Phenoxy-pyridyl-pyrimidine compounds and methods of use

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R0 is hydrogen or fluoro;
• R1 is C3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —(C1-6 alkylene)-(C3-C12 cycloalkyl), or —(C1-6 alkylene)-(3- to 14-membered heterocyclyl), —(C1-6 alkylene)-OR1c, or —(C1-6 alkylene)-NR1aR1b;
• wherein the C3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C1-6 alkylene of R1 are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R1a, R1b and R1c is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R1a and R1b are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• R2A and R28 are independently hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), or —O(C1-6 haloalkyl);
• R3 is hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), or —O(C1-6 haloalkyl);
• R4 and R5 are independently hydrogen, halogen, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-20 aryl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR7A, —NR8AR8B, —NR8C(O)R7, —NR8C(O)OR7A, —NR8C(O)NR8AR8B, —NR8SO2R9, —NR8SO2NR8AR8B, —NR8S(O)(═NR8C)R9, —C(O)N(R8)SO2R9, C(O)R7, —C(O)OR7A, —SO2R9, —NR8S(O)(═NR8C)R9, or —SO2NR8AR8B;
• wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-20 aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl of R4 and R5 are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• n is 0, 1, 2, or 3;
• each R6 is independently halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), —O(C1-6 haloalkyl), —SO2(C1-6 alkyl) or —SO2(C1-6 haloalkyl);
• each R7 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R7 and R7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R7A is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R7 and R7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R8 is independently hydrogen or C1-C6 alkyl;
• each R8A is independently hydrogen or C1-C6 alkyl;
• each R8B is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, and 3- to 12-membered heterocyclyl of R8B are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R8C is independently hydrogen or C1-C6 alkyl;
• each R9 is independently C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R10 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, —C(O)Ra, —C(O)ORb, —C(O)NRcRd, —ORb, —OC(O)Ra, —OC(O)NRcRd, —SRb, —S(O)Re, —S(O)2Re, —S(O)(═NH)Re, —S(O)2NRcRd, —NRcRd, —N(Rf)C(O)Ra, —N(Rf)C(O)ORb, —N(Rf)C(O)NRcRd, —N(Rf)S(O)2Re, —N(Rf)S(O)2NRcRd, —P(O)RgRh or —SiRiRjRk;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R10 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Ra is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Ra are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rb is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rb are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rc and Rd is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rc and Rd are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Re is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Re are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rf is independently hydrogen or C1-6 alkyl;
• each Rg and Rh is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rg and Rh are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• or Rg and Rh are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Ri, Rj and Rk is independently C1-6 alkyl;
• each R11 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, —C(O)Ra1, —C(O)ORb1, —C(O)NRc1Rd1, —ORb1, —OC(O)Ra1, —OC(O)NRc1Rd1, —SRb1, —S(O)Re1, —S(O)2Re1, —S(O)2NRc1Rd1, —NRc1Rd1, —N(Rf1)C(O)Ra1, —N(Rf1)C(O)ORb1, —N(Rf1)C(O)NRc1Rd1, —N(Rf1)S(O)2Re1, —N(Rf1)S(O)2NRc1Rd1, —P(O)Rg1Rh1, or —SiRi1Rj1Rk1;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R11 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Ra1 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Ra1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rb1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rb1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rc1 and Rd1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rc1 and Rd1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• or Rc1 and Rd1 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Re1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Re1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rf1 is independently hydrogen or C1-6 alkyl;
• each Rg1 and Rh1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rg1 and Rh1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• or Rg1 and Rh1 are taken together with the phosphorus atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Ri1, Rj1 and Rk1 is independently C1-6 alkyl;
• each R12 is independently oxo, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano,—C(O)Ra2, —C(O)ORb2, —C(O)NRc2Rd2, —ORb2, —OC(O)Ra2, —OC(O)NRc2Rd2, —S(O)2Re2, —S(O)2NRc2Rd2, —NRc2Rd2, —N(Rf2)C(O)Ra2, —N(Rf2)C(O)ORb2, —N(Rf2)C(O)NRc2Rd2, —N(Rf2)S(O)2Re2, —N(Rf2)S(O)2NRc2Rd2, or —P(O)Rg2Rh2;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R12 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Ra2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of Ra2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rb2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl of Rb2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rc2 and Rd2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 8-membered heterocyclyl of Rc2 and Rd2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• or Rc2 and Rd2 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Re2 is independently C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of Re2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rf2 is independently hydrogen or C1-6 alkyl;
• each Rg2 and Rh2 is independently C1-6 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of Rg2 and Rh2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• or Rg2 and Rh2 are taken together with the phosphorus atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• and
• each R13 is independently oxo, halogen, hydroxyl, —CKC1-6 alkyl), cyano, C1-6 alkyl or C1-6 haloalkyl;
• provided that the compound is other than
• No.
• Name
• 2x
• 2-Pyrrolidinone, 1-[3-[[4-[2-
• (4-amino-2-methylphenoxy)-3-pyridinyl]-2-
• pyrimidinyl]amino]propyl]-,
• 3x
• 4-Morpholinepropanamine, N-[4-[2-
• (4-amino-2-methylphenoxy)-3-pyridinyl]-2-
• pyrimidinyl]-,
• 4x
• Urea, N-(3-fluoro-4-methylphenyl)-N′-[4-[[3-
• [2-[[3-(4-morpholinyl)propyl]amino]-
• 4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
• 5x
• Urea, N-(2,3-dihydro-1H-inden-5-yl)-N′-[4-
• [[3-[2-[[3-(4-morpholinyl)propyl]amino]-
• 4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
• 6x
• Urea, N-(4-chlorophenyl)-N′-[4-[[3-[2-
• [[3-(4-morpholinyl)propyl]amino]-4-
• pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
• 7x
• Urea, N-[3-methyl-4-[[3-[2-[[3-(2-oxo-
• 1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-
• pyridinyl]oxy]phenyl]-N′-[3-(trifluoromethyl)phenyl]-,
• 8x
• Urea, N-(5-chloro-2-methoxyphenyl)-N′-[3-
• methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-
• 4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, or
• 9x
• Urea, N-(5-chloro-2-methoxyphenyl)-N′-[3-
• methyl-4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-
• 4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
• and salts thereof.