Heteroaryl compounds and uses thereof

1. A method for treating a FGFR4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is NR 4 , N, CR 4 R 4 , or —CR 4 ;

X 2 is —NR 5 , N, —CR 5 R 5 , or —CR 5 ;

X 3 is N or CR 6

X 4 is N or CR 7 ;

X 5 is N, C, or CH; wherein at least one of X 1 , X 2 , X 3 , X 4 , or X 5 is N;

G is H, O, OR, or N(R)(R);

Ring A is an optionally substituted group selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 1 is a warhead group -L-Y; wherein R 1 is attached to an atom adjacent to the atom where T is attached, wherein:

R 1 is selected from

 or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one additional methylene unit of L is replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and

the Y group of R 1 is hydrogen, C 1-6 aliphatic optionally with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; or

L is a covalent bond, —CH 2 , —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 — or —SO 2 NH—, and the Y group of R 1 is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

 or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and the Y group of R 1 is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

 or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, or diazonium, wherein:

Q is a bivalent C 1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and

each Z is independently hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 or CN;

each R 2 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

R 3 is hydrogen, C 2-6 alkenyl, —W-Cy, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, —OR′, or —C(O)O(C 1-6 alkyl);

W is absent or is a bivalent C 1-3 alkylene chain optionally substituted with one or more R″ and wherein one methylene unit of W is optionally replaced with —O—, —S—, or —NR′—;

each R′ is independently hydrogen or C 1-6 alkyl;

each R″ is independently halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, or —OR′;

Cy is phenyl, C 3-7 cycloalkyl, or a 3-7 membered monocyclic or 5-10 membered bicyclic saturated, partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy is optionally substituted with 1-3 R x ;

each R x is independently H, —CN, oxo, —NH 2 , C 1-6 alkyl, halogen, —OR, —N(R′) 2 , —NHC(O)(C 1-6 alkyl), —C(O)N(R′) 2 , —C(O)O(C 1-6 alkyl), —NHSO 2 (C 1-6 alkyl), or —SO 2 N(R′) 2 ;

or R 3 is absent if not allowed by valence;

each of R 4 and R 4′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring which is optionally bridged, a 4-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring, which is optionally bridged;

each of R 5 and R 5′ is independently —R, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

Y is O or NR a ;

R a is hydrogen or an optionally substituted C 1-6 aliphatic group;

T is a covalent bond or a bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units are optionally replaced by —O—, —S—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, or —N(R)SO 2 N(R)—;

q is 0-6; and

each of R 6 and R 7 is independently —R, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .

2. The method according to claim 1 , wherein Ring A is cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, cyclopropyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, piperidine, piperidin-one, pyrrolidine, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene dioxide, or cyclobutene dione.

3. The method according to claim 1 , wherein Ring A is

4. The method according to claim 3 , wherein each R 2 is independently halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .

5. The method according to claim 3 , wherein each R 2 is independently —CH 3 , —Cl, —F, —CF 3 , or —OMe; or is selected from

6. The method according to claim 1 , wherein Ring A is selected from:

7. The method according to claim 1 , wherein R 3 is

8. The method according to claim 1 , wherein R 4 is an optionally substituted phenyl.

9. The method according to claim 1 , wherein R 4 is an optionally substituted C 1-6 aliphatic, or an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The method according to claim 1 , wherein R 4 is ethyl, phenyl, cyclohexyl,

11. The method according to claim 1 , wherein each of R 5 and R 5′ is independently H, or -Me.

12. The method according to claim 1 , wherein T is a covalent bond.

13. The method according to claim 1 , wherein T is a bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units are optionally replaced by —O—, —S—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —N(R)SO 2 —, or —N(R)SO 2 N(R)—.

14. The method of claim 1 , wherein the compound is a compound of one of the following formulae:

or a pharmaceutically acceptable salt thereof.

15. The method according to claim 1 , wherein the compound is a compound of formula I-h:

or a pharmaceutically acceptable salt thereof.

16. The method according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

17. The method according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable sale thereof.

18. The method according to claim 1 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.

19. The compound method according to claim 18 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and

the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

20. The method according to claim 19 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

21. The method according to claim 19 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—.

22. The method according to claim 19 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

23. The method according to claim 22 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, or —NHC(O)C(═CH 2 )CH 2 —.

24. The compound method according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

25. The method according to claim 1 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—.

26. The method according to claim 25 , wherein the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

27. The method according to claim 26 , wherein L is —C≡C—, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 C≡C—CH 2 —, or —CH 2 OC(═O)C≡C—.

28. The method according to claim 1 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one additional methylene unit of L is replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—.

29. The method according to claim 1 , wherein:

L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain.

30. The method according to claim 1 , wherein L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, or —SO 2 NH—.

31. The method according to claim 30 , wherein L is a covalent bond.

32. The method according to claim 1 , wherein the Y group of R 1 is selected from:

wherein each R e is independently selected from halogen.

33. The method according to claim 1 , wherein R 1 is selected from:

wherein each R e is independently a suitable leaving group, NO 2 , CN, or oxo.

34. The method of claim 1 , wherein R 1 is selected from:

35. The method according to claim 15 , wherein:

Ring A is an optionally substituted group selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 1 is a warhead group -L-Y; wherein R 1 is attached to an atom adjacent to the atom where T is attached, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and

the Y group of R 1 is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups;

R 3 is C 1-6 alkyl;

R 4 is optionally substituted phenyl; and

R a is hydrogen.

36. The method according to claim 15 , wherein:

is selected from

R 1 is a warhead group -L-Y; wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and

the Y group of R 1 is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups;

R 3 is C 1-6 alkyl;

R 4 is optionally substituted phenyl; and

R a is hydrogen.

37. The method according to claim 35 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

38. The method according to claim 35 , wherein R 1 is

39. The method according to claim 38 , wherein R 4 is selected from:

40. The method according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

41. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

42. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

43. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

44. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

45. The method according to claim 1 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma, rhabdomyosarcoma, esophageal cancer, breast cancer, or cancer of the head or neck.

46. The method according to claim 45 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

47. The method according to claim 45 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.

48. The method according to claim 35 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

49. The method according to claim 35 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.

50. The method according to claim 48 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

51. The method according to claim 50 , wherein R 1 is

52. The method according to claim 51 , wherein R 4 is selected from:

53. The method according to claim 49 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and the Y group of R 1 is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

54. The method according to claim 53 , wherein R 1 is

55. The method according to claim 54 , wherein R 4 is selected from:

56. The method according to claim 41 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

57. The method according to claim 41 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.

58. The method according to claim 42 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

59. The method according to claim 42 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.

60. The method according to claim 43 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

61. The method according to claim 43 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.

62. The method according to claim 44 , wherein the FGFR4-mediated disorder is hepatocellular carcinoma.

63. The method according to claim 44 , wherein the FGFR4-mediated disorder is rhabdomyosarcoma.