Substituted pyrazolo[1,5-a]pyrimidines as TYK2 inhibitors
The present invention provides compounds of Formula I′: compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
1. A compound of Formula I′:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is:
L 1 -R 1A ,
wherein:
L 1 is:
-Cy-,
wherein:
Cy is:
(i) a saturated or partially unsaturated, bivalent 7- to 12-membered bicyclic heterocyclic ring;
wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OR, and ═O; or
(ii) a bivalent 8- to 10-membered bicyclic heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen and OR;
R 1A is:
(i) oxo, halogen, CN, a C 1-6 aliphatic group, C(O)R, C(O)N(R) 2 , C(O)N(R)OR, C(O)OR, N(R) 2 , NO 2 , N(R)C(NR)N(R) 2 , N(R)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, N(R)S(O) 2 R, N(R)S(O) 2 N(R) 2 , OR, OC(O)R, OC(O)N(R) 2 , SR, S(O)R, S(O)N(R) 2 , S(O) 2 R, or S(O) 2 N(R) 2 ;
wherein the C 1-6 aliphatic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , OR, and ═O;
(ii) a saturated or partially unsaturated 3- to 7-membered carbocyclic ring;
wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , OR, and ═O;
(iii) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , OR, and ═O;
(iv) a saturated or partially unsaturated, bicyclic 7- to 12-membered heterocyclic ring;
wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , OR, and ═O;
(v) phenyl;
(vi) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , and OR; or
(vii) a bicyclic 8- to 10-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C(O)N(R) 2 , and OR;
R 2 is C(O)NH 2 , C(O)NHR 2A , or C(O)N(R 2A ) 2 ;
each R 2A is independently:
(i) a C 1-6 aliphatic group;
(ii) a saturated or partially unsaturated 3- to 7-membered carbocyclic ring;
(iii) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(iv) a saturated or partially unsaturated, bicyclic 7- to 12-membered heterocyclic ring;
wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(v) phenyl;
(vi) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
(vii) a bicyclic 8- to 10-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each R 2A is optionally and independently substituted with n R 2C substituents;
each R 2C is independently:
(i) oxo, halogen, CN, a C 1-6 aliphatic group, C(O)R, C(O)N(R) 2 , C(O)N(R)OR, C(O)OR, N(R) 2 , NO 2 , N(R)C(NR)N(R) 2 , N(R)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, N(R)S(O) 2 R, N(R)S(O) 2 N(R) 2 , OR, OC(O)R, OC(O)N(R) 2 , SR, S(O)R, S(O)N(R) 2 , S(O) 2 R, or S(O) 2 N(R) 2 ;
wherein the C 1-6 aliphatic group is optionally substituted with one or more independently selected halogen substituents;
(ii) a saturated or partially unsaturated 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(iii) phenyl; or
(iv) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
two geminal R 2C substituents, taken together with the carbon atom to which they are attached, form a saturated or partially unsaturated, spiro-fused 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
two vicinal R 2C substituents, taken together with the carbon atoms to which they are attached, form a saturated or partially unsaturated, fused 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is NH 2 , NHR 3A , or NHC(O)R 3A ;
R 3A is:
(i) a C 1-6 aliphatic group;
(ii) a saturated or partially unsaturated 3- to 7-membered carbocyclic ring;
(iii) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(iv) a saturated or partially unsaturated, bicyclic 7- to 12-membered heterocyclic ring;
wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(v) phenyl;
(vi) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
(vii) a bicyclic 8- to 10-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein R 3A is optionally substituted with p R 3B substituents;
each R 3B is independently:
(i) oxo, halogen, CN, a C 1-6 aliphatic group, C(O)R, C(O)N(R) 2 , C(O)N(R)OR, C(O)OR, N(R) 2 , NO 2 , N(R)C(NR)N(R) 2 , N(R)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, N(R)S(O) 2 R, N(R)S(O) 2 N(R) 2 , OR, OC(O)R, OC(O)N(R) 2 , SR, S(O)R, S(O)N(R) 2 , S(O) 2 R, or S(O) 2 N(R) 2 ;
wherein the C 1-6 aliphatic group is optionally substituted with one or more substituents independently selected from the group consisting of OR and ═O;
(ii) a saturated or partially unsaturated 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(iii) phenyl; or
(iv) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
two geminal R 3B substituents, taken together with the carbon atom to which they are attached, form a saturated or partially unsaturated, spiro-fused 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
two vicinal R 3B substituents, taken together with the carbon atoms to which they are attached, form a saturated or partially unsaturated, fused 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 4 is hydrogen;
each R is independently:
(i) hydrogen or a C 1-6 aliphatic group;
(ii) a saturated or partially unsaturated 3- to 7-membered heterocyclic ring;
wherein the heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(iii) phenyl; or
(iv) a monocyclic 5- or 6-membered heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or
two geminal R substituents, taken together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring or a 5- or 6-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 0, 1, 2, or 3 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
n is 0, 1, or 2; and
p is 0, 1, or 2;
with the proviso that each hydrogen bound to carbon is optionally and independently replaced by deuterium.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1A is selected from the group consisting of:
3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2A is independently selected from the group consisting of:
4. The compound of claim 1 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
Cy is a bivalent 8- to 10-membered bicyclic heteroaryl ring;
wherein the heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further
wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen and OR.
5. The compound of claim 1 , wherein the compound is of Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound of claim 1 , wherein the compound is of Formula VI:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein the compound is of Formula VIII:
or a pharmaceutically acceptable salt or stereoisomer thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
9. The A compound, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.