Nova Patents
IL260674A

Inhibitors of receptor-interacting protein kinase 1

Abstract

This record has no abstract on file.

IL260674A, drawing sheet 1
Sheet 1 of 808

Term

No projected expiry on record.

  1. Priority
  2. Filed
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  4. Today

4 claims: 3 independent, 1 dependent

  1. 1
    A compound of Formula II:or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2;X 6 , X 7 , and X 8 each N or CH, wherein only one of X 6 , X 7 , and X 8 is N;X 9 is N;R 1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy, deuterium, or cyano;Y 2 is -O- or -C(R6)2- each R6 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R6 together with the carbon atom to which they are attached form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;R 3 and R 4 are independently H, halo, or optionally substituted C1-C6 alkyl, or R 3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;A is an optionally substituted heteroaryl ring;L is -C(R 8 )2-, or is absent, or is -O-;R 7 is H or optionally substituted C1-C6 alkyl;each R 8 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;R 9 is optionally substituted phenyl, optionally substituted heteroaryl, or cycloalkyl, wherein said cycloalkyl refers to cyclopentyl which is re-fused to a phenyl ring;and each R 10 is independently cyano, halo, or optionally substituted alkyl;415 260674/4 provided that at least one of the following occurs: (1) at least one of R 3 and R 4 are halo or optionally substituted C1-C6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
  2. 2
    (2) L is absent or -C(R 8 )2-, and each R 8 is optionally substituted C1-C6 alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
  3. 3
    (3) Y 2 is -C(R6)2-;and one R6 is hydrogen, halo, or optionally substituted C1-C6 alkyl, and the other R 6 is halo or optionally substituted C1-C6 alkyl;or two R 6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
  4. 4
    (4) Y 2 is -O-; and A is substituted with halo or cyano; or A is thiazolyl; or (5) R 1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; and wherein each optionally substituted pyridyl, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom’s normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, -SH, thioxo, Noxide, -Si(R 100 )3 wherein each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,-OC(O)R, and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; and further wherein:416 260674/4 each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro;each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and/or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro;and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2. The compound of claim 1, wherein the compound is of Formula (IIe) or (IIf): or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;wherein q is 0, 1 or 2;R 1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;Y2 is -O- or -C(R6)2-;each R6 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R6 together with the carbon atom to which they are attached form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;R 3 and R 4 are independently H, halo, or optionally substituted C1-C6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an 417 260674/4 optionally substituted cycloalkyl or heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;L is -C(R 8 )2- or is absent, -O-, -S-, -S(O)-, -S(O)2-, or -NR 7 -;R 7 is H or optionally substituted C1-C6 alkyl;each R 8 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl ring;R 9 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;and each R 10 is independently cyano, halo, or optionally substituted alkyl. 3. The compound of claim 2, wherein the compound is of Formula IIf-1 or IIe-1: or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;wherein q is 0, 1 or 2;R 1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy, or cyano;R 4 is H, halo, or optionally substituted C1-C6 alkyl;A is an optionally substituted heteroaryl ring, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;L is -C(R 8 )2- or is absent, -O-, -S-, -S(O)-, -S(O)2-, or -NR 7 -;R 7 is H or optionally substituted C1-C6 alkyl;418 260674/4 each R 8 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl ring;R 9 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;and each R 10 is independently cyano, halo, or optionally substituted alkyl. 