HPK1 antagonists and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Z is CR or N;
X is a covalent bond or —NR—;
R 1 is selected from the group consistig of C 1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R C ;
R 2 is selected from the group consisting of 6-11 membered saturated, partially unsaturated, or unsaturated fused bicyclic ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R C ;
each instance of R 3 is independently hydrogen or an optionally substituted C 1-6 aliphatic group;
each instance of R C is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —N═S(O)R 2 , —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR 2 , —P(O)(R)OR or —P(O)R 2 ; or each instance of R C is independently an optionally substituted group selected from C 1-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R and s instances of R D ;
each instance of R D is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —N═S(O)R 2 , —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR 2 , —P(O)(R)OR or —P(O)R 2 ;
each R is independently hydrogen, —CN, halogen, or an optionally substituted group selected from C 1-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
m is 0, 1, or 2;
each q is independently 0, 1, 2, 3, or 4;
each r is independently 0, 1, 2, 3, or 4; and
each s is independently 0, 1, 2, 3, or 4.
2. The compound of claim 1 , wherein the compound is any one of formulae II, IV, V, or VII:
or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R C , and q are as defined in claim 1 .
3. The compound of claim 1 , wherein the compound is any one of formulae XI-a, XI-b, XIV-a, XIV-b, XVII-a, XVII-b, XX-a, or XX-b:
or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R C , and q are as defined in claim 1 .
4. The compound of claim 1 , wherein the compound is any one of formulae XXIII-a, XXIII-b, XXVI-a, XXVI-b, XXIX-a, or XXIX-b:
or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R C , and q are as defined in claim 1 .
5. The compound of claim 1 , wherein X is —NR—.
6. The compound of claim 1 , wherein R 1 is C 1-6 aliphatic which is substituted with q instances of R C ; phenyl which is substituted with q instances of R C ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R C ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, which is substituted with q instances of R C ; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, which is substituted with q instances of R C .
7. The compound of claim 6 , wherein R 1 is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, each of which is substituted with q instances of R C .
8. The compound of claim 1 , wherein R 1 is phenyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is substituted by q instances of R C .
9. The compound of claim 8 , wherein R 1 is phenyl, pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl; each of which is substituted by q instances of R C .
10. The compound of claim 1 , wherein R 1 is
wherein R C and q are as defined in claim 1 .
11. The compound of claim 1 , wherein R 1 is
12. The compound of claim 1 , wherein R 2 is a 6-11 membered saturated, partially unsaturated, or unsaturated fused bicyclic ring having 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R C ; wherein each instance of R C is independently optionally substituted by r instances of R and s instances of R D .
13. The compound of claim 12 , wherein R 2 is a 7-10-membered fused bicyclic ring having 1-3 nitrogen atoms; each of which is substituted by q instances of R C .
14. The compound of claim 12 , wherein R 2 is
wherein R C and q are as defined in claim 1 .
15. The compound of claim 1 , wherein R 2 is
wherein R C and q are as defined in claim 1 .
16. The compound of claim 12 , wherein R 2 is
17. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.