Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death

A method of treating an individual with a condition, disorder, or disease, comprising administering a therapy that delivers a pharmaceutically effective amount of a compound for treatment of the condition, disorder, or disease, wherein the compound is selected from the group consisting of a spiropyrazine derivative having the general formula (I)

• and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labeled forms, prodrugs, and combinations thereof,
• wherein
• E is —N(R6)—;
• L is selected from the group consisting of a bond, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH2)m—[Y—(CH2)n]o—, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1;
• Y is independently selected from O, S, and —N(R7)—;
• and each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups, is optionally substituted with one or more independently selected R8;
• or L and G together form C3-10 alkyl comprising a tertiary or quaternary carbon atom, wherein the C3-10 alkyl group is optionally substituted with one or more independently selected R30;
• ring A is a cycloalkylene or heterocycloalkylene, optionally substituted with one or more independently selected R9;
• R1 is H
• ring B is selected from benzo, a 5- or 6-membered heteroareno, a 5- or 6-membered cycloalkeno, and a 5- or 6-membered heterocycloalkeno, wherein the benzo, 5- or 6-membered heteroareno, 5- or 6-membered cycloalkeno, and 5- or 6-membered heterocycloalkeno is fused to the 1,2-dihydropyrazine moiety through carbons a and b and is optionally substituted with one or more independently selected R2;
• R2 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR1, —X C(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or any two R2 on adjacent ring atoms of ring B may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R6 is H;
• R7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR11, and —NHR20, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R8 is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR1, —X C(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O) 1-2 N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30, and/or any two R9 which are bound to the same carbon atom of ring A may join together to form ═X;
• X is independently selected from O, S, and N(R14);
• R1 is, in each case, selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R12 and R13 are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R12 and R13 may join together with the nitrogen atom to which they are attached to form the group —N═CR15R16, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R14 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R15 and R16 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NHyR202-y, or R15 and R16 may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R30, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• y is an integer from 0 to 2;
• R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• and
• R30 is a 1st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R7), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —NR71S(O)1-2N(R72)(R73), —C(═X1)R71,
• —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, and/or any two R30 which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1st level substituent is optionally substituted by one or more 2nd level substituents, wherein said 2nd level substituent is, in each case, independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OR81, —N(R82)(R83), —S(O)0-2R81, —S(O)1-2OR81, —OS(O)1-2R81, —OS(O)1-2OR81, —S (O)1-2N(R82)(R83), —OS(O)1-2N(R82)(R83), —N(R81)S(O)1-2R81, —NR81S(O)1-2OR81, —NR81S(O)1-2N(R82)(R83), —C(═X2)R81, —C(═X2)X2R81, —X2C(═X2)R81, and —X2C(═X2)X2R81, and/or any two 2nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1st level substituent may join together to form ═X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2nd level substituent is optionally substituted with one or more 3rd level substituents, wherein said 3rd level substituent is, in each case, independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C1-3 alkyl);
• wherein
• R71, R72, and R73 are independently selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z,
• —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• R81, R82, and R83 are independently selected from the group consisting of —H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• and
• X1 and X2 are independently selected from O, S, and N(R84), wherein R84 is —H or C1-3 alkyl, with the proviso that
• (1) when L is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, and —(CH2)m—[Y—(CH2)n]o—, wherein each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• and ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene, a monocyclic 4- to 10-membered O/S-heterocycloalkylene, or a monocyclic 3- to 10-membered cycloalkylene, wherein each of the N-heterocycloalkylene, O/S-heterocycloalkylene, and cycloalkylene groups is optionally substituted with one or more independently selected R9;
• and ring B is
• wherein R2′, R3′, R4′, and R5′ are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or wherein R2′ and R3′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R3′ and R4′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• and/or R4′ and R5′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• then G is not phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R8;
