US 12,168,057 B2
IRAK degraders and uses thereof
Nello Mainolfi, Watertown, MA (US); Nan Ji, Watertown, MA (US); Arthur F. Kluge, Watertown, MA (US); Matthew M. Weiss, Watertown, MA (US); and Yi Zhang, Watertown, MA (US)
Assigned to Kymera Therapeutics, Inc., Watertown, MA (US)
Filed by Kymera Therapeutics, Inc., Watertown, MA (US)
Filed on Apr. 24, 2023, as Appl. No. 18/305,911.
Application 18/305,911 is a continuation of application No. 17/650,545, filed on Feb. 10, 2022, granted, now 11,723,980.
Application 17/650,545 is a continuation of application No. 17/073,019, filed on Oct. 16, 2020, granted, now 11,318,205, issued on May 3, 2022.
Application 17/073,019 is a continuation of application No. 16/230,792, filed on Dec. 21, 2018, granted, now 10,874,743, issued on Dec. 29, 2020.
Claims priority of provisional application 62/712,377, filed on Jul. 31, 2018.
Claims priority of provisional application 62/694,955, filed on Jul. 6, 2018.
Claims priority of provisional application 62/653,178, filed on Apr. 5, 2018.
Claims priority of provisional application 62/610,397, filed on Dec. 26, 2017.
Prior Publication US 2023/0398223 A1, Dec. 14, 2023
Int. Cl. A61K 47/54 (2017.01); A61K 31/404 (2006.01); A61K 31/422 (2006.01); A61K 31/427 (2006.01); A61K 31/4439 (2006.01); A61K 31/444 (2006.01); A61K 31/454 (2006.01); A61K 31/472 (2006.01); A61K 31/496 (2006.01); A61K 31/519 (2006.01); A61K 31/53 (2006.01); A61K 31/5377 (2006.01); A61P 35/00 (2006.01)
CPC A61K 47/545 (2017.08) [A61K 31/404 (2013.01); A61K 31/422 (2013.01); A61K 31/427 (2013.01); A61K 31/4439 (2013.01); A61K 31/444 (2013.01); A61K 31/454 (2013.01); A61K 31/472 (2013.01); A61K 31/496 (2013.01); A61K 31/519 (2013.01); A61K 31/53 (2013.01); A61K 31/5377 (2013.01); A61P 35/00 (2018.01)] 17 Claims
 
1. A compound of formula I-xxx-1:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
(a)
X and X′ are each independently CR8, N or —N+—O; Y is independently N, —N+—O or CR8; provided that at least one of X, X′ or Y is neither N nor —N+—O and that no more than one of X, X′ or Y is —N+—O;
R1 is C1-C6alkyl; C2-C6alkenyl; C2-C6alkynyl; —(CR3aR3b)m-(3-to 7-membered cycloalkyl); —(CR3aR3b)m-(3 to 7-membered heterocycloalkyl) having one to three heteroatoms; —(CR3aR3b)m-(5-to 10-membered heteroaryl), having one to three heteroatoms; or —(CR3aR3b)m—C6-C12 aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five halogen, deuterium, —OR5, —SR5, —NR11aR11b, cyano, C1-C6alkyl, C3-C6cycloalkyl or —C1-C6alkoxy;
R2 is —(CR3aR3b)m-(3- to 10-membered cycloalkyl); —(CR3aR3b)m-(3- to 10-membered heterocycloalkyl) having one to three heteroatoms; —(CR3aR3b)m-(5- to 10 membered heteroaryl) having one to three heteroatoms; or —(CR3aR3b)m—C6-C12aryl; wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five R4; and wherein, if the heteroatom on said heterocycloalkyl and heteroaryl is N, said N is
optionally substituted with R4′; or R2 is C1-C6alkyl, wherein said alkyl is optionally substituted with NH2, OH or cyano;
R3a and R3b for each occurrence are independently hydrogen or C1-C3alkyl;
R4 for each occurrence is independently a bond, deuterium halogen, cyano, C1-C6alkyl, C2-C6alkenyl, oxo, —OR5, —SR5, —S(O)R9, —S(O)2R9, —NR11aR11b, —C(O)R10—(CR3aR3b)n-(3- to 7-membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl), having one to three heteroatoms, —(CR3aR3b)n-(5- to 10 membered heteroaryl), having one to three heteroatoms, or —(CR3aR3b)n—C6-C12aryl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each optionally and independently substituted with one to five deuterium, halogen, OR5, —SR5, —NR11aR11b, cyano, C1-C6alkyl, C3-C6cycloalkyl or —C1-C6alkoxy; or two R4 taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NR11aR11b, cyano or C1-C6alkyl or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, —SR5, —NR11aR11b, or cyano; and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R4′;
R4′ is independently C1-C6alkyl, C2-C6alkenyl, —C(O)R10, —S(O)2R9, —(CR3aR3b)n-(3- to 7-membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl) or C(O)(CH2)tCN; wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C1-C6alkoxy; or R4 and R4′ taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NR11aR11b, cyano, C1-C6alkyl or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, —SR5, —NR11aR11b, or cyano;
R5 is independently hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with halogen, deuterium, C1-C6alkoxy, C1-C6alkylthiolyl, —NR11aR11b, cyano, C1-C6alkyl or C3-C6cycloalkyl; or two R taken together with the oxygen atoms to which they are bonded form a 5- or 6-membered heterocycloalkyl;
R6 is —C(O)NHR7, CO2R7 or cyano;
R7 is hydrogen or C1-C6alkyl;
each R8 is independently hydrogen, halogen, cyano, —OR5, —SR5, —NR11aR11b, C6alkyl, C3-C6cycloalkyl, 3 to 10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogen, —NR11aR11b OR5, —SR5, cyano, C1-C3 alkyl, —C(O)R10 or oxo;
R8′ is hydrogen, deuterium, halogen, cyano, —OR5, —SR5 or NR11aR11b;
R9 is —(CR3aR3b)p—(C1-C3alkyl), —(CR3aR3b)p-(4- to 6-membered cycloalkyl), —(CR3aR3b)p-(4- to 6-membered heterocycloalkyl) or —(CR3aR3b)p—(C5-C9aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fluoro or C1-C3alkyl;
R10 is C1-C6alkyl, wherein said alkyl is optionally substituted with deuterium, halogen, OH, C1-C6alkoxy or cyano;
R11a and R11b are each independently hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with deuterium, C1-C6alkoxy or cyano; and if C2-C6alkyl, said alkyl is optionally substituted with deuterium, C1-C6alkoxy, cyano, halogen or OH;
m is independently 0, 1, 2 or 3;
n is independently 0, 1, 2 or 3;
p is independently 0 or 1; and
t is 1,2 or 3;
(b)
L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

OG Complex Work Unit Chemistry
wherein:
each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
(c)
LBM is

OG Complex Work Unit Chemistry
wherein:
X1 is —C(O)—;
X2 is —C(O)—;
X3 is —CH2— or —C(O)—;
R1 is hydrogen or C1-4 aliphatic;
each of R2 is independently hydrogen, halogen, C1-4 aliphatic or —OC1-4 aliphatic;
Ring A is a fused ring selected from 6-membered aryl containing 0-1 nitrogen atoms; and
m is 0, 1, 2, 3 or 4.