Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds

A compound having the absolute stereochemistry of formula (I-a)

• wherein
• R1 is hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R2 is halogen, hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R3a is hydrogen, C1-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —(C(R5aR5b))m—OR7, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R5a and R5b are each independently fluoro, hydrogen, C1-6alkyl;
• R6 is independently fluoro, —CN, C1-6alkyl or OR9;
• R7 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three R10;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three fluoro;
• R9 is independently hydrogen, C1-6alkyl or C3-6alkenyl, optionally substituted with one to three fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl or —OC1-6alkyl;
• wherein said alkyl groups are optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1 or 2;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound having the absolute stereochemistry of formula (I-b)

• wherein
• R3a is methyl (substituted with at least one halogen), C2-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —OR7a, —CH2—OR7b, —(C(R5aR5b))q—OR7c, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R5a and R5b are each independently fluoro, hydrogen or C1-6alkyl;
• R6 is independently fluoro, —CN, C1-6alkyl or OR9;
• R7a is hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three R10;
• R7b is C2-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —C6-10aryl, —(C(R5aR5b))q—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three R10;
• R7c is hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10 aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three R10;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three fluoro;
• R9 is independently hydrogen or C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl or —OC1-6alkyl;
• wherein said alkyl groups are optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1, 2 or 3;
• q is 2 or 3;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound having the absolute stereochemistry of formula (I-c)

• wherein
• R1 is hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R2 is halogen, hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R2a is hydrogen, C1-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —(C(R5aR5b))m—OR7, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R4c is halogen, C1-6alkyl, —CN or —OR9;
• wherein said alkyl is optionally substituted by one to three fluoro;
• R4d is halogen, hydrogen, C1-6alkyl, —CN or —OR12;
• wherein said alkyl is optionally substituted by one to three fluoro;
• or R4c and R4d, together with the carbons to which they are bonded, form a 5- to 6-membered cycloalkyl or a 6-membered aryl, wherein said cycloalkyl or aryl is optionally substituted with one to three CF3, fluoro, C1-6alkyl, —OC1-6alkyl, —OH, —NH2 or —NH—C1-6alkyl;
• R5a and R5b are each independently fluoro, hydrogen or C1-6alkyl;
• R6 is independently fluoro, —CN, C1-6alkyl or OR9;
• R7 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three R10;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three fluoro;
• R9 is independently hydrogen, C1-6alkyl or C3-6alkenyl, optionally substituted with one to three fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl, —OC1-6alkyl;
• wherein said alkyl is optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1 or 2;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound having the absolute stereochemistry of formula (I-d)

• wherein
• R1 is hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R2 is halogen, hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R3a is hydrogen, C1-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —(C(R5aR5b))m—OR7, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R4d is halogen, hydrogen, C1-6alkyl, —CN or —OR12;
• wherein said alkyl is optionally substituted by one to three fluoro;
• or R4c and R4d, together with the carbons to which they are bonded, form a 5- to 6-membered cycloalkyl or a 6-membered aryl, wherein said cycloalkyl or aryl is optionally substituted with one to three —CF3, fluoro, C1-6alkyl, —OC1-6alkyl, —OH, —NH2 or —NH—C1-6alkyl;
• R5a and R5b are each independently fluoro, hydrogen or C1-6alkyl;
• R6 is independently fluoro, —CN, C1-6alkyl or OR9;
• R7 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three R10;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are optionally substituted with one to three fluoro;
• R9 is independently hydrogen, C1-6alkyl or C3-6alkenyl, optionally substituted with one to three fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl, —OC1-6alkyl;
• wherein said alkyl is optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or —NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1 or 2;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound having the absolute stereochemistry of formula (I-e)

• wherein
• R1 is hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R2 is halogen, hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• provided that both R1 and R2 are not hydrogen;
• R3a is C1-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10 aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —(C(R5aR5b))m—OR7, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R5a and R5b are each independently fluoro, hydrogen or C1-6alkyl;
• R6 is fluoro, —CN, C1-6alkyl or OR9;
• R7 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three R10;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three fluoro;
• R9 is independently hydrogen, C1-6alkyl or C3-6alkenyl, optionally substituted with one to three fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl, —OC1-6alkyl;
• wherein said alkyl is optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1 or 2;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition of a compound of formula (I)

