EGFR INHIBITORS

1 . A compound of Formula (A):

or a pharmaceutically acceptable salt thereof, wherein

X is CR x or N;

R x is H or F;

L 1 is a bond, NH, —NHC(O)—*, —NHC(O)O—*, O, or —OC(O)—*; wherein -* represents the point which attaches to R 1 ;

L 2 is a bond or O;

R 1 is H; or

C 1 -C 4 alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b , C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl; or

C 3 -C 8 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl, or 5 to 12 membered heteroaryl, wherein the cycloalkyl, phenyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 4 groups independently selected from R 11 ;

each R 11 is independently selected from halo, deuterium, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR a , NR a R b , S(O) 2 R a , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl and 5 to 12 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl represented by R 11 are each optionally substituted with 1 to 4 groups selected from deuterium, halo, C 1 -C 4 alkyl, OR a and NR a R b , or two R 11 which are attached to the same carbon atom are taken together to form ═O;

R 2 is

H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, C 1 -C 4 alkyl, C(O)R a and 4 to 12 membered heterocyclyl which is optionally substituted with 1 to 4 groups selected from halo, deuterium and C 1 -C 4 alkyl;

R 3 is attached to either nitrogen atom in the pyrazole ring, and is selected from H, deuterium, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and 4 to 6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl represented by R 3 are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and C 3 -C 6 cycloalkyl:

each R 4 is independently selected from halo, deuterium and OR a ;

R 5 is selected from H, deuterium, halo and C 1 -C 4 alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b , C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl

each R a is independently selected from H, deuterium, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl and 4 to 6 membered heterocyclyl;

each R b is independently selected from H, deuterium and C 1 -C 4 alkyl; and

n is 0, 1, 2, 3, 4 or 5.

2 . The compound of claim 1 , wherein the compound is of Formula (B) or (C):

or a pharmaceutically acceptable salt thereof.

3 . The compound of any one of claims 1-2 , or a pharmaceutically acceptable salt thereof, wherein when L 1 and L 2 are each a bond, R 1 is H, R 2 is not H.

4 . The compound of any one of claims 1-3 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl: or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, C 1 -C 4 alkyl, C(O)R a and 4 to 12 membered heterocyclyl which is optionally substituted with 1 to 4 groups selected from halo, deuterium and C 1 -C 4 alkyl.

5 . The compound of any one of claims 1-4 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F or methyl.

6 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is CR x or N;

R x is H or F;

L 1 is a bond, NH, —NHC(O)—*, —NHC(O)O—*, O, or —OC(O)—*; wherein -* represents the point which attaches to R 1 ;

L 2 is a bond or O;

R 1 is H; or

C 1 -C 4 alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b , C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl; or

C 3 -C 8 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl, or 5 to 12 membered heteroaryl, wherein the cycloalkyl, phenyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 4 groups independently selected from R 11 ;

each R 11 is independently selected from halo, deuterium, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR a , NR a R b , S(O) 2 R a , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl and 5 to 12 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl represented by R 11 are each optionally substituted with 1 to 4 groups selected from deuterium, halo, C 1 -C 4 alkyl, OR a and NR a R b , or two R 11 which are attached to the same carbon atom are taken together to form ═O;

R 2 is:

C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, C 1 -C 4 alkyl, C(O)R a and 4 to 12 membered heterocyclyl which is optionally substituted with 1 to 4 groups selected from halo, deuterium and C 1 -C 4 alkyl;

R 3 is H, deuterium, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl represented by R 3 are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and C 3 -C 6 cycloalkyl;

each R 4 is independently selected from halo, deuterium and OR a ;

each R a is independently selected from H, deuterium, C 1 -C 4 alkyl, C1-C 4 haloalkyl, C 3 -C 6 cycloalkyl and 4 to 6 membered heterocyclyl;

each R b is independently selected from H, deuterium and C 1 -C 4 alkyl; and

n is 0, 1, 2, 3, 4 or 5.

7 . The compound of claim 6 , wherein the compound is represented by one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 6 , wherein the compound is represented by one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

9 . The compound of any one of claims 1-8 , or a pharmaceutically acceptable salt thereof, wherein R x is H.

10 . The compound of any one of claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H: or

C 1 -C 3 alkyl optionally substituted with 1 to 2 groups independently selected from halo, OR a , NR a R b , C 3 -C 8 cycloalkyl, 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 2 groups independently selected from halo and —CH 3 ; or

C 3 -C 8 cycloalkyl, phenyl, 4 to 9 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the cycloalkyl, phenyl, heterocyclyl and heteroaryl in the group represented by R 1 are each optionally substituted with 1 to 3 groups independently selected from R 11 ; and

each R a is independently H or —CH 3 ; and each R b is —CH 3 .