• (2) ring A is not
• (3) when ring A is cyclohexylene;
• L is a bond;
• and G is cyclohexyl;
• then ring B is not benzo or
• (4) when (i) ring B is benzo;
• ring A is cyclohexylene,
• and -LG is tert-butyl;
• (ii) ring B is
• ring A is
• and -LG is tert-butyl;
• (iii) ring B is
• ring A is
• wherein R is selected from the group consisting of —C(O)NH(2-methoxyphenyl), —C(O)NH(2,5-dimethoxyphenyl), —C(O)(3,4-dimethoxyphenyl), —C(O)(3,5-dimethoxyphenyl), and —S(O)2(CH2)2CH3;
• L is a bond;
• and G is cyclohexyl;
• (iv) ring B is
• ring A is
• wherein R is —NH(2-methoxyphenyl) or 3,4-dimethoxyphenyl;
• L is a bond, and G is cyclopentyl;
• (v) ring B is benzo;
• ring A is
• wherein R is selected from the group consisting of 4-(dimethylamino)phenyl, (1-methyl-1H-pyrazol-5-yl), 3-pyrdinyl, 2-pyrazinyl, and (3-chloro-4,6-dimethoxyphenyl)amino;
• L is a bond;
• and G is cyclopentyl;
• (vi) ring B is benzo;
• ring A is
• wherein R is 2-propyl or —CH(CH3)C(O)OCH2CH3;
• L is a bond;
• and G is cyclohexyl;
• (vii) ring B is benzo;
• ring A is
• wherein R is 1-(ethoxycarbonylmethyl)cyclohexan-1-yl or furan-2-ylmethyl;
• and -LG is 3-methylbutan-1-yl;
• (viii) ring B is benzo;
• ring A is
• wherein R is 3-fluorophenyl;
• L is a bond;
• and G is cyclopentyl;
• (ix) ring B is
• ring A is
• wherein R is 2-thienyl;
• L is a bond;
• and G is cyclopentyl;
• or
• (x) ring B is benzo;
• and ring A is
• wherein R is 1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl or 2-(acetylamino)-5-methylphenyl;
• and -LG is 3-methylbutan-1-yl;
• wherein the condition, disorder or disease is cancer.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the group consisting of a spiropyrazine derivative having the general formula (I)

• and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labeled forms, prodrugs, and combinations thereof,
• wherein
• E is —N(R6)—;
• L is selected from the group consisting of a bond, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH2)m—[Y—(CH2)n]o—, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1;
• Y is independently selected from O, S, and —N(R7)—;
• and each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups, is optionally substituted with one or more independently selected R8;
• or L and G together form C3-10 alkyl comprising a tertiary or quaternary carbon atom, wherein the C3-10 alkyl group is optionally substituted with one or more independently selected R30;
• ring A is a cycloalkylene or heterocycloalkylene, optionally substituted with one or more independently selected R9;
• R1 is H
• ring B is selected from benzo, a 5- or 6-membered heteroareno, a 5- or 6-membered cycloalkeno, and a 5- or 6-membered heterocycloalkeno, wherein the benzo, 5- or 6-membered heteroareno, 5- or 6-membered cycloalkeno, and 5- or 6-membered heterocycloalkeno is fused to the 1,2-dihydropyrazine moiety through carbons a and b and is optionally substituted with one or more independently selected R2;
• R2 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R1, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or any two R2 on adjacent ring atoms of ring B may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R6 is H;
• R7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR11, and —NHR20, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R8 is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O) 1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30, and/or any two R9 which are bound to the same carbon atom of ring A may join together to form ═X;
• X is independently selected from O, S, and N(R14);
• R11 is, in each case, selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R12 and R13 are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R12 and R13 may join together with the nitrogen atom to which they are attached to form the group —N═CR15R16, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R14 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R15 and R16 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NHyR202-y, or R15 and R16 may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R30, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• y is an integer from 0 to 2;
• R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• and
• R30 is a 1st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R73), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —NR71S(O)1-2N(R72)(R73), —C(═X1) R71,
• —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, and/or any two R30 which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1st level substituent is optionally substituted by one or more 2nd level substituents, wherein said 2nd level substituent is, in each case, independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OR81, —N(R82)(R83), —S(O)0-2R81, —S(O)1-2OR81, —OS(O)1-2R81, —OS(O)1-2OR81, —S(O) 1-2N(R82)(R83), —OS(O)1-2N(R82)(R83), —N(R81)S(O)1-2R81, —NR81S(O)1-2OR81, —NR81S(O)1-2N(R82)(R83), —C(═X2)R81, —C(═X2)X2R81, —X2C(═X2)R81, and —X2C(═X2)X2R81, and/or any two 2nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1st level substituent may join together to form ═X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2nd level substituent is optionally substituted with one or more 3rd level substituents, wherein said 3rd level substituent is, in each case, independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C1-3 alkyl);