• wherein
• R1 and R2 are independently halogen, hydrogen, C1-6alkyl, C2-6alkenyl or —(C(R5aR5b))m—(C3-6cycloalkyl);
• wherein said alkyl, alkenyl or cycloalkyl moieties may independently be optionally substituted with one to three R6;
• R3a is hydrogen, C1-6alkyl, C2-6alkenyl, —(C(R5aR5b))m—(C3-6cycloalkyl), —(C(R5aR5b))m-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))m—(C6-10aryl), —(C(R5aR5b))m-(5- to 10-membered heteroaryl), —(C(R5aR5b))m—OR7, —C(O)N(R8)2, —(C(R5aR5b))n—NHC(O)R8 or —(C(R5aR5b))n—N(R8)2;
• wherein said alkyl, alkenyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• and wherein the aryl or heteroaryl moieties may independently be optionally substituted with one to five R10;
• R3b is hydrogen, C1-3alkyl, —(C(R5aR5b))m—(C3-5cycloalkyl), —(C(R5aR5b))m-(4- to 5-membered heterocycloalkyl) or —(C(R5aR5b))m—OR7;
• wherein said alkyl, cycloalkyl or heterocycloalkyl moieties may independently be optionally substituted with one to three R10;
• R4a is halogen, hydrogen, C1-6alkyl, —CN or —OR9;
• wherein said alkyl is optionally substituted by one to three fluoro;
• R4b and R4c are independently halogen, hydrogen, C1-6alkyl, —CN or —OR12;
• wherein said alkyl is optionally substituted by one to three fluoro;
• or R4b and R4c, together with the carbons to which they are bonded, form a 5-5 to 6-membered cycloalkyl or a 6-membered aryl, wherein said cycloalkyl or aryl is optionally substituted with one to three —CF3, fluoro, C1-6alkyl, —OC1-6alkyl, —OH, —NH2 or —NH—C1-6alkyl;
• R4d is halogen, hydrogen, C1-6alkyl, —CN, —NO2 or —OR12;
• wherein said alkyl is optionally substituted by one to three fluoro;
• or R4b and R4c, or R4c and R4d, together with the carbons to which they are bonded, form a 5- to 6-membered cycloalkyl or a 5- to 6-membered aryl, wherein said cycloalkyl or aryl optionally substituted with one to three CF3, fluoro, C1-6alkyl, —OC1-6alkyl, —OH, —NH2 or —NH—C1-6alkyl;
• R4e is halogen, hydrogen, C1-6alkyl, —CN or —OR9;
• wherein said alkyl is optionally substituted by one to three fluoro;
• R5a and R5b are independently fluoro, hydrogen or C1-6alkyl;
• R6 is fluoro, —CN, C1-6alkyl or OR9;
• R7 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl), —(C(R5aR5b))t-(5- to 10-membered heteroaryl) or —C(O)R11;
• wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three fluoro;
• R8 is independently hydrogen, C1-6alkyl, —(C(R5aR5b))t—(C3-6cycloalkyl), —(C(R5aR5b))t-(4- to 10-membered heterocycloalkyl), —(C(R5aR5b))t—(C6-10aryl) or —(C(R5aR5b))t-(5- to 10-membered heteroaryl), wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three fluoro;
• R9 is independently hydrogen, C1-6alkyl or C3-6alkenyl, optionally substituted with one to two fluoro;
• R10 is independently halogen, —OH, —CN, C1-6alkyl, —OC1-6alkyl;
• wherein said alkyl is optionally substituted with one to three fluoro;
• R11 is independently C6-10aryl, C1-6alkyl or —NR13aR13b;
• R12 is hydrogen or C1-6alkyl optionally substituted with one to three fluoro;
• R13a and R13b are each independently hydrogen, C1-6alkyl, wherein said alkyl is optionally substituted with one to three fluoro;
• or R13a and R13b taken together with the nitrogen to which they are bonded form a 4- to 6-membered heterocycloalkyl ring, which may optionally include one oxygen to form a morpholine moiety;
• m is 0, 1 or 2;
• n is 1 or 2;
• and
• t is 0 or 1;
• or a pharmaceutical salt thereof, and a pharmaceutically acceptable vehicle, diluents or carrier.