4. The compound of claim 2, wherein the compound is of Formula (IIe): or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 5. The compound of claim 4, wherein the compound is of Formula IIe-2, Formula IIe-3, Formula IIe-4, Formula IIe-5, or Formula IIe-6: 419 260674/4 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 6. The compound of claim 5, wherein the compound is of Formula IIe-2 or IIe-4, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 7. The compound of claim 2, wherein the compound is of Formula IIf, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 8. The compound of claim 7, wherein the compound is of Formula IIf-2, Formula IIf-3, Formula IIf-4, Formula IIf-5, or Formula IIf-6: 420 260674/4 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 9. The compound of any one of claims 1-8, wherein the A ring is an optionally substituted 5-membered heteroaryl ring. 10. The compound of any one of claims 1-8, wherein the A ring is: N=N r=N N-N N-N N-NH ,,,,, N=N N=^ A or N ז wherein each ring is optionally substituted with one or more halo, cyano or C1-C6 alkyl. 11. The compound of any one of claims 1-8, wherein A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4Hpyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl. 421 260674/4 12. The compound of claim 11, wherein A is pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. 13. The compound of claim 11, wherein A is oxadiazolyl. 14. The compound of claim 11, wherein A is triazolyl. 15. The compound of any one of claims 1-14, wherein L is -C(R 8 )2-. 16. A compound of Formula V: R 3 O v or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2;X 6 is independently N or CR 14 ;X 9 is N;R 1 is H or optionally substituted C1-C6 alkyl;Y 2 is -O- or -C(R 6 )2-;each R 6 is independently H, halo, optionally substituted C1-C6 alkyl;R 3 is H, halo, optionally substituted C1-C6 alkyl, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;L is -C(R 8 )2-;each R 8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;R 9 is optionally substituted phenyl or optionally substituted heteroaryl;each R 10 is independently cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted 422 260674/4 heterocyclyl, optionally substituted cycloalkyl, optionally substituted C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl;each R 14 is independently hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo, or C1-C3 alkoxy optionally substituted with halo;and wherein each optionally substituted pyridyl, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom’s normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, -SH, thioxo, Noxide, -Si(R 100 )3 wherein each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,-OC(O)R, and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;and further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro;each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and/or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro;and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 423 260674/4 17. The compound of claim 16, wherein R 14 is hydrogen, cyano, halo or methyl optionally substituted with 1-3 fluoro or oxo. 18. A compound of Formula VI: VI or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2;X 6 is N or CR 14 ;R 1 is H or optionally substituted C1-C6 alkyl;Y 2 is -O- or -C(R 6 )2-;each R 6 is independently H, halo, optionally substituted C1-C6 alkyl;R 3 is H, halo, optionally substituted C1-C6 alkyl, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;L is -C(R 8 )2-;each R 8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;R 9 is optionally substituted phenyl;each R 10 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted C1-C6 alkoxy;R 14 is hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo or oxo, or C1-C3 alkoxy optionally substituted with halo or oxo;and wherein each optionally substituted pyridyl, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom’s normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, 424 260674/4 amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, -SH, thioxo, Noxide, -Si(R 100 )3 wherein each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,-OC(O)R, and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;and further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro;each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and/or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro;and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 19. The compound of any one of claims 16-18, wherein X 6 is CR 14 . 