• wherein
• R71, R72, and R73 are independently selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• R81, R82, and R83 are independently selected from the group consisting of —H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• and
• X1 and X2 are independently selected from O, S, and N(R84), wherein R84 is —H or C1-3 alkyl, with the proviso that
• (1) when L is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, and —(CH2)m—[Y—(CH2)n]o—, wherein each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• and ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene, a monocyclic 4- to 10-membered O/S-heterocycloalkylene, or a monocyclic 3- to 10-membered cycloalkylene, wherein each of the N-heterocycloalkylene, O/S-heterocycloalkylene, and cycloalkylene groups is optionally substituted with one or more independently selected R9;
• and ring B is
• wherein R2′, R3, R4′, and R5′ are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —N R11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or wherein R2′ and R3′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R3′ and R4′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• and/or R4′ and R5′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• then G is not phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R8;
• (2) ring A is not H or
• (3) when ring A is cyclohexylene;
• L is a bond;
• and G is cyclohexyl;
• then ring B is not benzo or

A compound selected from the group consisting of a spiropyrazine derivative having the general formula (I)

• and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labeled forms, prodrugs, and combinations thereof,
• wherein
• E is —N(R6)—;
• L is selected from the group consisting of a bond, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH2)m—[Y—(CH2)n]o—, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1;
• Y is independently selected from O, S, and —N(R7)—;
• and each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups, is optionally substituted with one or more independently selected R8;
• or L and G together form C3-10 alkyl comprising a tertiary or quaternary carbon atom, wherein the C3-10 alkyl group is optionally substituted with one or more independently selected R30;
• ring A is a cycloalkylene or heterocycloalkylene, optionally substituted with one or more independently selected R9;
• R1 is H
• ring B is selected from benzo, a 5- or 6-membered heteroareno, a 5- or 6-membered cycloalkeno, and a 5- or 6-membered heterocycloalkeno, wherein the benzo, 5- or 6-membered heteroareno, 5- or 6-membered cycloalkeno, and 5- or 6-membered heterocycloalkeno is fused to the 1,2-dihydropyrazine moiety through carbons a and b and is optionally substituted with one or more independently selected R2;
• R2 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR1, —X C(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or any two R2 on adjacent ring atoms of ring B may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R6 is H;
• R7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR11, and —NHR20, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R8 is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR1, —X C(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S (O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR1lS(O)1- 2 N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30, and/or any two R9 which are bound to the same carbon atom of ring A may join together to form ═X;
• X is independently selected from O, S, and N(R14);
• R11 is, in each case, selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R12 and R13 are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R12 and R13 may join together with the nitrogen atom to which they are attached to form the group —N═CR15R16, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R14 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• R15 and R16 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NHyR202-y, or R15 and R16 may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R30, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• y is an integer from 0 to 2;
• R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• and
• R30 is a 1st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R7), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —NR71S(O)1-2N(R72)(R73), —C(═X1)R71,
• —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, and/or any two R30 which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1st level substituent is optionally substituted by one or more 2nd level substituents, wherein said 2nd level substituent is, in each case, independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OR81, —N(R82)(R83), —S(O)0-2R81, —S(O)1-2OR81, —OS(O)1-2R81, —OS(O)1-2OR81, —S (O)1-2N(R82)(R83), —OS(O)1-2N(R82)(R83), —N(R81)S(O)1-2R81, —NR81S(O)1-2OR81, —NR81S(O)1-2N(R82)(R83), —C(═X2)R81, —C(═X2)X2R81, —X2C(═X2)R81, and —X2C(═X2)X2R81, and/or any two 2nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1st level substituent may join together to form ═X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2nd level substituent is optionally substituted with one or more 3rd level substituents, wherein said 3rd level substituent is, in each case, independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C1-3 alkyl);
• wherein
• R71, R72, and R73 are independently selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z,
