NOVEL AMINE-SUBSTITUTED PHTHALAZINES AND DERIVATIVES AS SOS1 INHIBITORS

1 . A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 2 are independently hydrogen, alkyl, or R 1 and R 2 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is hydrogen, alkyl, —(C═O)—OR A , —(C═O)—N(R A ) 2 , cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein R A is hydrogen or alkyl;

 is a heteroaryl;

R 6 is H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl;

R 7 is H, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 8 is H, halogen, alkyl, alkoxy, alkylene-O-alkyl, cycloalkyl, or heterocyclyl;

L 1 and L 2 are each independently absent or a linking group; and

X is independently selected from the group consisting of C 1-5 alkyl, F, CF 3 , CHF 2 , CH 2 F, and —NH 2 ;

m is 1 or 2; and

n is an integer from 1-5,

provided that:

(a)

 is not

 and

(b) the compound of Formula (Ia) is not:

2 . The compound of claim 1 , wherein

is selected from the group consisting of:

wherein R 9 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, or alkylene-heterocyclyl.

3 . The compound of claim 1 or 2 , wherein the linking group is —O—, alkylene, alkylene-O—, alkylene-N(R B )—, —O-alkylene, —N(R B )-alkylene, —O—, or —N(R B )—, wherein R B is hydrogen, alkyl, or alkylenecycloalkyl.

4 . The compound of claim 1 or 2 , wherein L 1 and L 2 are each independently absent or a linking group selected from the group consisting of alkylene, —O-alkylene, —N(R B )-alkylene, —O—, and —N(R B )—, wherein R B is hydrogen, alkyl, or alkylenecycloalkyl.

5 . The compound of any one of claims 1-4 , wherein L 1 is absent or a linking group selected from alkylene, —O-alkylene, —N(R B )-alkylene, —O—, and —N(R B )— and L 2 is absent, —O—, or —N(R B )—, wherein R B is hydrogen, alkyl, or alkylenecycloalkyl.

6 . The compound of any one of claims 1-4 , wherein L 1 is a linking group selected from alkylene, —O-alkylene, —N(R B )-alkylene, —O—, and —N(R B )—, wherein R B is hydrogen, alkyl, or alkylenecycloalkyl and L 2 is absent or —O—.

7 . The compound of any one of claims 1-4 , wherein L 1 is alkylene or —O— and L 2 is absent or —O—.

8 . The compound of any one of claims 1-4 , wherein L 1 and L 2 are —O—.

9 . The compound of any one of claims 1-4 , wherein L 1 is -alkylene- and L 2 is absent.

10 . The compound of any one of claims 1-9 , wherein R 6 is alkyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

11 . The compound of any one of claims 1-9 , wherein R 6 is C 1-5 alkyl, C 3-6 cycloalkyl, or 6-membered heterocyclyl having a heteroatom selected from N, O, and S.

12 . The compound of any one of claims 1-9 , wherein R 6 is heterocyclyl.

13 . The compound of any one of claims 1-9 , wherein R 6 is a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S.

14 . The compound of any one of claims 1-9 , wherein R 6 is a morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, or tetrahydrofuranyl.

15 . The compound of any one of claims 1-9 , wherein R 6 is a piperazinyl, piperidinyl, azetidinyl, tetrahydropyranyl, or tetrahydrofuranyl.

16 . The compound of any one of claims 1-9 , wherein R 6 is 3-tetrahydrofuranyl, 3-oxetanyl, 3-piperidinyl, 4-piperidinyl, or 4-tetrahydropyranyl.

17 . The compound of any one of claims 1-9 , wherein R 6 is alkyl or cycloalkyl.

18 . The compound of any one of claims 1-9 , wherein R 6 is cyclopentyl or cyclopentenyl.

19 . The compound of claim 1-9 , wherein R 6 is methyl, ethyl, or isopropyl.

20 . The compound of any one of claims 1-9 , wherein R 6 is:

21 . The compound of any one of claims 1-20 , wherein R 7 is H, halogen, C 1-5 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, or 5-6-membered heteroaryl.

22 . The compound of any one of claims 1-20 , wherein R 7 is cyclopentyl or 3-tetrahydrofuranyl.