11 . The compound of any one of claims 1-10 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H; or

R 1 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 3 CH 3 and —CH(CH 3 ) 2 , each of which is optionally substituted with 1-3 groups selected from F, —OH, —OCH 3 , —N(CH 3 ) 2 , cyclopropyl, morpholinyl, oxadiazolyl, oxetanyl, oxazolyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl and triazolyl, wherein the pyridinyl, thiadiazolyl, thiazolyl and triazolyl are each optionally substituted with F, —CH 3 or —CH 2 CH 3 ; or

R 1 is selected from azabicyclo[3.1.0]hexanyl, azetidinyl, 1H-benzo[d]imidazolyl, bicyclo[1.1.1]pentanyl, cubanyl, cyclobutyl, cyclopropyl, dihydroisoquinolinyl, dihydropyrrolyl, dihydro-2H-benzo[b][1,4]oxazinyl, dioxepanyl, hexahydro-1H-pyrrolizinyl, imidazolidinyl, indazolyl, isoindolinyl, isothiazolyl, morpholinyl, octahydropyrrolo[1,2-a]pyrazinyl, oxabicyclo[3.1.0]hexanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, oxabicyclo[3.3]heptanyl, 7-oxa-4-azaspiro[2.5]octanyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl and thiazolyl, each of which is optionally substituted with 1 to 3 groups independently selected from R 11 .

12 . The compound of any one of claims 1-11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, —CH 3 , —CH 2 (R 11 ), —CH(R 11 ) 2 , —CH 2 CH 3 , —CH(R 11 )—CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 2 —R 14 , —CH—CH—CH 2 —R 11 , —CH(CH 3 )CH 2 —R 11 ,

13 . The compound of any one of claims 1-12 , or a pharmaceutically acceptable salt thereof, wherein:

each R 11 is independently selected from halo, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR a , NR a R b , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 12 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, and heteroaryl represented by R 11 are each optionally substituted with 1 to 3 groups selected from deuterium, halo, OR a and NR a R b , or two R 11 which are attached to the same carbon atom are taken together to form ═O;

each R a is independently selected from H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and 4 to 6 membered heterocyclyl; and

each R b is independently selected from H and C 1 -C 4 alkyl.

14 . The compound of any one of claims 1-13 , or a pharmaceutically acceptable salt thereof, wherein:

each R 11 is independently selected from halo, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR a , NR a R b , C 1 -C 3 alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl, wherein the alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl represented by R 11 are each optionally substituted with 1 to 3 groups selected from deuterium, halo, OR a and NR a R b , or two R 11 which are attached to the same carbon atom are taken together to form ═O;

each R a is independently selected from H, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 ,

and

each R b is independently H or —CH 3 .

15 . The compound of any one of claims 1-14 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from Cl, F, —OH, —OCH 3 , —C(O)CH 2 CH 3 , —N(CH 3 ) 2 , —NHC(O)OC(CH 3 ) 3 , —CH 3 , —CD 3 , —CHF 2 , —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 —N(CH 3 ) 2 , —CH 2 CH 3 , —CH 2 CF 3 , —CH 2 CH 2 —N(CH 3 ) 2 , —CH(CH 3 ) 2 , —C(CH 3 ) 2 —OH,

or two R 11 which are attached to the same carbon atom are taken together to form ═O.

16 . The compound of any one of claims 1-15 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a O.

17 . The compound of any one of claims 1-16 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 3 groups independently selected from halo, OR a , NR a R b and 4 to 12 membered heterocyclyl, or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from C 1 -C 4 alkyl, C(O)R a and 4 to 12 membered heterocyclyl which is optionally substituted with 1 to 3 groups selected from halo, and C 1 -C 4 alkyl;

each R a is independently selected from H and C 1 -C 4 alkyl; and

each R b is independently selected from H and C 1 -C 4 alkyl.

18 . The compound of any one of claims 1-17 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl or C 3 -C 4 alkynyl, each of which is optionally substituted with 1 to 2 groups independently selected from halo, OR a , NR a R b and 4 to 6 membered heterocyclyl, or 5 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the heterocyclyl and heteroaryl in the group represented by R 2 are each optionally substituted with 1 to 2 groups selected from C 1 -C 3 alkyl, C(O)R a and 6 membered heterocyclyl optionally substituted with C 1 -C 3 alkyl;

each R a is independently selected from H and —CH 3 ; and

each R b is —CH 3 .

19 . The compound of any one of claims 1-18 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl or

each of which is optionally substituted with F, —OCH 3 , —N(CH 3 ) 2 , morpholinyl or oxetanyl: or

R 2 is diazaspiro[3.3]heptanyl, pyrazolyl, pyrimidinyl or tetrahydrofuranyl, each of which is optionally substituted with C 1 -C 3 alkyl, C(O) C 1 -C 4 alkyl or piperidinyl optionally substituted with —CH 3 .

20 . The compound of any one of claims 1-19 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is —CH 3 , —CHF 2 , —CH 2 CH 3 , —CH 2 CH 2 —OCH 3 , —CH 2 CH 2 —N(CH 3 ) 2 , —CH(CH 3 ) 2 , cyclopropyl,

or

R 2 is

each of which is optionally substituted with —CH 3 , C(O)CH 3 or

21 . The compound of any one of claims 1-20 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl represented by R 3 are each optionally substituted with 1 to 3 groups independently selected from halo, deuterium, OR a , NR a R b and C 3 -C 6 cycloalkyl;

each R a is independently H or C 1 -C 4 alkyl; and

each R b is independently H or C 1 -C 4 alkyl.