20. The compound of any one of claims 16-18, wherein X 6 is N. 21. The compound of any one of claims 18-20, wherein R 14 is hydrogen. 22. The compound of any one of the preceding claims, wherein R 1 is C1-C6 alkyl. 23. The compound of claim 22, wherein R 1 is methyl. 425 260674/4 24. The compound of any one of claims 1-2 and 4, wherein Y 2 is O. 25. The compound of any one of claims 1-2 and 4, wherein R 3 is hydrogen or fluoro. 26. The compound of claim 25, wherein R 3 is H. 27. The compound of any one of claims 1-2 and 4, wherein R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. 28. The compound of claim 27, wherein R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring. 29. The compound of any preceding claim, wherein R 4 is optionally substituted C1-C6 alkyl. 30. The compound of claim 29, wherein R 4 is methyl. 31. The compound of claim 29, wherein R 4 is H. 32. The compound of any one of claims 1-31, wherein L is -C(R 8 )2- and each R 8 is independently H, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl. 33. The compound of claim 32, wherein L is -C(R 8 )2- and two R 8 together with the carbon atom to which they are attached form a cycloalkyl ring. 34. The compound of claim 33, wherein L is -C(R 8 )2- and two R 8 are taken together with the carbon atom to which they are attached to form cyclopropyl. 35. The compound of any one of claims 1-34, wherein L is CH2. 426 260674/4 36. The compound of any one of claims 1-35, wherein R 9 is optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted cycloalkyl. 37. The compound of claim 36, wherein R 9 is phenyl, dihydroindenyl, pyridyl, 2fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4cyanophenyl, 2,4-difluorophenyl, 3-cyano-4-fluorophenyl, or 5-fluoropyridin-3-yl. 38. The compound of claim 36, wherein R 9 is optionally substituted phenyl. 39. The compound of claim 38, wherein R 9 is phenyl optionally substituted with one or more halo, cyano, or C1-C6 alkyl optionally substituted with halo. 40. The compound of claim 39, wherein R 9 is phenyl substituted by one to two halo. 41. The compound of any one of claims 1-36, wherein R 9 is optionally substituted pyridyl, phenyl, or 2,3-dihydro-1H-indenyl. 42. The compound of any preceding claim, wherein each R 10 is independently halo. 43. The compound of claim 42, wherein each R 10 is independently fluoro. 44. The compound of any one of claims 1-43 wherein q is 2. 45. A compound of claim 1 that is: No. Structure No. Structure 110A z=< I \ Z x ZT z^O 0.4 / tz y z Λ __// 427 260674/4 No. Structure No. Structure 110B Η Ό \ T Vnh n 111A \ .0 111B \ .0 112 \ O — 115 \ .0 00 117 \ o °־yj F 119A \ .0 ζΑΎ Ν 'Ν - 0Haj3 119B \ .0 \ || 0ΝΗ N 428 260674/4 No. Structure No. Structure 120A \ .0 120B 0. \ NH n״τ y \ 121A \ p Ν,χΝ-Ϋ if I \״NH N—λ \_d A 0 /=\ °17־ F F 121B \ p Ν,χΝ-Ϋ if | )—NH N—λ \_d A 0 /=\ °AP־ F F 122 \ .0 123 Η Ό VLO 124 \ .0 125A 0. \ ׳ν,Ν-Ρ ί J YNH N 125B \ .0 ί Ύ Unh n 429 260674/4 No. Structure No. Structure 126 \ O 127 \ .0 «/«or 128 \ .0 XUo CN 130 \ .0 CQ-O, a 132 \ o : s.. 133 \ O XXhU O Ν׳ ν \α\Χ F 134 \ .0 W.....o 135 \ .0 «Wo. F 136 \ Ό I 1 Hnh .....o 430 260674/4 No. Structure No. Structure 137 \ .0 F 138 \ .0 *XfWj n x 0 oXAz 139 \ O >—NH N=N x X 140 \ .0 142 \ .0 o z 7 ΧχΧ+χ 143 \ .0 =:.. 144 \ O υ'Χ, A =' KLv 145A \ .0 (JX / N \ H Λν 145B \ .0 (JT \NH IZ N 0^^ 431 260674/4 No. Structure No. Structure 146 \ O AAuo 42 \ .0 η c> nAAJ H 147 0. \ Aa Aa (HA״ s ^°A״o ח 148A 4 z // ץ \ z כוץ cxz 1 1 cAz )= z 148B \ . O n n-A LX j״ΤΑ״־־ m oAaJA 149 \ .0 r N v N ^ | Anh n=n A b 150 \ /0 Αίγνο 151 \ .° ίΎ $nh n v cn 152A \ /° ®Ay CN 152B \ .0 CN 432 260674/4 No. Structure No. Structure 153 \ O ίΧΗΰη o n״ n \^Ka NG — 155 \ .0 Cx cP 156A \ . O CCt-W O N N x.^^ 156B /O ^7.. 157A 4 z // ץ z Y,\ / O^Z \ 1 157B 4 Z // ץ )7 1 O^z \ 1 158 \ Ό 54A 0. \ \־/ ύ // h ץ yJJ Diastereomer 1 159 .. 