23 . The compound of any one of claims 1-20 , wherein R 7 is cyclopentyl.

24 . The compound of any one of claims 1-20 , wherein R 7 is morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl.

25 . The compound of any one of claims 1-20 , wherein R 7 is pyrazolyl, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, or thiazolyl.

26 . The compound of any one of claims 1-9 , wherein R 6 is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl and R 7 is H, halogen, or alkyl.

27 . The compound of any one of claims 1-9 , wherein R 6 is alkyl, cycloalkyl, cycloalkenyl, or heterocyclyl, and R 7 is H, halogen, or alkyl.

28 . The compound of any one of claims 1-9 , wherein R 7 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R 6 is H or alkyl.

29 . The compound of any one of claims 1-28 , wherein R 8 is H, halogen, C 1-5 alkyl, C 1-5 alkoxy, or —CH 2 —O—C 1-5 alkyl.

30 . The compound of any one of claims 1-29 , wherein R 9 is H or CH 3 .

31 . The compound of any one of claims 1-30 , wherein each X is independently —CF 2 CH 3 , —CF 2 CH 2 OH, —CF 2 C(CH 3 ) 2 OH, —CHF 2 , —CF 3 , F, or —NH 2 .

32 . The compound of any one of claims 1-31 , wherein n is 1.

33 . The compound of any one of claims 1-31 , wherein n is 2.

34 . The compound of any one of claims 1-33 , wherein

is:

wherein the C 1-5 alkyl is a C 1-5 haloalkyl.

35 . The compound of claim 34 , wherein the C 1-5 alkyl is a C 1-5 fluoroalkyl.

36 . The compound of claim 33 or 34 , wherein the C 1-5 alkyl is selected from the group consisting of —CF 2 CF 3 , —CF 2 CH 3 , —CF 2 CH 2 OH, —CF 2 C(CH 3 ) 2 OH, —CHF 2 , —CF 3 , and —CH 2 F.

37 . The compound of any one of claims 1-33 , wherein

is:

38 . The compound of any one of claims 1-33 , wherein

is:

39 . The compound of any one of claims 1-38 , wherein

is

40 . The compound of any one of claims 1-39 , wherein R 3 is C 1-5 alkyl.

41 . The compound of any one of claims 1-39 , wherein R 3 is methyl, ethyl, isopropyl, n-propyl, —CH 2 OH, —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , —CH(OH)(CH 3 ) 2 or —CH 2 (OH)CH 3 .

42 . The compound of any one of claims 1-41 , wherein R 3 is methyl.

43 . The compound of any one of claims 1-42 , wherein R 1 is methyl and R 2 is H.

44 . The compound of any one of claims 1-42 , wherein R 1 and R 2 together with the atom to which they are attached form a C 3-6 cycloalkyl.

45 . The compound of any one of claims 1-42 , wherein R 1 and R 2 together with the atom to which they are attached form a cyclopropyl.

46 . The compound of any one of claims 1-39 and 42-45 , having the structure of Formula (Ic-2) or Formula (Id):

or a pharmaceutically acceptable salt thereof.

47 . The compound of any one of claims 1-39 and 42-45 , wherein the compound is selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

48 . A composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1-47 and a pharmaceutically acceptable excipient.

49 . A method of treating a condition associated with or modulated by SOS1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-47 or a composition of claim 48 .

50 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-47 or a composition of claim 48 .

51 . The compound of any one of claims 1-47 or the composition of claim 48 for use in the treatment of a condition associated with or modulated by SOS1.

52 . The compound of any one of claims 1-47 or the composition of claim 48 for use in the treatment of cancer.

53 . Use of the compound of any one of claims 1-47 or the composition of claim 48 in the manufacture of a medicament for the treatment of a condition associated with or modulated by SOS1.

54 . Use of the compound of any one of claims 1-47 or the composition of claim 48 in the manufacture of a medicament for the treatment of cancer.

55 . The compound of any one of claims 1-47 or the composition of claim 48 for use in therapy.

56 . The compound of any one of claims 1-47 or the composition of claim 48 for use in a method of treating a condition associated with or modulated by SOS1.

57 . The compound of any one of claims 1-47 or the composition of claim 48 for use in a method of treating cancer.