Isoquinolines as inhibitors of hpk1

Abstract

Isoquinoline compounds and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibitng HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  is hydrogen, halogen, cyano, C 1-6  alkyl, C 3-7  cycloalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, hydroxyl, C 1-6  alkoxyl, optionally substituted amino or optionally substituted acylamino; 
 R 2  is (a), (b), (c), (d), (e), (f), (g) or (h):
 (a) a 5-10 membered heteroaryl or 5-10 membered heterocyclyl, having 1-4 heteroatoms selected from O, S, and N; and optionally substituted with one, two, three, four or five substituents; or 
 (b) a C 6-10  aryl optionally substituted with one, two, three, four or five substituents; or 
 (c) hydrogen, halogen, cyano, —NR b C(O)R a , —NR b SO 2 R a , —SO 2 NR a R b ; or —SO 2 R a ; 
 
 wherein each R a  is independently C 1-6  alkyl, and R b  is independently hydrogen or C 1-6  alkyl; or R a  and R b  are taken together with the atom(s) to which they are attached to form an optionally substituted 5-10 membered heterocyclyl; or
 (d) —OR a1  or —(C 1-6  alkylene)-OR a1 ; wherein each R a1  is independently C 1-6  alkyl optionally substituted with C 6-10  aryl; 5-10 membered heteroaryl; or 5-10 membered heterocyclyl; wherein the C 6-10  aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are optionally substituted; or 
 (e) a C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, each optionally substituted with one to five substituents; or 
 (f) a C 3-8  cycloalkyl optionally substituted with one to five substituents; 
 (g) —C(O)NR a2 R b2  or NR a2 (CO)R b2 , wherein each R a2  is independently hydrogen or C 1-6  alkyl, and R b2  is hydrogen, C 1-6  alkyl, C 6-10  aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl; or R a2  and R b2  are taken together with the atom(s) to which they are attached to form an optionally substituted 5-10 membered heterocyclyl; wherein the C 1-6  alkyl, C 6-10  aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted; or 
 (h) 5-10 membered heteroaryl fused with a ring selected from the group consisting of 5 or 6 membered heteroaryl, 5-10 membered heterocyclyl, C 6-10  aryl and C 3-7  cycloalkyl, wherein the 5-10 membered heteroaryl of R 2  and the fused ring are optionally substituted with one to four substituents; 
 
 R 3  is hydrogen, cyano, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-6  alkoxy; and 
 R 4  is A-C(O)— or D; 
 A is C 1-6  alkyl, C 3-7  cycloalkyl, C 2-9  heteroaryl, C 2-9  heterocyclyl, —NHR g  or —OR h ; wherein the C 1-6  alkyl, C 3-7  cycloalkyl, 7 C 2-9  heteroaryl and C 2-9  heterocyclyl of A are optionally substituted independently with one, two, three, four or five substituents; 
 R g  and R h  are independently C 1-6  alkyl, C 2-6  alkenyl, C 3-7  cycloalkyl, C 6-10  aryl, C 2-9  heteroaryl, or C 2-9  heterocyclyl; wherein the C 1-6  alkyl, C 2-6  alkenyl, C 3-7  cycloalkyl, C 6-10  aryl, C 2-9  heteroaryl and C 2-9  heterocyclyl of R g  and R h  are optionally substituted independently with one, two, three, four or five substituents; and 
 D is hydrogen, a C 6-10  aryl, or a 5-10 membered heteroaryl having 1-4 heteroatoms selected from O, S, and N; or a 5-10 membered heteroaryl fused with a ring selected from the group consisting of 5- or 6-membered heteroaryl, 5-10 membered heterocyclyl, C 6  aryl and C 3-8  cycloalkyl; wherein the 5-10 membered heteroaryl of D and the fused ring are optionally substituted with one, two, three, four or five substituents; 
 provided that the compound is other than compounds selected from the group consisting of N-(8-amino-3-isoquinolinyl)-N′-ethyl-urea, 5-[(8-amino-3-isoquinolinyl)amino]-2-pyrazinecarbonitrile, and 5-[(8-amino-3-isoquinolinyl)amino]-3-[(1R)-2-(dimethylamino)-1-methylethoxy]-2-pyrazinecarbonitrile, and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is a 5-10 membered heteroaryl or 5-10 membered heterocyclyl, having 1-4 heteroatoms selected from O, S, and N; and optionally substituted with one, two, three, four or five substituents. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       each of which can be optionally substituted. 
     
