Tetrahydropyridopyrimidines and related analogs for inhibiting YAP/TAZ-TEAD

1 . A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

R 1 and R 2 are selected from the group consisting of:

(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:

(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:

(1) halogen,

(2) cyano,

(3) C 1 -C 6 alkyl,

(4) C 3 -C 6 cycloalkyl,

(5) C 1 -C 6 haloalkyl,

(6) —OZ 1 ,

(7) C 2 -C 6 alkenyl, and

(8) C 2 -C 6 alkynyl,

(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:

(1) halogen,

(2) cyano,

(3) C 1 -C 6 alkyl,

(4) C 3 -C 6 cycloalkyl,

(5) C 1 -C 6 haloalkyl, and

(6) —OZ 1 ,

(c) C 2 -C 6 alkynyl,

(ii) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano,

(c) C 1 -C 6 alkyl,

(d) C 3 -C 6 cycloalkyl,

(e) C 1 -C 6 haloalkyl,

(f) —OZ 1 , and

(g) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,

(iii) unsubstituted or substituted 5-to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano,

(c) C 1 -C 6 alkyl,

(d) C 3 -C 6 cycloalkyl,

(e) C 1 -C 6 haloalkyl,

(f) —OZ 1 , and

(g) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,

(vi) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano,

(c) C 1 -C 6 alkyl,

(d) C 3 -C 6 cycloalkyl,

(e) C 1 -C 6 haloalkyl, and

(f) —OZ 1 ,

(v) unsubstituted or substituted C 3 -C 6 heterocycle, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano,

(c) C 1 -C 6 alkyl,

(d) C 3 -C 6 cycloalkyl,

(e) C 1 -C 6 haloalkyl, and

(f) —OZ 1 ;

Y 1 is selected from the group consisting of:

(i) —N(R 4a )—,

(ii) —CR 6e R 6f N(R 4a )—, and

(iii) —CR 6g R 6h CR 6i (NR 5a R 5b )—;

R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 3a is selected from the group consisting of:

(i) hydrogen,

(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:

(a) hydroxy,

(b) —OZ 1 ,

(c) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:

(1) halogen,

(2) cyano,

(3) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,

(4) C 1 -C 6 haloalkyl,

(5) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,

(6) —C(═O) NZ 3 Z 4 ,

(7) —NZ 3 Z 4 ,

(8) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of—NZ 3 Z 4 and 4-to 8-membered heterocycle,

(9) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,

(10) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,

(11) —OZ 1 ,

(12) —C(═O) OH,

(13) hydroxy,

(14) —NZ 5 C(═O) Z 2 ,

(15) —NZ 5 S(═O) 2 Z 2 , and

(16) —NZ 5 S(═O) 2 NZ 3 Z 4 ,

(d) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:

(1) C 1 -C 6 alkyl, and

(2) C 1 -C 6 haloalkyl,

(e) unsubstituted or substituted 5-to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:

(1) halogen,

(2) cyano,

(3) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,

(4) C 1 -C 6 haloalkyl,

(5) C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,

(6) —C(═O) NZ 3 Z 4 ,

(7) —NZ 3 Z 4 ,

(8) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of—NZ 3 Z 4 ,

(9) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,

(10) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,

(11) —OZ 1 ,

(12) —C(═O) OH,

(13) hydroxy, and

(14) —NZ 5 C(═O) Z 2 ,

(iii) C 1 -C 6 haloalkyl;

(iv) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C 1 -C 6 alkyl;

(v) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of:

(a) C 1 -C 6 alkyl,

(b) —C(—O) Z 2 , and

(c) —S(═O) 2 Z 8 ,

(vi) unsubstituted or substituted 5-to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano,

(c) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,

(d) C 1 -C 6 haloalkyl,

(e) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,

(f) —C(═O) NZ 3 Z 4 ,

(g) —NZ 3 Z 4 ,

(h) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4-to 8-membered heterocycle

(i) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,

(j) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,

(k) —OZ 1 ,

(l) —C(—O) OH,

(m) hydroxy, and

(n) —NZ 5 C(═O) Z 2 ,

(vii) unsubstituted or substituted 5-to 10-membered aryl, wherein one or more substituents are independently selected from the group consisting of:

(a) halogen,

(b) cyano, and

(c) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ;

R 3b , R 3c , and R 3d are independently selected from the group consisting of:

