Small molecules for the treatment of autoimmune diseases and cancer

1. A compound of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

X 1 is —(CH 2 ) o — or a covalent bond;

o is an integer equal to 1, 2, 3, 4, 5, or 6;

X 2 is hydrogen and X 3 is represented by Formula (IX3):

where

X a is selected from the group consisting of CH and N;

m is independently an integer selected from 1, 2, 3, or 4;

n is independently an integer selected from 0, 1, 2, 3, or 4;

X b is selected from the group consisting of CH 2 , —NR a , NH, O, S, and SO 2 ;

l is an integer selected from 0, 1, or 2;

each instance of R a , where present, is independently selected from the group consisting of amino, —OH, halogen, cyano, hydroxy, optionally substituted C 1 -C 3 alkyl, C-carboxy, and optionally substituted C 1 -C 6 alkoxy(C 1 -C 6 )alkyl; and

wherein each R a can be provided at any position of the “A” ring by replacing one or more —H atoms of any carbon or nitrogen atom present within the “A” ring;

X 4 is selected from the group consisting of —CN, —OR 1 , —SR 1 , optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkenyl, optionally substituted C 1 -C 10 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and —NR 2 R 3 ;

R 1 is hydrogen or an optionally substituted C 1 -C 10 alkyl;

each of R 2 and R 3 is independently selected from hydrogen and optionally substituted C 1-10 alkyl; or alternatively, R 2 and R 3 attached to the same nitrogen atom may be together with the atom to which they are attached, form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-10 membered heteroaryl;

R 4 is represented by one of:

where

f is independently an integer selected from 1, 2, 3, or 4;

g is independently an integer selected from 0, 1, 2, 3, or 4;

X i is selected from the group consisting of CH 2 , NH, O, S, and SO 2 ;

each instance of R g , where present, is independently selected from the group consisting of amino, —OH, halogen, cyano, hydroxy, optionally substituted C 1 -C 6 alkyl, C-carboxy, and optionally substituted C 1 -C 6 alkoxy(C 1 -C 6 )alkyl;

h is an integer selected from 0, 1, 2, 3, or 4; and

wherein each R g can be provided at any position of the “F” ring by replacing one or more —H atoms of any carbon or nitrogen atom present within the “F” ring; and

R 5 is selected from the group consisting of hydrogen, halogen, and —OMe;

provided that, if X 3 is

R 5 is —OMe, and R a , where present, is methyl, isopropyl, cyclopropyl, cyclohexyl, or —CH 2 -cyclohexyl, then X 4 is not optionally substituted cyclohexyl, an optionally substituted 5-membered to 7-membered heterocyclyl, an optionally substituted furanyl, or an optionally substituted pyrrolyl.

2. The compound of claim 1 , wherein n is 1 and m is 1, n is 1 and m is 3, or n is 2 and m is 2.

3. The compound of claim 2 , wherein X b is —NH, —NR a , O or SO 2 .

4. The compound of claim 3 , where R 4 is one of the following structures:

5. The compound of claim 1 , wherein

is represented by the following one of the following structures:

6. The compound of claim 1 , wherein X 4 is represented by Formula (IX4):

X f is selected from the group consisting of CH and N;

b is independently an integer selected from 1, 2, and 3;

c is independently an integer selected from 0, 1, 2, and 3;

d is independently an integer selected from 0, 1, 2, and 3;

X g is selected from the group consisting of CH 2 , NH, O, and SO 2 ;

R f is optionally present and can be provided at any position of the “D” ring by replacing one or more —H of any carbon or nitrogen atom present within the “D” ring; and

R f is selected from the group consisting of halogen, amino, —OH, optionally substituted C 1 -C 6 alkyl, and C-carboxy.

7. The compound of claim 6 , wherein the optional substitutions of the “D” ring are selected from one or more of amino, —OH, optionally substituted C 1 -C 6 alkyl, and halogen.

8. The compound of claim 1 , wherein X 4 is an optionally substituted 5-membered heteroaryl.

9. The compound of claim 1 , wherein X 4 is represented by:

any one of which may be optionally substituted by replacing one or more —H atoms of any carbon or nitrogen atom present on X 4 .

10. The compound of claim 1 , wherein X 1 is a covalent bond.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:

4-((2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(1-(2-methoxyethyl)piperidin-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-((1-methylpiperidin-4-yl)methyl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

(R)-6-methoxy-N-(piperidin-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

2-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)piperidin-1-yl)acetic acid;

2-(azetidin-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

(S)-6-methoxy-N-(piperidin-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

N-(1-isopropylpiperidin-4-yl)-6-methoxy-2-(1H-pyrazol-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

4-((1-isopropylpiperidin-4-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2-carbonitrile;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(piperidin-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

2-(azetidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)thiomorpholine 1,1-dioxide;

4-((6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

4-((6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

4-((6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

4-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)thiomorpholine 1,1-dioxide;

4-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

4-((2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;

2-(1H-imidazol-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;

(R)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazolin-4-amine;

2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazolin-4-amine;

6-methoxy-N2,N2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-3-yl)quinazoline-2,4-diamine;

or a stereoisomer, tautomer, or pharmaceutically acceptable salt of any of the foregoing.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.