     
         4 . The compound of  claim 2 , wherein R 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       each of which is optionally substituted. 
     
     
         5 . The compound of  claim 4 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
       wherein R 6 , R 7 , and R 5  are each independently selected from the group consisting of:
 i. branched or linear C 1-6  alkyl, C 1-6  alkenyl, or C 1-6  alkenylene, wherein said alkyl, alkenyl and alkenylene can be optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halogen, nitrile, amino, mono(C 1-6 a 1 kyl)amino-, di(C 1-6 alkyl)amino-, —SO 2 R y , —S(O)NR y , —(CO)NR y R z  and —NR y (CO)R z , wherein R y  and R z , in each instance, is independently hydrogen or C 1-6  alkyl, wherein said alkyl can optionally be substituted with one to four substituents independently selected from the group consisting of hydroxyl and halogen; 
 ii. NR y R z —C(O)—, wherein R y  and R z  are each independently hydrogen or C 1-6  alkyl, wherein said alkyl can optionally be substituted with one to four substituents independently selected from the group consisting of hydroxyl and halogen; 
 iii. hydroxy(C 1-6  alkyl); 
 iv. C 1-6  alkoxy, wherein said alkoxy can be optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl and halogen; 
 v. C 3-9  cycloalkyl, substituted or unsubstituted C 6  aryl, substituted or unsubstituted 5-membered heteroaryl, or C 2-9  heterocyclyl; 
 vi. halogen; 
 vii. amino; 
 viii. cyano; 
 ix. —NR y C(O)R z , wherein R y  and R z  are each independently hydrogen or C 1-6  alkyl, wherein said alkyl can optionally be substituted with one to four substituents independently selected from the group consisting of hydroxyl and halogen; 
 x. —SO 2 R′, wherein R′ is H or C 1-6  alkyl; 
 xi. —SO 2 NR′R″, wherein R′ and R″ are independently H or C 1-6  alkyl; 
 xii. —NR′C(O)OR″, —NR′SO 2 NR″ or —NR′S(O)R″, wherein R′ is independently H or C 1-6  alkyl and R″ is independently C 1-6  alkyl, halo(C 1-6  alkyl) or C 6-10  aryl optionally substituted with C 1-6  alkyl; and 
 xiii. wherein a carbon embedded in said heterocyclyl taken together with an oxygen to which it is bound can form a carbonyl. 
 
     
     
         6 . The compound of  claim 5 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein R 2  is: 
       
         
           
           
               
               
           
         
         wherein R 6 , R 7 , and R 8  are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C 1-6  alkyl, C 1-6  alkoxy, and mono(C 1-6  alkyl)amino. 
       
     
     
         9 . The compound of  claim 8 , wherein R 6  is C 1-6  alkyl; R 7  is hydrogen, amino, or mono(C 1-6  alkyl)amino; and R 5  is hydrogen, hydroxyl, or C 1-6  alkoxy. 
     
     
         10 . The compound of  claim 9 , wherein R 6  is methyl. 
     
     
         11 . The compound of  claim 10 , wherein R 7  is amino. 
     
     
         12 . The compound of  claim 10 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein R 4  is -A-C(O)—. 
     