(i) hydrogen,

(ii) C 1 -C 6 alkyl,

(iii) C 1 -C 6 haloalkyl,

(iv) C 3 -C 6 cycloalkyl,

(v) C 5 -C 10 heteroaryl,

(vi) halogen,

(vii) cyano,

(viii) —OZ 1 ,

(ix) alkenyl,

(x) alkynyl,

(xi) SR 1 ,

(xii) SOR 1 ,

(xiii) —S(═O) 2 Z 8 ,

(xiv) —C(═O) Z 2 ,

(xv) —NZ 5 C(═O) Z 2 , and

(xvi) —C(═O) NZ 3 Z 4 ;

R 4a is selected from the group consisting of:

(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:

(a) cyano,

(b) hydroxy,

(c) —NZ 3 Z 4 ,

(d) —C(═O) Z 2

(e) C(═O) OH,

(f) —C(═O) OZ 2 ,

(g) —C(═O) NZ 3 Z 4 ,

(h) —NZ 5 C(═O) Z 2 ,

(i) —NZ 5 C(═O) OZ 2 ,

(j) —NZ 5 C(═O) NZ 3 Z 4 ,

(k) —S(═O) 2 Z 8 ,

(l) —S(═O) 2 NZ 3 Z 4 ,

(m) —S(═O) (═NZ 6 ) Z 2 ,

(n) —S(═Z 6 ) (═NZ 7 ) Z 2 ,

(o) —S(═O) (═NZ 6 ) NZ 3 Z 4 ,

(p) —NZ 5 S(═O) 2 Z 2 ,

(q) —NZ 5 S(═O) 2 NZ 3 Z 4 ,

(r) —NZ 5 S(═O) (═NZ 6 ) Z 2 ,

(s) —NZ 5 S(═NZ 6 ) (═NZ 7 ) Z 2 , and

(t) —NZ 5 S(═O) (═NZ 6 ) NZ 3 Z 4 ;

(ii) —C(═O) Z 2

(iii) —C(═O) NZ 3 Z 4 ,

(iv) —S(═O) 2 Z 8 ,

(v) —S(═O) 2 NZ 3 Z 4 ,

(vi) —S(═O) (═NZ 6 ) Z 2 ,

(vii) —S(═Z 6 ) (═NZ 7 ) Z 2 ,

(viii) —S(═O) (═NZ 6 ) NZ 3 Z 4 ,

(ix) cyano, and

(x) C 1 -C 6 haloalkyl;

R 5a is selected from the group consisting of:

(i) hydrogen,

(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:

(a) cyano,

(b) hydroxy,

(c) —NZ 3 Z 4 ,

(d) —C(═O) Z 2

(e) C(═O) OH,

(f) —C(═O) OZ 2 ,

(g) —C(═O) NZ 3 Z 4 ,

(h) —NZ 5 C(═O) Z 2 ,

(i) —NZ 5 C(═O) OZ 2 ,

(j) —NZ 5 C(═O) NZ 3 Z 4 ,

(k) —S(═O) 2 Z 8 ,

(l) —S(═O) 2 NZ 3 Z 4 ,

(m) —S(═O) (═NZ 6 ) Z 2 ,

(n) —S(═Z 6 ) (═NZ 7 ) Z 2 ,

(o) —S(═O) (═NZ 6 ) NZ 3 Z 4 ,

(p) —NZ 5 S(═O) 2 Z 2 ,

(q) —NZ 5 S(═O) 2 NZ 3 Z 4 ,

(r) —NZ 5 S(═O) (═NZ 6 ) Z 2 ,

(s) —NZ 5 S(═NZ 6 ) (═NZ 7 ) Z 2 , and

(t) —NZ 5 S(═O) (═NZ 6 ) NZ 3 Z 4 ;

(iii) C 1 -C 6 haloalkyl;

(iv) —C(═O) OZ 2 ,

(v) —C(═O) NZ 3 Z 4 ,

(vi) —S(═O) 2 Z 8 ,

(vii) —S(═O) 2 NZ 3 Z 4 ,

(viii) —S(═O) (═NZ 6 ) Z 2 ,

(ix) —S(═Z 6 ) (═NZ 7 ) Z 2 ,

(x) —S(═O) (═NZ 6 ) NZ 3 Z 4 , and

(xi) -cyano;

R 5b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

each Z 2 is independently selected from the group consisting of:

(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , cyano, —NZ 3 Z 4 , and 3-to 6-membered heterocycle;

(ii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 , halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4-to 8-membered heterocycle,

