	US 12,419,962 B2
	Quinazolines, pharmaceutical compositions, and therapeutic applications
Paul E. Erdman, San Diego, CA (US); Leah M. Fung, San Diego, CA (US); Patrick Papa, Carlsbad, CA (US); and Brandon W. Whitefield, San Diego, CA (US)
Assigned to BioTheryX, Inc., San Diego, CA (US)
Filed by BioTheryX, Inc., San Diego, CA (US)
Filed on Mar. 15, 2023, as Appl. No. 18/184,077.
Claims priority of provisional application 63/269,462, filed on Mar. 16, 2022.
Prior Publication US 2023/0293702 A1, Sep. 21, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/55 (2017.01); A61K 47/54 (2017.01); A61P 1/00 (2006.01); A61P 35/00 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01)

CPC A61K 47/55 (2017.08) [A61K 47/545 (2017.08); A61P 1/00 (2018.01); A61P 35/00 (2018.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01)]

23 Claims

1. A compound of Formula (I):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or

a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:

R¹is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl;

R³, R^4a, R^4b, and R^4care each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R^1a, —C(O)OR^1a, —C(O)NR^1bR^1c, —C(O)SR^1a, —C(NR^1a)NR^1bR^1c, —C(S)R^1a, —C(S)OR^1a, —C(S)NR^1bR^1c, —OR^1a, —OC(O)R^1a, —OC(O)OR^1a, —OC(O)NR^1bR^1c, —OC(O)SR^1a, —OC(NR^1a) NR^1bR^1c, —OC(S)R^1a, —OC(S)OR^1a, —OC(S)NR^1bR^1c, —OS(O)R^1a, —OS(O)₂R^1a, —OS(O)NR^1bR^1c, —OS(O)₂NR^1bR^1c, —NR^1bR^1c, —NR^1aC(O)R^1d, —NR^1aC(O)OR^1d, —NR^1aC(O)NR^1bR^1c, —NR^1aC(O)SR^1d, —NR^1aC(NR^1d)NR^1bR^1c, —NR^1aC(S)R^1d, —NR^1aC(S)OR^1d, —NR^1aC(S)NR^1bR^1c, —NR^1aS(O)R^1d, —NR^1aS(O)₂R¹⁴, —NR^1aS(O)NR^1bR^1c, —NR^1aS(O)₂NR^1bR^1c, —SR^1a, —S(O)R^1a, —S(O)₂R^1a, —S(O)NR^1bR^1c, or —S(O)₂NR^1bR^1c,

R^2aand R^2bare each independently hydrogen, deuterium, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;

R^2cis C_3-10cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;

R^Eis a moiety having the structure of Formula (EC-I), (EC-XV), (EC-XXVIII), or (EC-XXXV):

wherein:

each A^Eis independently a bond, —O—, —N(R^1b)—, —S—, C_1-6alkylene, C_1-6heteroalkylene, C_2-6alkenylene, C_2-6heteroalkenylene, C_2-6alkynylene, C_2-6heteroalkynylene, C_3-10cycloalkylene, C_6-14arylene, C_7-15aralkylene, heteroarylene, heterocyclylene, C_1-6heteroalkylene-C_6-14arylene, C_1-6heteroalkylene-heterocyclylene, or C_2-6alkynylene-heterocyclylene;

each X^Eis independently C(R^E1) or N;

Y^Eis a bond, C_1-6alkylene, —O—, —S—, —S(O)—, —S(O₂)—, or —N(R^E7)—;

Z is —CH₂— or —C(O)—;

one of Z¹, Z², Z³, and Z⁴is —C═ and the remaining three of Z¹, Z², Z³, and Z⁴are each independently —C(R^E5)═; or Z¹is a bond; one of Z², Z³, and Z⁴is —C═, and the remaining two of Z², Z³, and Z⁴are each independently —C(R^E5)═ or —S—;

each R^E1is independently hydrogen, deuterium, halo, or C_1-6alkyl;

each R^E2is independently hydrogen or C_1-6alkyl;