     
         14 . The compound of  claim 13 , wherein A is:
 i. C 3-7  cycloalkyl, C 2-9  heteroaryl, or C 2-9  heterocyclyl, wherein said cycloalkyl, heteroaryl, or heterocyclyl can be optionally substituted with one, two, three or four of R 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkenylene, halogen, cyano, hydroxyl, C 1-6  alkoxy, optionally substituted C 2-9  heteroaryl, —SO 2 R e , —NR e R f , —NR e C(O)R f , —NR e SO 2 R f  and NR e R f —C(O)—; wherein the C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkenylene of R 5  can be optionally substituted with one to four substituents independently selected from the group consisting of C 1-6  alkoxy, hydroxyl, halogen, cyano, —SO 2 R e , —NR e R f —NR e C(O)R f  and —C(O)NR e R f , wherein R e  and R f  in each occurrence are independently selected from the group consisting of hydrogen, branched or linear C 1-6  alkyl and C 3-7  cycloalkyl;
 or, said cycloalkyl or heterocyclyl together with two of R 5  form a bicyclic or spiro ring, wherein two of R 5  attached to different atoms are taken together with the carbon to which each is attached to form a bicyclic, or two of R 5  attached to the same carbon are taken together with the carbon to which each is attached to form a spiro ring; 
   ii. —NHR g  or —OR h , wherein R g  and R h  are independently selected from the group consisting of:
 a. branched or linear C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkenylene, C 2-9  heterocyclyl, and C 3-7  cycloalkyl, wherein said alkyl, alkenyl, alkenylene, heterocyclyl and cycloalkyl can be optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halogen, —CHF 2 , —CF 3 , amino, di(C 1-6  alkyl)amino, mono(C 1-6  alkyl)amino, cyano, C 3-7  cycloalkyl, C 1-6  alkoxy, —SO 2 R′, —SO 2 NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R″′, —NR′SO 2 NR″R′″ or —NR′S(O)R″, wherein R′ and R′″ are independently H or C 1-6  alkyl and R″ is independently C 1-6  alkyl, halo(C 1-6  alkyl) or C 6-10  aryl optionally substituted with C 1-6  alkyl; or R″ and R′″ are taken together with the nitrogen to which they are attached to form a substituted or unsubstituted heterocyclyl; and 
 b. C 2-9  heteroaryl or C 6-10  aryl, wherein said heteroaryl has 1-4 heteroatoms selected from O, S and N; and wherein said aryl and heteroaryl can be optionally substituted with one, two, three or four substituents selected from the group consisting of branched or linear C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkenylene, C 2-9  heterocyclyl, C 3-7  cycloalkyl, hydroxyl, halogen, —CHF 2 , —CF 3 , amino, di(C 1-6  alkyl)amino, mono(C 1-6  alkyl)amino, cyano, C 3-7  cycloalkyl, C 1-6  alkoxy, —SO 2 R′, —SO 2 NR′R″, —C(O)NR′R″, and —NR′C(O)R″, wherein R′ and R″ are independently H or C 1-6  alkyl; or 
   iii. C 1-6  alkyl optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halogen, cyano, C 1-6  alkoxy, amino, mono(C 1-6  alkyl)amino, di(C 1-6  alkyl)amino, C 3-7  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, —SO 2 R′, —SO 2 NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R′″, —NR′SO 2 NR″R′″ and —NR′S(O)R″;
 wherein R′ and R′″ are independently H or C 1-6  alkyl and R″ is independently C 1-6  alkyl, halo(C 1-6  alkyl) or C 6-10  aryl optionally substituted with C 1-6  alkyl; or R″ and R′″ are taken together with the nitrogen to which they are attached to form an optionally substituted C 3-7  heterocyclyl. 
   
     
     
         15 . The compound of  claim 14 , wherein A is optionally substituted C 3-7  cycloalkyl. 
     
     
         16 . The compound of  claim 15 , wherein R 4  is: 
       
         
           
           
               
               
           
         
         wherein, v is 0, 1, 2 or 3; and 
         R 5  is selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkenylene, halogen, cyano, hydroxyl, C 1-6  alkoxy, optionally substituted C 2-9  heteroaryl, —SO 2 R e , —NR e R f , —NR e C(O)R f , —NReSO 2 R f  and NR e R f —C(O)—; wherein the C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkenylene of R 5  can be optionally substituted with one to four substituents independently selected from the group consisting of C 1-6  alkoxy, hydroxyl, halogen, cyano, —SO 2 R e , —NR e R f —NR e C(O)R f  and —C(O)NR e R f , wherein R e  and R f  in each occurrence are independently selected from the group consisting of hydrogen, branched or linear C 1-6  alkyl and C 3-7  cycloalkyl. 
       
     
     
         17 . The compound of  claim 16 , wherein each R 5  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, halogen, cyano, hydroxyl, C 1-6  alkoxy, and C 2-9  heteroaryl, wherein said alkyl, cycloalkyl, and heteroaryl are optionally substituted. 
     
     
         18 . The compound of  claim 17 , wherein at least one R 5  is C 1-6  alkyl. 
     
     
         19 . The compound of  claim 18 , wherein said C 1-6  alkyl is methyl or ethyl. 
     
     
         20 . The compound of  claim 17 , wherein one of R 5  is optionally substituted C 2-9  heteroaryl. 
     
     
         21 . The compound of  claim 20 , wherein said optionally substituted C 2-9  heteroaryl is an optionally substituted C 3  heteroaryl. 
     
     
         22 . The compound of  claim 21 , wherein said optionally substituted C 3  heteroaryl is an optionally substituted pyrazole. 
     