(iii) C 2 -C 6 alkynyl,

(iv) C 3 -C 6 cycloalkyl,

(v) C 3 -C 6 cycloalkenyl,

(vi) C 1 -C 6 haloalkyl, and

(vii) 3- to 6-membered heterocycle;

each Z 3 is independently selected from the group consisting of:

(i) hydrogen,

(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —C(═O) C 1 -C 6 alkyl, —S(═O) 2 C 1 -C 6 alkyl, hydroxy, —OZ 1 , cyano, —NZ 3 Z 4 , unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl; and unsubstituted or substituted C 5 -C 9 heteroaryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,

(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4-to 8-membered heterocycle,

(iv) C 2 -C 6 alkynyl,

(v) C 3 -C 6 cycloalkyl,

(vi) C 3 -C 6 cycloalkenyl, and

(vii) C 1 -C 6 haloalkyl;

each Z 4 , Z 3 , Z 6 and Z 7 is independently selected from the group consisting of:

(i) hydrogen,

(ii) C 1 -C 6 alkyl, and

(iii) C 3 -C 6 cycloalkyl; and

each Z 8 is independently selected from the group consisting of:

(i) hydrogen,

(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , cyano, —NZ 3 Z 4 , and 3-to 6-membered heterocycle;

(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 , and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4-to 8-membered heterocycle,

(iv) halogen,

(v) hydroxy, and

(vi) haloalkyl.

2 . The compound of claim 1 of Formula IV:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

3 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4a is selected from the group consisting of unsubstituted or substituted C 1 -C 6 alkyl, —C(═O) Z 2 , and —S(═O) 2 Z 8 .

4 . The compound of claim 3 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is selected from the group consisting of unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted C 2 -C 6 alkenyl.

5 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 is selected from the group consisting of hydrogen, —C(═O) NZ 3 Z 4 ,

6 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is selected from the group consisting of unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted C 2 -C 6 alkenyl.

7 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is selected from the group consisting of unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted C 6 -C 10 aryl.

8 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 is R 2 -1.

9 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

1-(2-benzyl-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-benzyl-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

2-benzyl-4-(1-methyl-1H-pyrazol-3-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;

1-(2-benzyl-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-benzyl-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

2-benzyl-7-(methylsulfonyl)-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(2-(4-fluorobenzyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(4-fluorobenzyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(2-(3-fluorobenzyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(3-fluorobenzyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(3-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(3-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(pyridin-3-ylmethyl)-1 H-pyrazol-3-yl)-2-(3-(trifluoromethyl) benzyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(4-fluorophenyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(3-fluorophenyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(3,4-difluorophenyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(3-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-4-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-isopropyl-1H-pyrazol-4-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

7-acryloyl-2-phenyl-N-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxamide;

1-(4-(1-ethyl-1H-pyrazol-3-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-isopropyl-1H-pyrazol-3-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-phenyl-4-(pyridin-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2,4-diphenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-phenyl-4-(pyridin-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-phenyl-4-(pyridin-2-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(difluoromethyl)-1 H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-(4-fluorophenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

2-fluoro-1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

(E)-1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) but-2-en-1-one;

3-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl)-3-oxopropanenitrile;

1-(8-methyl-4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

2-methyl-1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carbonitrile;

4-(1-methyl-1H-pyrazol-3-yl)-7-(methylsulfonyl)-2-(4-(trifluoromethyl) phenyl)-5,6,7,8-tetrahy dropyrido[3,4-d]pyrimidine;

4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-7-(vinylsulfonyl)-5,6,7,8-tetrahy dropyrido[3,4-d]pyrimidine;

1-(4-(2-methyl-2H-tetrazol-5-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(1-methyl-1H-tetrazol-5-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

(E)-4-(dimethylamino)-1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) but-2-en-1-one;

cyclopent-1-en-1-yl(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) methanone;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) but-2-yn-1-one;

1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

(4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) (oxiran-2-yl) methanone;

1-(2-(4,4-difluorocyclohexyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(2-(4,4-difluorocyclohexyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(4-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) prop-2-en-1-one;

1-(4-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4-(trifluoromethyl) phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) propan-1-one;

1-(2-(4,4-difluorocyclohexyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) but-2-yn-1-one; and

(E)-1-(2-(4,4-difluorocyclohexyl)-4-(1-methyl-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7 (6H)-yl) but-2-en-1-one.

10 . A pharmaceutical composition comprising the compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.