R^E3is hydrogen, deuterium, halo, or C_1-6alkyl;

each R^E4is independently (i) deuterium, cyano, halo, or nitro; (ii) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R^1a, —C(O)OR^1a, —C(O)NR^1bR^1c, —C(O)SR^1a, —C(NR^1a) NR^1bR^1c, —C(S)R^1a, —C(S)OR^1a, —C(S)NR^1bR^1c, —OR^1a, —OC(O)R^1a, —OC(O)OR^1a, —OC(O)NR^1bR^1c, —OC(O)SR^1a, —OC(NR^1a) NR^1bR^1c, —OC(S)R^1a, —OC(S)OR^1a, —OC(S)NR^1bR^1c, —OS(O)R^1a, —OS(O)₂R^1a, —OS(O)NR^1bR^1c, —OS(O)₂NR^1bR^1c, —NR^1bR^1c, —NR^1aC(O)R^1d, —NR^1aC(O)OR^1d, —NR^1aC(O)NR^1bR^1c, —NR^1aC(O)SR^1d, —NR^1aC(NR^1d) NR^1bR^1c, —NR^1aC(S)R^1d, —NR^1aC(S)OR^1d, —NR^1aC(S)NR^1bR^1c, —NR^1aS(O)R^1d, —NR^1aS(O)₂R^1d, —NR^1aS(O)NR^1bR^1c, —NR^1aS(O)₂NR^1bR^1c, —SR^1a, —S(O)R^1a, —S(O)₂R^1a, —S(O)NR^1bR^1c, or —S(O)₂NR^1bR^1c;

each R^E5is independently hydrogen or R^E4;

R^E6is (i) hydrogen; (ii) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R^1a, —C(O)OR^1a, —C(O)NR^1bR^1c, —C(O)SR^1a, —C(NR^1a) NR^1bR^1c, —C(S)R^1a, —C(S)OR^1a, —C(S)NR^1bR^1c, —OR^1a, —OC(O)R^1a, —OC(O)OR^1a, —OC(O)NR^1bR^1c, —OC(O)SR^1a, —OC(NR^1a) NR^1bR^1c, —OC(S)R^1a, —OC(S)OR^1a, —OC(S)NR^1bR^1c, —OS(O)R^1a, —OS(O)₂R^1a, —OS(O)NR^1bR^1c, —OS(O)₂NR^1bR^1c, —NR^1bR^1c, —NR^1aC(O)R¹⁴, —NR^1aC(O)OR^1d, —NR^1aC(O)NR^1bR^1c, —NR^1aC(O)SR^1d, —NR^1aC(NR^1d) NR^1bR^1c, —NR^1aC(S)R^1d, —NR^1aC(S)OR^1d, —NR^1aC(S)NR^1bR^1c, —NR^1aS(O)R^1d, —NR^1aS(O)₂R^1d, —NR^1aS(O)NR^1bR^1c, —NR^1aS(O)₂NR^1bR^1c, —S(O)R^1a, —S(O)₂R^1a, —S(O)NR^1bR^1c, or —S(O)₂NR^1bR^1c;

R^E7is hydrogen or C_1-6alkyl;

each m is independently an integer of 0, 1, or 2; and

each n is independently an integer of 0, 1, 2, or 3;

L is a linker having the structure of —Z^L—(R^L—Z^L)_z—, wherein:

each R^Lis independently C_1-10alkylene, C_2-10alkenylene, C_2-10alkynylene, C_3-10cycloalkylene, C_6-14arylene, heteroarylene, or heterocyclylene;