     
         23 . The compound of  claim 22 , wherein said optionally substituted pyrazole is 
       
         
           
           
               
               
           
         
         wherein the wavy line denotes the point of attachment to the cyclopropyl ring; and wherein R B1  is C 1-6  alkyl. 
       
     
     
         24 . The compound of  claim 17 , wherein R 4  is: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein R 4  is D. 
     
     
         26 . The compound of  claim 25 , wherein D is a 5-10 membered heteroaryl, having 1-4 heteroatoms selected from O, S, and N; and optionally substituted with one, two, three or four substituents, wherein two of the substituents attached to different atoms are taken together with the atom to which each is attached to form a bicyclic or tricyclic, wherein said bicyclic or tricyclic is optionally substituted; or the 5-10 membered heteroaryl is fused with a ring selected from the group consisting of 5 or 6 membered heteroaryl, 5-10 membered heterocyclyl, C 6  aryl and C 3-8  cycloalkyl, wherein the 5-10 membered heteroaryl of D and the fused ring are optionally substituted, wherein said fused ring forms an optionally substituted bicyclic or tricyclic system. 
     
     
         27 . The compound of  claim 26 , wherein D is an optionally substituted heteroaryl containing at least one nitrogen. 
     
     
         28 . The compound of  claim 27 , wherein said optionally substituted 5-member heteroaryl is an optionally substituted pyrazole. 
     
     
         29 . The compound of  claim 28 , wherein said optionally substituted pyrazole is fused with another cyclic moiety to form an optionally substituted bicyclic or tricyclic. 
     
     
         30 . The compound of  claim 29 , wherein said bicyclic or tricyclic is 
       
         
           
           
               
               
           
         
         wherein X′ and Y′ are each independently C, N, S, or O; and 
         wherein said bicyclic is optionally substituted with one, two, three or four substituents independently selected from the group consisting of hydrogen, hydroxyl, amino and C 1-6  alkyl; 
         and wherein two of the substituents taken together with the atoms to which they are attached can form a C 3 -C 5  spiro or a C 2-9  heteroaryl ring; wherein said C 2-9  heteroaryl ring may be fused to said bicyclic to form a tricyclic. 
       
     
     
         31 . The compound of  claim 30 , wherein at least one of X′ or Y′ are N. 
     
     
         32 . The compound of  claim 30 , wherein said bicyclic or tricyclic is: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 25 , wherein D is a 5-membered heteroaryl having the formula 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         or a 6-membered heteroaryl having the formula wherein: 
         Q is NR 20 , CR 20 , O or S; 
         each T is independently N or CR 21 ; 
         each Z is independently N or C, provided that only one Z is N; 
         each R 20  and R 21  is independently hydrogen, alkyl, haloalkyl, alkoxy, halogen, hydroxy, or cyano; and 
         R 22  and R 23  are taken together with the atoms to which they are attached to form a bicyclic; wherein the bicyclic may contain one or more heteroatoms selected from N, S and O; 
         and wherein the bicyclic is optionally substituted with one, two, three, four or five R 30 ; 
         wherein each R 30  is independently C 1-6  alkyl, C 2-6  alkenyl, C 3-7  cycloalkyl, C 3-7  heterocyclyl, halogen, cyano, oxo, —NR 31 R 32 , —SO 2 NR 31 R 32 , —C(O)NR 31 R 32 , —C(O)OR 33 , —OR 33 , —NR 33 C(O)R 34 , —NR 33 SO 2 R 35  or —SO 2 R 35 ; wherein the C 1-6  alkyl, C 2-6  alkenyl, C 3-7  cycloalkyl and C 3-7  heterocyclyl of R 30  are optionally substituted with one to four R 40 ; or two R 30  groups are taken together with the parent moiety to with they are attached to form a ring which is optionally substituted with one to four R 40 ; 
         each R 31  and R 32  is independently hydrogen or C 1-6  alkyl; or R 31  and R 32  are taken together with the nitrogen atom to which they are attached to form a C 3-7  heterocyclyl optionally substituted with one to four R 40 ; 
         each R 33  and R 34  are independently hydrogen or C 1-6  alkyl; 
         R 35  is C 1-6  alkyl; 
         each R 40  is independently selected from the group consisting of halogen, cyano, oxo, —NR 41 R 42 , —SO 2 NR 41 R 42 , —C(O)NR 41 R 42 , —C(O)OR 43 , —OR 43 , —NR 43 C(O)R 44 , —NR 43 SO 2 R 45  or —SO 2 R 45 ; C 1-6  alkyl, C 1-6  haloalkyl, C 2-9  heteroaryl, C 6-10  aryl, oxo; or two R 40  groups are taken together with the parent moiety to with they are attached to form a ring which is optionally substituted with one to three substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, hydroxyl and oxo; 
         each R 41  and R 42  is independently hydrogen or C 1-6  alkyl; or R 41  and R 42  are taken together with the nitrogen atom to which they are attached to form a C 3-7  heterocyclyl optionally substituted with one to three substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, hydroxyl and oxo; 
         each R 43  and R 44  are independently hydrogen or C 1-6  alkyl; and 
         R 45  is C 1-6  alkyl. 
       
