Phosphatidylinositol 3-kinase inhibitors

1. A compound having the structure of formula (I):

wherein: R 1 is selected from:

n is 1, 2, 3 or 4;

s is 1, 2 or 3;

t is 1 or 2;

each X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 is independently selected from C and N;

R 2 is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 2 is optionally substituted with one to four R 101 ;

R 3 is selected from halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 3 is optionally substituted with one to four R 102 ;

R 4 is selected from 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 4 is optionally substituted with one to four R 103 ;

each R 5 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 5 is optionally substituted with one to four R 104 ;

each R 6 is independently hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

each R 7 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 7 is optionally substituted with one to four R 100 ;

each R a and R b is independently selected from hydrogen, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

wherein each C 1-6 alkyl, C 2-6 alkynyl of R a and R b , C 2-6 alkynyl, is optionally substituted with one to four R 200 ;

each R 100 , R 101 , R 102 , R 103 and R 104 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R c , —C(O)OR c , —C(O)NR c R d , —N(R c )C(O)R d , —N(R c )C(O)NR c R d , —N(R c )C(O)NR c R d , —OC(O)NR c R d , —NR c S(O) 2 NR c R d , —NR c S(O) 2 R c , —OC(O)NR c R d , —NR c S(O) 2 NR c R d , —NR c S(O) 2 R c , —S(O)NR c R d , —S(O) 2 NR c R d , —S(O)R c , —S(O) 2 R g , —NR c R d , —OR c , —SR d , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 100 , R 101 , R 102 , R 103 and R 104 is optionally substituted with one to four R 201 , and

each R c and R d is independently selected from hydrogen, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

each R 200 and R 201 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R e , —C(O)OR e , —C(O)NR e R f , —N(R e )C(O)R f , —S(O)NR e R f , —S(O) 2 NR e R f , NR e R f , —OR e , —SR e , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl,

each R e and R f is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; and

each R g is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R g is optionally substituted with one to four R 200 ,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

2. The compound of claim 1 having the structure of formula IA:

wherein t, R 1 , R 2 , R 4 , and R 6 are as defined in claim 1 ;

represents a single or double bond;

X 12 is N or C;

each X 8 , X 9 , X 10 and X 11 is independently selected from S, O, CR 10 and NR 11 ;

wherein each R 10 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 201 ;

wherein each R 11 is independently selected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; or

one R 10 and one R 11 group, together with the atoms to which they are attached form a five, six or seven membered fused, or bridged ring,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

3. The compound of claim 1 having the structure of formula IB:

wherein m is 1, 2 or 3;

each R 14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

4. The compound of claim 2 having the structure of formula IC:

wherein m is 1, 2 or 3;

each R 14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

5. The compound of claim 1 , wherein R 3 is selected from:

k is 1 or 2;

each R 13 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

6. The compound of claim 1 , wherein R 4 is selected from:

m is 1, 2 or 3;

each R 14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

7. The compound of claim 1 , wherein R 1 is selected from:

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

8. The compound of claim 1 , wherein R 2 is selected from:

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

9. The compound of claim 1 , wherein R 3 is selected from:

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

10. The compound of claim 1 , wherein the compound is selected from:

Compound

Image

2-1

2-2

2-3

3-1

3-2

4-1

4-2

4-3

4-4

5-1

5-2

5-3

5-4

5-5

5-6

5-7

5-8

5-9

 5-10

 5-11

 5-12

 5-13

6-1

6-2

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof, and at least one pharmaceutically acceptable vehicle.

12. A kit comprising the compound of claim 1 , or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof, and a label and/or instructions for use.

13. A compound selected from:

Compound

Image

5-14

5-15

or a pharmaceutically acceptable salt thereof.