuran moiety; wherein each of which is attached to L 2 through a saturated carbon atom, and wherein each of which is optionally substituted on one or more available unsaturated carbons with 1-4 R W2 , and wherein each R W2 is independently selected from the group consisting of Ci-C 6 alkyl, halo-Ci-C6 alkyl, halo, oxo, cyano, and -OR A . 37. The compound of any one of claims 26-36, wherein W is selected from the group 38. The compound of any one of claims 1-24, wherein L 2 is Ci-C 6 alkylene optionally substituted by 1-5 R L2 .;
claim 26: 39. The compound of any one of claims 1-24 and 38, wherein L 2 is Ci-C 6 alkylene substituted by 0 R L2 .;
claim 27: 40. The compound of any one of claims 1-24 and 38-39, wherein L 2 is CH 2 -*, wherein “- : indicates the attachment point to W.;
claim 28: 41. The compound of any one of claims 1-24 and 38-40, wherein W is represented by Formula (W-b): Formula (W-b) wherein: T 5 is nitrogen or C(R W2 ) T 6 is nitrogen or C(R W2 ) T 7 is nitrogen or C(R W2 ) T 8 is nitrogen or C(R W2 ) 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 N3 – # , -C(R V21 R V22 )-NR N3 – # , -C(0)-C(R V23 R V24 )- # , -C(O)- C(R V23 R V24 ) _ C(R V23 R V24 ) _# 5 *_ C(0) _ NR N3_# ^ *_ C(0) _ 0 _# wherem ^ the attachment points of V 2 as indicated in Formula (W-b); 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 (W-b); 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-C6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , d-C 6 alkyl-C(0)OH, and Ci-C 6 alkyl- C(0)OR u ; R V21 and R V22 are each independently selected from the group consisting of hydrogen, C – C 6 alkyl, hydro y-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OH, and -C(0)OR D ; and R V23 and RV24 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 .;
claim 29: 42. The compound of claim 41, wherein W is represented by Formula (W-b-1), Formula (W- b-2), Formula (W-b-3), Formula (W-b-4), or Formula (W-b-5): Formula (W-b-1), Formula (W-b-2), Formula (W-b-3), Formula (W-b-4), or Formula (W-b-5).;
claim 30: The compound of claim 42, wherein W is represented by Formula (W-b-1): Formula (W-b-1).;
claim 31: 44. The compound of any one of claims 41-43, 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 (W-b).;
claim 32: V21 V22 45. The compound of any one of claims 41-44, wherein each of R and R is independently selected from the group consisting of hydrogen and C1-C 3 alkyl.;
claim 33: V 1 V22 46. The compound of any one of claims 41-45, wherein each of R and R is hydrogen.;
claim 34: 47. The compound of any one of claims 41-46, wherein each of R V23 and R V24 is independently selected from the group consisting of hydrogen, halo, C1-C 3 alkyl, cyano, -OR A , and -NR B R C . 48. The compound of any one of claims 41-47, wherein each of R V23 and R V24 is hydrogen.;
claim 35: 49. The compound of any one of claims 41-48, 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 (W-b); 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 (W-b).;
claim 36: 50. The compound of any one of claims 41-49, wherein W is an indoline, indolin-2-one, isoindoline, isoindolin-l-one, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, quinazoline-2,4(lH,3H)-dione, or 2,3-dihydroquinazolin-4(lH)-one moiety; wherein each of which is attached to L 2 through a nitrogen atom, and wherein each of which is optionally substituted on one or more available unsaturated carbon atoms with 1-4 R W2 , and wherein each R W2 is independently selected from the group consisting of Ci-C 6 alkyl, halo-Ci-C 6 alkyl, hydroxy-C 2 -C6 alky 1-0-, halo, cyano, and -OR A .;
claim 37: 51. The compound of any one of claims 41-50, wherein W is selected from the group consisting of: alkyl, and hydro y-C2-C6 alkyl.;
claim 38: 52. The compound of any one of claims 1-51, wherein each R Y is independently selected from the group consisting of hydrogen, chloro, fluoro, CHF2, CF 3 , CH 3 , CH2CH 3 , CH(C]¾)2, OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH 3 ) 2 , and CN.;
claim 39: 53. The compound of any one of claims 1-51, wherein 2 R Y on adjacent carbons, together with the atoms to which they are attached form a 1,3-dioxolanyl ring, which is optionally substituted with 1-2 R x .;
claim 40: 54. The compound of claim 53, wherein each R x is independently fluoro.;
claim 41: 55. The compound of any one of claims 1-54, wherein the compound of Formula (I) is a compound of Formula (Ta): Formula (I- a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is bicyclo[l.l.l]pentanyl or bicyclo[2.2.2]octanyl, each of which is optionally substituted with 1-4 R x groups; L 1 is selected from the group consisting of a bond, CJ¾0-* , CH 2 OCH 2 -*, -NCH 3 -, – NH-, and -0-, wherein “-*” indicates the attachment point to A; L 2 is a bond; R 1 is selected from the group consisting of hydrogen and CH 3 ; R 2 is selected from the group consisting of hydrogen and CH 3 ; A is phenyl, pyrazine or pyridyl, each of which is optionally substituted with 1 -5 R Y groups; W is a benzo[

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