     
     
         34 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein q is 0, 1, 2, 3, 4, 5 or 6;
 R 36  is independently hydrogen or R 30 ; and 
 R 20  and R 30  are as defined in  claim 33 . 
 
     
     
         35 . The compound of  claim 34 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein R 36  is independently hydrogen or C 1-6  alkyl; and R 20  is hydrogen. 
     
     
         36 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1, 2, 3 or 4;
 R 36  is independently hydrogen or R 30 ; and 
 R 20  and R 30  are as defined in  claim 33 . 
 
     
     
         37 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein X is CH 2 , N, O or S;
 n is 1, 2, 3 or 4; 
 p is 0, 1, 2,3 or 4; 
 R 36  is hydrogen or R 30 ; and 
 R 20  and R 30  are as defined in  claim 33 . 
 
     
     
         38 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein q is 0, 1, 2, 3, 4, 5 or 6; and R 20  and R 30  are as defined in  claim 33 . 
     
     
         39 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein Q is NR 20 , O or S;
 X is CR 38a R 38b , NR 36 , O or S, 
 X′ is CR 39a R 39b , NR 36 , O, S or SO 2 , 
 R 36 , R 37a , R 37b , R 38a  and R 38b  are independently hydrogen or R 30 ; 
 R 39a  and R 39b  are independently hydrogen or R 30 , or R 39a  and R 39b  are taken together with the carbon atom to which they are attached to form a C 3-7  cycloalkyl or C 3-7  heterocyclyl; and 
 R 20  and R 30  are as defined in  claim 33 . 
 
     
     
         40 . The compound of  claim 39 , wherein D is 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 33 , wherein D is 
       
         
           
           
               
               
           
         
       
       wherein q is 0, 1, 2, 3, 4, 5 or 6;
 G is independently C or N; 
 G′ is independently N, NR 46 , CR 47,  S or O; 
 R 46  and R 47  are independently hydrogen or R 40 ; or two groups R 46  and R 47  are taken together to form a ring; and 
 R 20  and R 40  are as defined in  claim 33 . 
 
     
     
         42 . The compound of  claim 41 , wherein D is 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of  claim 1 , wherein R 1  is hydrogen, halo, or methyl. 
     
     
         44 . The compound of  claim 43 , wherein R 1  is fluoro. 
     
     
         45 . The compound of  claim 1 , wherein R 3  is hydrogen. 
     
     
         46 . The compound of  claim 1 , wherein the compound is selected from the group consisting of Compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 113, 115, 116, 117, 118, 119, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230 in Table 1, or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The compound of  claim 1 , wherein the compound is selected from the group consisting of Compound Nos. 9-12, 29, 33-36, 53, 58, 64, 83, 84, 96, 97, 111, 112, 114, 120, 121, 129, 137, 141, 142, 152 and 158 in Table 1 and Compound Nos, 231-390 in Table 2, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The compound of  claim 1 , wherein the compound is selected from Compound Nos. 391-528 in Table 3, or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein said composition further comprises a chemotherapeutic agent. 
     
     
         51 . A method of inhibiting HPK1 comprising contacting HPK1 in a subject with an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method for enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 52 , wherein the subject has cancer. 
     
     
         54 . A method for treating a HPK1-dependent disorder comprising administering to a subject in need thereof an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 54 , wherein said HPK1-dependent disorder is a cancer. 
     
     
         56 . The method of  claim 55 , wherein the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, a hematological malignancy, and a renal cell carcinoma. 
     
     
         57 . The method of  claim 56 , further comprising administering a chemotherapeutic agent to the subject. 
     
     
         58 . A method for making a compound of Formula I as defined in  claim 1 , wherein the method comprises the steps in Scheme 1 or Scheme 2.