each Z^Lis independently a bond, —C(O)—, —C(O)O—, —C(O)NR^1b, —C(O)S—, —C(NR^1a) NR^1b—, —C(S)—, —C(S)O—, —C(S)NR^1b—, —O—, —OC(O)O—, —OC(O)NR^1b—, —OC(O)S—, —OC(NR^1a) NR^1b—, —OC(S)—, —OC(S)O—, —OC(S)NR^1b—, —OS(O)—, —OS(O)₂—, —OS(O)NR^1b—, —OS(O)₂NR^1b—, —NR^1b—, —NR^1aC(O)NR^1b—, —NR^1aC(O)S—, —NR^1aC(NR^1d) NR^1b—, —NR^1aC(S)NR^1b—, —NR^1aS(O)NR^1b—, —NR^1aS(O)₂NR^1b—, —S—, —S(O)—, —S(O)₂—, —S(O)NR^1b—, or —S(O)₂NR^1b—; and

z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R^1a, R^1b, R^1c, and R^1dis independently hydrogen, deuterium, C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl;

with the proviso that the compound is not any one of 3-(4-(1-(7-(4-(((R)-1-(3-bromo-phenyl)ethyl)amino)-6,7-dimethoxy-2-methyl-quinazolin-8-yl) heptyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione; 3-(4-(1-(7-(6,7-dimethoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione; and 3-(4-(1-(7-(6,7-dimethoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino)-quinazolin-8-yl) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione;

wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q^a, and (c) —C(O)R^a, —C(O)OR^a, —C(O)NR^bR^c, —C(O)SR^a, —C(NR^a) NR^bR^c, —C(S)R^a, —C(S)OR^a, —C(S)NR^bR^c, —OR^a, —OC(O)R^a, —OC(O)OR^a, —OC(O)NR^bR^c, —OC(O)SR^a, —OC(NR^a) NR^bR^c, —OC(S)R^a, —OC(S)OR^a, —OC(S)NR^bR^c, —OP(O)(OR^b) OR^c, —OS(O)R^a, —OS(O)₂R^a, —OS(O)NR^bR^c, —OS(O)₂NR^bR^c, —NR^bR^c, —NR^aC(O)R^d, —NR^aC(O)OR^d, —NR^aC(O)NR^bR^c, —NR^aC(O)SR^d, —NR^aC(NR^d) NR^bR^c, —NR^aC(S)R⁴, —NR^aC(S)OR^d, —NR^aC(S)NR^bR^c, —NR^aS(O)R^d, —NR^aS(O)₂R^d, —NR^aS(O)NR^bR^c, —NR^aS(O)₂NR^bR^c, —SR^a, —S(O)R^a, —S(O)₂R^a, —S(O)NR^bR^c, and —S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^dis independently (i) hydrogen or deuterium; (ii) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q^a; or (iii) Rb and Re together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q^a;

wherein each Q^ais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C_1-6alkyl, C_1-6heteroalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^e, —C(O)OR^e, —C(O)NR^fR^g, —C(O)SR^e, —C(NR^e) NR^fR^g, —C(S)R^e, —C(S)OR^e, —C(S)NR^fR^g, —OR^e, —OC(O)R^e, —OC(O)OR^e, —OC(O)NR^fR^g, —OC(O)SR^e, —OC(NR^e) NR^fR^g, —OC(S)R^e, —OC(S)OR^e, —OC(S)NR^fR^g, —OP(O)(OR^f)OR^g, —OS(O)R^e, —OS(O)₂R^e, —OS(O)NR^fR^g, —OS(O)₂NR^fR^g, —NR^fR^g, —NR^eC(O)R^h, —NR^eC(O)OR^f, —NR^eC(O)NR^fR^g, —NR^eC(O)SR^f, —NR^eC(NR^h) NR^fR^g, —NR^eC(S)R^h, —NR^eC(S)OR^f, —NR^eC(S)NR^fR^g, —NR^eS(O)R^h, —NR^eS(O)₂R^h, —NR^eS(O)NR^fR^g, —NR^eS(O)₂NR^fR^g, —SR^e, —S(O)R^e, —S(O)₂R^e, —S(O)NR^fR^g, and —S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^his independently (i) hydrogen or deuterium; (ii) C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-14aryl, C_7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and R^gtogether with the N atom to which they are attached form heterocyclyl.