1, /O a oX N X' b /</׳ O N N x^ 54B \ .0 y־\ 0 B'/JJ Diastereomer 2 160A \ .0 ( X|klo 433 260674/4 No. Structure 62 Q o ^־ N ^o ο 7 No. Structure 160B \ /O Ahuo 161 ס. \ ך. 0 nAXX Η X- X N 162 \ .o UJl/j X 0 X N — 165 \ .0 ^XoHXjO 166 \ . O Ci 5־NHuV ryF ο O NN\/-^ 167 \ .0 168 0. \ A n ^A^A״0 n 169 D $¾1.....0 434 260674/4 No. Structure No. Structure 63 o sA/\J 171 \ .0 ¾1.....Cq 66 C£^ n Ki n 0 0 Λ γΥ 172 \ .0 1 1 Ynh Αζγ n 173 D ο oYAJ׳ 174 D °O J (to 175 o ס \ O\ Z 8 177A 2/ \z V // 1 cYz \ / / z 177B \ Ό OOh!.....0 435 260674/4 No. Structure No. Structure 178A \ O ( XAn o n׳ n \>v F 178B \ O AAn o n׳ n \>v F 179A \ Ό F 179B \ Ό «ד Ko F 180A \ .0 0 oAAC 73 ci ^A n x׳ n 'nh cA h o 180B ס. \ 0 oAAqJ 74 ( ^ΧΧ) 75A \ o nN-X׳ ( A / \ H / N 'N 7 \ Ϊ j /) 0 א nAA f H 436 260674/4 No. Structure No. Structure 75B \ O ( J. /\ H / N 'N A f 1 0 n^vA A H 182A 0. \ ¢07 a Ν \Α<γ_Ν״Ο Ν 76 a:M..... o 182B \ .0 CA. hr. Ο Ν״ Ν \Α<γ_Ν 77 ο w ya 184 \ .o CC r N 0 oHLA 80A ΑΑζό 80B ' /° N N -A O > N « N-NH ־־- o^OaLXo 186 \ Ό ( X2^T< n ''n Ai 0 AaAj 81A .....0 187 \ Ό ( XJ־ n a^n o n' n \A%a 81B 188 \ Ό ¢:0-^° yr 82A ®Aw 189 \ Ό ®Aw 437 260674/4 No. Structure No. Structure 82B 190 \ O 191 \ O 192 \ O | ANH / X Y-QU.O 85 O sAJ^J 194 ס. \ .n.h-'x f ] Vnh /x A/nw 86 195 z z \\ // עץ O\ z X 196 \ Ό (J r N Ly^N N'X/ AY N 1 ί 197 \ Ό 198 \ .0 ( X Η,ν-ν ^x, )rx, h 1 H N O 199 \ Ό N N-aX J! 1 /^ NH N-n ־' a -aaW 438 260674/4 No. Structure No. Structure 201 \ O QC ° J /PpQ 91 CX GA O 202 \ p N 1 ί 92 \ .o Ά. 203 Q o z 1 T ν' \ n z-z 93 A O z u'^yAo O-. Z V1 P 204 \ p XX GA °X ο^ν·ν Jp 94 \ .0 H 95 0. \ Huo־X^ 96 H /0 G 0XauO H 207 A z Z 'Z : z °xj\ Q / \ A--Z ) Cr] \__/ ם YA z y 97 H /0 n '׳·׳ c/ NAy%J H 208 \ p f ] Vnh /x '%ggAC) 98A H /0 NH N P px> 209 \ p r׳ ° O^N-N-fo 0 ^־ 439 260674/4 No. Structure 98B Η 0 f ] 0ΝΗ N 0700 99 \ O n O N00\־־J η γ 100A o-Z F 100B \ O l| j \״NH N^\ Ϋ__(/ A Ά d ל=\ /=\ 00 V F 102A C^a0 r\ ϋ N0\״X // h ץ v-A First eluting isomer 102B H /0 X־y ץ0־5”)ס ° Second eluting isomer No. Structure 213 \ Ό 0U) 215 \ .0 Ο N000 217 0. \ ן>;218 \ .0 ί A J N 9// N ' N 0, א nAA0 H 440 260674/4 No. Structure No. Structure 219 \ .0 fl ] Anh ΑΑχΑ Hl Π 0 s-Ά/ΆΑ A 221 \ .0 Ax F F 222 \ O N .N—ft Wη:ϊ n * 0 nA-AJ 223 0. \ N 'N׳X X N tft ) χν II /I׳־Ν 0 0AXV א 106 \ .0 Αχ o h A 107A \ .0 \ T /' NH N A n 107B /T־y jo T IZ A Z \ / / z 226 \ z O A AA jl 11! א O O^v 108 ft Ο Z A 227 \ z O N^/N^Z f| A A NH N-^ Aftr/ AA 1 III y ο o־־״AAA F F or or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 441 260674/4 46. A compound that is: 442 260674/4 443 260674/4 444 260674/4 445 260674/4 Diastereomer 1 446 260674/4 Diastereomer 2 447 260674/4 448 260674/4 449 260674/4 450 260674/4 C Xhf > O N'N 451 260674/4 Η /0 r ''' d n^\Av H H /° ί 1 ) ΝΗ N A A.....c H /0 f Ύ Anh n AA%c \ .0 n d nAAyJ H Δ \ o AM״ 0-4 z F \ O C0״ma A d 7=\ 0-4 z F Η 0 d nAA / h ן A® First eluting isomer Ci^Ka m ° Second eluting isomer \ .0 ;!ΪΑ- i 0 n' n v®A \ .0 ex A n a n n o \ .0 CC A n vM n Y7 dA d ΝγΝγ 0 ׳ ULA n a n ~? m \ .0 ιψ^νΑ׳ f ] Anh n^y m\ > '“׳A MCO ס. \ . ®Mm 452 260674/4 453 260674/4 or a tautomer, stereoisomer, or mixture stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 47. The compound of claim 46, wherein the compound is: or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 454 260674/4 48. The compound of claim 47, wherein the compound is: or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 49. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, tautomer, prodrug, stereoisomer, or a mixture of stereoisomers thereof, of any one of claims 1-48, and an excipient. 50. A compound, or a pharmaceutically acceptable salt, tautomer, prodrug, stereoisomer, or a mixture of stereoisomers thereof, of any one of claims 1 to 48, or a pharmaceutical composition of claim 49, for use in the treatment of a disease or disorder, chosen from an inflammatory disease or disorder, a necrotic cell disease, a neurodegenerative disease, a central nervous system disease, an ocular disease, a malignancy, an immune-mediated disease, an allergic disease, an autoimmune disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial or cardiac infarction, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, asthma, multiple sclerosis, type I diabetes, Wegener’s granulomatosis, pulmonary sarcoidosis, Behqet’s disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher’s disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease), HIV-associated dementia, retinal 455 260674/4 degenerative disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, brain injury, spinal cord injury, dementia, Huntington’s disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, Friedreich’s ataxia, rheumatoid arthritis, Lewy body disease, and a prion disorder. 51. The compound, or a pharmaceutically acceptable salt, tautomer, prodrug, stereoisomer, a mixture of stereoisomers thereof, or the pharmaceutical composition, for use of claim 50, wherein the disease or disorder is chosen from multiple sclerosis, amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease), Alzheimer’s disease, rheumatoid arthritis, and psoriasis.
Independent claims4