US 12,134,611 B2
Compounds and compositions for treating conditions associated with NLRP activity
Jason Katz, Newton, MA (US); William Roush, Boston, MA (US); Hans Martin Seidel, Concord, MA (US); Dong-Ming Shen, Edison, NJ (US); and Shankar Venkatraman, Lansdale, PA (US)
Assigned to Novartis AG, Basel (CH)
Appl. No. 17/292,887
Filed by Novartis AG, Basel (CH)
PCT Filed Nov. 11, 2019, PCT No. PCT/US2019/060775
§ 371(c)(1), (2) Date May 11, 2021,
PCT Pub. No. WO2020/102100, PCT Pub. Date May 22, 2020.
Claims priority of provisional application 62/760,244, filed on Nov. 13, 2018.
Claims priority of provisional application 62/760,248, filed on Nov. 13, 2018.
Claims priority of provisional application 62/760,279, filed on Nov. 13, 2018.
Claims priority of provisional application 62/795,373, filed on Jan. 22, 2019.
Claims priority of provisional application 62/796,361, filed on Jan. 24, 2019.
Claims priority of provisional application 62/796,356, filed on Jan. 24, 2019.
Prior Publication US 2023/0024859 A1, Jan. 26, 2023
Int. Cl. C07D 417/12 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 275/06 (2006.01); C07D 279/02 (2006.01); C07D 281/10 (2006.01); C07D 285/18 (2006.01); C07D 285/36 (2006.01); C07D 513/04 (2006.01); C07D 513/10 (2006.01)
CPC C07D 417/12 (2013.01) [A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 275/06 (2013.01); C07D 279/02 (2013.01); C07D 281/10 (2013.01); C07D 285/18 (2013.01); C07D 285/36 (2013.01); C07D 513/04 (2013.01); C07D 513/10 (2013.01)] 20 Claims
 
1. A compound of Formula AA

OG Complex Work Unit Chemistry
wherein
o=1 or 2;
p=0, 1, 2, or 3;
Y is —CR15R15— or —NR16—;
ring A is:
(i) a saturated or unsaturated monocyclic ring that includes from 5-8 ring atoms (inclusive of N—R3 and S(O)); or
(ii) a saturated or unsaturated bicyclic or tricyclic ring that includes from 8-20 ring atoms (inclusive of N—R3 and S(O)),
wherein the dotted, circular line connecting N—R3 and S is a divalent group that includes from 3-6 ring atoms; wherein:
(a) from 0-2 of the divalent group's ring atoms are ring heteroatoms, which are each independently selected from the group consisting of O, N, NH, NR13, S, S(O), and S(O)2; and
(b) from 1-6 of the divalent group's ring atoms are ring carbon atoms, which are each independently selected from the group consisting of C, CH, CH2, C(O), CR1, C(R1)2, and CHR1;
wherein:
(1) when ring A is a monocyclic ring, then each of the divalent group's 1-6 ring carbon atoms is independently selected from the group consisting of CH, CH2, C(O), CR1, C(R1)2, and CHR1; and
(2) when ring A is a bicyclic or tricyclic ring, then (A) or (B) applies:
(A) two or three adjacent ring carbon atoms of the divalent group are each independently selected from the group consisting of C, CH, and CR1, and are fused to a second ring that is selected from the group consisting of:
(a) C6-10 aryl optionally substituted with from 1-5 independently selected Ra;
(b) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(RN), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected Ra;
(c) C3-10 cycloalkyl optionally substituted with from 1-4 independently selected Rb;
(d) heterocycloalkyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(RN), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected Rb; or
(B) one of the divalent group's ring carbon atoms is C and is spiro-fused to a second ring that is selected from the group consisting of:
(a) C3-10 cycloalkyl optionally substituted with from 1-4 independently selected Rb;
(b) heterocycloalkyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(RN), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected Rb;
each R1 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5-to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 alkyl, S(O2)NR11R12, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,
wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
wherein when R1 is C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent on R1, when present, is further optionally independently substituted with one to three hydroxy, C1-C6 alkoxy, halo, NR8R9, or oxo;
wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) substituents on R1 are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
each Ra is independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, OC6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3-to 10-membered heterocycloalkyl, CO2H, and CONR8R9,
wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C1-4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, CO2H, and CONR8R9,
each Rb is independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, OC6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, CO2H, and CONR8R9,
wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, CO2H, and CONR8R9;
each RN is independently selected from hydrogen, C1-C6 alkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12;
wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
ring B is a 5-10-membered heteroaryl or a C6-C10 aryl;
R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and a C2-C6 alkenyl,
wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9;
wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
OR
at least one pair of R6 and R7 on adjacent carbon atoms taken together with the carbon atoms to which each is attached form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1-3 heteroatoms and/or heteroatomic groups independently selected from O, N, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9,
each occurrence of R8 and R9 is independently selected from hydrogen, C1-C6 alkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12;
wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R8 and R9taken together with the nitrogen atom to which each is attached form a 3- to 7-membered ring optionally containing one or more additional heteroatoms;
R10 is C1-C6 alkyl;
R13 is C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;
each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl;
R3 is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and

OG Complex Work Unit Chemistry
wherein the C1-C2 alkylene group is optionally substituted by oxo;
R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl, or heteroaryl is optionally independently substituted with 1 or 2 R6;
each occurrence of R15 is independently selected from hydrogen and C1-C6 alkyl; and
R16 is selected from hydrogen and C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof.