Compounds and compositions for treating conditions associated with NLRP activity

1. A compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from the group consisting of

X 2 is N;

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 8′ is selected from CN, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 2′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 2″ is hydrogen or C 1 -C 6 alkyl;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3″ is hydrogen, CN, or C 1 -C 6 alkyl;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4″ is hydrogen or C 1 -C 6 alkyl;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5″ is hydrogen, CN, or C 1 -C 6 alkyl;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 1′ is selected from unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl substituents are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10″ is selected from Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl;

wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10′″ is selected from Cl, C 1 -C 6 alkyl substituted with hydroxy, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl;

wherein the C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

or R 1 and R 10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C 1 -C 6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

each R 19 is the same and is C 1 -C 6 alkyl;

R 20 is selected from H, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 21 is selected from H, halo, or C 1 -C 6 alkyl substituted with hydroxy.

2. A compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from the group consisting of

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, and F;

R 8′ is selected from CN and CONR 11 R 12 ;

R 2 is hydrogen or C 1 -C 6 alkyl;

R 2′ is C 1 -C 6 alkyl;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, or halo;

R 3′ is hydrogen or halo;

R 4 is hydrogen or C 1 -C 6 alkyl;

R 4′ is C 1 -C 6 alkyl;

R 5 is hydrogen;

R 5′ is hydrogen;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is 3;

m1 is 0;

wherein ring B is a saturated carbocyclic ring;

n2 is 3;

m2 is 0;

R 1 is H;

R 1′ is selected from C(R 19 ) 2 OH and C 3 -C 6 cycloalkyl;

wherein the C 3 -C 6 cycloalkyl above is optionally substituted with one or more hydroxy;

R 10 is selected from H, Cl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein R 10 is optionally substituted with one or more substituents each independently selected from hydroxy;

R 10″ is selected from C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein R 10″ is optionally substituted with one or more hydroxy;

R 10′″ is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;

wherein R 10′″ is optionally substituted with one or more hydroxy;

each of R 11 and R 12 is hydrogen;

each R 19 is the same and is selected from C 1 -C 6 alkyl.

3. The compound of claim 1 , wherein the compound of Formula II is

or a pharmaceutically acceptable salt thereof, and wherein:

X 2 is N;

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl substituents are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

or R 1 and R 10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C 1 -C 6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

each R 19 is the same and is selected from C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein the compound of Formula II is

or a pharmaceutically acceptable salt thereof, wherein:

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 1′ is selected from unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy,

NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C 1 -C 6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

each R 19 is the same and is selected from C 1 -C 6 alkyl.

5. The compound of claim 1 , wherein the compound of Formula II is

or a pharmaceutically acceptable salt thereof, and wherein:

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

or R 1 and R 10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C 1 -C 6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;

each R 19 is the same and is selected from C 1 -C 6 alkyl.

6. The compound of claim 1 , wherein the compound of Formula II is

7. The compound of claim 2 , wherein the compound of Formula II is

8. A compound selected from the group consisting of compounds in the Table below:

Com-

pound

Structure

101

102

103

104

105

106

108

109

110

111

112

113

114

116

117

118

119

120

121

122

123

124

126

127

128

129

130

132

138

139

142

144

145

146

147

148

149

150

151

152

155

158

160

163

165

167

168

169

170

172

179

181

182

183

190

192

193

196

197

206

207

209

213

219

220

221

226

227

233

235

247

255

259

260

261

263

266

267

268

269

270

271

272

273

274

and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a compound or salt as claimed in claim 1 and one or more pharmaceutically acceptable excipients.

10. A pharmaceutical composition comprising a compound or salt as claimed in claim 2 and one or more pharmaceutically acceptable excipients.

11. The compound of claim 1 , wherein the compound of Formula II is

or a pharmaceutically acceptable salt thereof, wherein:

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and =NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , =NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 10″ is selected from Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein the Ci-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, Ci-C6 alkoxy,

NR 11 R 12 , =NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C1-C6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and =NR 13 ;

each R 19 is the same and is selected from C 1 -C 6 alkyl.

12. The compound of claim 1 , wherein the compound of Formula II is

or a pharmaceutically acceptable salt thereof, wherein:

X 3 is NH or O;

or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;

or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ; Y is N or CR 8 ;

R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a saturated carbocyclic ring;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and =NR 13 ;

or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R 13 is C 1 -C 6 alkyl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;

R 15 is C 1 -C 6 alkyl;

each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and =NR 13 .