22 . The compound of any one of claims 1-21 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, cyclopropyl, oxetanyl, tetrahydropyanyl or C 1 -C 3 alkyl optionally substituted with 1 to 3 groups independently selected from halo, deuterium, OH, N(CH 3 ) 2 and cyclopropyl.

23 . The compound of any one of claims 1-22 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, —CH 3 , —CHF 2 , —CD 3 , —CH 2 CH 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 —OH, —CH 2 CH 2 —N(CH 3 ) 2 , —CH 2 CH 3 CH 3 , —CH(CH 3 ) 2 ,

24 . The compound of any one of claims 1-23 , or a pharmaceutically acceptable salt thereof, wherein:

each R 4 is halo or OR a ;

each R a is independently selected from H and C 1 -C 4 alkyl; and

n is 0, 1, 2 or 3.

25 . The compound of any one of claims 1-24 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

26 . The compound of any one of claims 1-25 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, and each R 4 is independently selected from F and OH.

27 . The compound of any one of claim 1-4 or 6-26 , wherein the compound is represented by one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

28 . The compound of any one of claim 1-4 or 6-26 , wherein the compound is represented by one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

29 . The compound of claim 27 or 28 , wherein:

R 1 is:

C 1 -C 4 alkyl optionally substituted with 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted with C 1 -C 3 alkyl, or

C 3 -C 8 cycloalkyl, 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 3 groups independently selected from R 11 ;

each R 11 is independently selected from halo, NR a R b , C 3 -C 6 cycloalkyl, and C 1 -C 4 alkyl optionally substituted with 1 to 3 halo, and each R a is independently selected from H and C 1 -C 4 alkyl;

R 2 and R 3 are each independently C 1 -C 4 alkyl; and

R 4 is halo, where n is 0, 1, or 2.

30 . The compound of any one of claims 27-29 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is:

C 1 -C 3 alkyl optionally substituted with 5 membered heteroaryl wherein the 5 membered heteroaryl is optionally substituted with C 1 -C 3 alkyl, or

C 3 -C 8 cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 2 groups independently selected from R 11 ;

each R 11 is independently selected from halo, N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, and C 1 -C 3 alkyl optionally substituted with 1 to 3 halo;

R 2 and R 3 are each independently C 1 -C 3 alkyl;

R 4 is halo; and

n is 0, 1, or 2.

31 . The compound of any one of claims 27-30 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —CH 2 CH 3 substituted with oxadiazolyl optionally substituted with —CH 3 ; or

R 1 is selected from azabicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cyclopropyl, 3-oxabicyclo[3.1.0]hexanyl, piperidinyl, pyrazolyl and pyridinyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 11 ,

each R 11 is independently selected from F, —N(CH 3 ) 2 , —CH 3 , —CF 3 ,

32 . The compound of any one of claims 27-31 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from

and each R 11 is independently selected from F, —N(CH 3 ) 2 , —CH 3 , —CF 3 ,

33 . The compound of any one of claims 27-32 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is C 1 -C 4 alkyl;

R 3 is C 1 -C 4 alkyl;

each R 4 is independently halo; and

n is 0, 1 or 2.

34 . The compound of any one of claims 27-33 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is —CH 3 or —CH 2 CH 3 ;

R 3 is —CH 3 ;

R 4 is F; and

n is 0 or 1.

35 . The compound of any one of claims 6, 9, and 16-26 , wherein the compound is represented by Formula (III):

or a pharmaceutically acceptable salt thereof.

36 . The compound of any one of claims 6 and 16-26 , wherein the compound is represented by Formula (III-1) or (III-2):

or a pharmaceutically acceptable salt thereof.

37 . The compound of claim 35 or 36 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

38 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-37 , or a pharmaceutically acceptable salt thereof.

39 . A method of treating a cancer, comprising administering a subject in need thereof an effective amount of a compound of any one of claims 1-37 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38 .

40 . The method of claim 39 , wherein the cancer is lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancers (glioma), ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, or mesothelioma.

41 . The method of claim 39 , wherein the cancer is non-small cell lung cancer.

42 . The method of any one of claims 39-41 , wherein the cancer in the subject in need thereof has metastasized.

43 . The method of any one of claims 39-42 , wherein the cancer is characterized by an epidermal growth factor receptor (EGFR) L858R mutation.

44 . The method of any one of claims 39-42 , wherein the cancer is characterized by an epidermal growth factor receptor (EGFR) exon 19 deletion.

45 . The method of any one of claims 39-44 , wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) C797S mutation.

46 . The method of any one of claims 39-45 , wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) T790M mutation.

47 . The method of any one of claims 39-46 , further comprises administering the subject in need thereof an effective amount of afatinib or osimertinib.

48 . A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound of any of claims 1-37 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38 .