• —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• R81, R82, and R83 are independently selected from the group consisting of —H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
• and
• X1 and X2 are independently selected from O, S, and N(R84), wherein R84 is —H or C1-3 alkyl, with the proviso that
• (1) when L is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, and —(CH2)m—[Y—(CH2)n]o—, wherein each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
• and ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene, a monocyclic 4- to 10-membered O/S-heterocycloalkylene, or a monocyclic 3- to 10-membered cycloalkylene, wherein each of the N-heterocycloalkylene, O/S-heterocycloalkylene, and cycloalkylene groups is optionally substituted with one or more independently selected R9;
• and ring B is
• wherein R2′, R3′, R4′, and R5 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —O S(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N)(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
• or wherein R2′ and R3′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• R3′ and R4′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• and/or R4′ and R5′ join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R30;
• then G is not phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R8;
• (2) ring A is not
• (3) when ring B is benzo;
• (i) L is a bond;
• and G is cyclopentyl;
• then ring A is not selected from the group consisting of
• (a)
• wherein R is tert-butyl, methyl, 3-pyridinylmethyl, 3-fluorophenyl, (2-methyl-1H-imidazol-1-yl)methyl, 2-pyrazinyl, 2,3-dimethoxyphenyl, 3-furanyl, (3,5-dimethyl-4-isoxazolyl)methyl, (4-fluorophenoxy)methyl, 2,6-dimethoxy-3-pyridinyl, (2-methylphenyl)amino, methoxymethyl, 1,3-benzodioxol-5-yl, 2-fluorophenyl, 1-ethyl-1H-pyrazol-5-yl, 1H-indazol-3-yl, [(3-methoxyphenyl)methyl]amino, pyrazolo[1,5-a]pyrimidin-3-yl, 2-methoxyethyl, 2-thienyl, (phenylmethyl)amino, 4,5,6,7-tetrahydro-1H-indazol-3-yl, 3-thienyl, 4-pyridinyl, 6-methoxy-3-pyridinyl, phenyl, 6-methyl-3-pyridinyl, 2,4-dimethoxyphenyl, 2-furanyl, (4-methoxyphenoxy)methyl, [(4-methoxyphenyl)methyl]amino, 2-pyridinyl, 3-fluoro-4-methoxyphenyl, CH2NHC(O)CH3, 3,5-dimethoxyphenyl, or (2-methoxyphenyl)methyl;
• (b)
• wherein R is dimethylamino, 3-pyridinyl, cyclopropyl, 3,5-dimethyl-4-isoxazolyl, or 1,2-dimethyl-1H-imidazol-4-yl;
• (c)
• wherein R is 3-fluorophenyl;
• (d)
• wherein R is (5-chloro-2,4-dimethoxyphenyl)amino, 2-pyrazinyl, 3-pyridinyl, 1-methyl-1H-pyrazol-5-yl, or 4-(dimethylamino)phenyl;
• (e)
• cyclohexylene, and cycloheptylene;
• (ii) L is a bond;
• and G is cyclohexyl;
• then ring A is not selected from the group consisting of cyclopentylene, cyclohexylene, cycloheptylene, and
• wherein R is —CH(CH3)C(O)OCH2CH3 or 2-propyl;
• (iii) L is a bond;
• and G is cycloheptyl;
• then ring A is not
• (iv) and -LG is tert-butyl;
• then ring A is not selected from the group consisting of
• (a)
• wherein R is 1,3-benzodioxol-5-yl, (3-acetylphenyl)amino, phenyl, 1H-benzimidazol-6-yl, 2-methylphenyl, (3,5-dimethyl-4-isoxazolyl)methyl, 2,3-dimethoxyphenyl, 3-furanyl, (2-methylphenoxy)methyl, (4-methoxyphenoxy)methyl, 3-pyridinyl, tert-butyl, methoxymethyl, 3-thienyl, 2-thienylmethyl, [(4-methoxyphenyl)methyl]amino, (2-methyl-1H-imidazol-1-yl)methyl, 3,5-dimethoxyphenyl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, 2-pyridinyl, 2,6-dimethoxy-3-pyridinyl, (2,3-dihydro-1,4-benzodioxin-6-yl)amino, 1,5-dimethyl-1H-pyrazol-3-yl, 6-methyl-3-pyridinyl, (2-methoxyphenyl)methyl, [(3-methoxyphenyl)methyl]amino, 1-ethyl-1H-pyrazol-3-yl, 3-pyridinylmethyl, 3-fluorophenyl, (3-methoxyphenyl)amino, 4-chloro-1-ethyl-1H-pyrazol-3-yl, 2-methoxyethyl, (2-fluorophenyl)methyl, benzyl, (3,4-difluorophenoxy)methyl, 3,4-dimethoxyphenyl, 4-cyanophenyl, 2-fluorophenyl, —CH2NHC(O)CH3, [1-(2-propyl)-4-piperidinyl]methyl, phenoxymethyl, 2-pyrazinyl, (2-furanylmethyl)amino, 1-ethyl-1H-pyrazol-5-yl, 6-methoxy-3-pyridinyl, 4-ethoxyphenyl, (2-methoxy-5-methylphenyl)amino, 4-pyridinyl, (3-methoxyphenyl)methyl, (1H-imidazol-1-yl)methyl, 2-(morpholin-4-yl)ethyl, 2,4-dimethoxyphenyl, pyrazolo[1,5-a]pyrimidin-3-yl, 2-thienyl, or 1H-indazol-3-yl;
• (b)
• wherein R is dimethylamino, 1-butyl, 3-pyridinyl, 3,5-dimethyl-4-isoxazolyl, methyl, 1,2-dimethyl-1H-imidazol-4-yl, 3-cyanophenyl, cyclopropyl, or 1,3,5-trimethyl-1H-pyrazol-4-yl;
• (c) cyclopentylene, cyclohexylene, cycloheptylene,
• (v) and -LG is 2,4,4-trimethylpentan-2-yl;
• then ring A is not selected from the group consisting of cyclopentylene, cyclohexylene, and cycloheptylene;
• (vi) and -LG is 3-methylbutan-1-yl;
• then ring A is not selected from the group consisting of
• (a) cycloheptylene;
• (b)
• wherein R is 1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl or 2-(acetylamino)-5-methylphenyl, and
• (c)
• wherein R is 1-(ethoxycarbonylmethyl)cyclohexan-1-yl or furan-2-ylmethyl;
• (vii) L is methylene;
• and G is 1,3-benzodioxol-5-yl;
• then ring A is not cycloheptylene or
• (4) when ring B is
• L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (5) when ring B is
• L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (6) when ring B is
• (i) L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (ii) and -LG is tert-butyl;
• then ring A is not cyclopentylene;
• (7) when ring B is
• (i) L is a bond;
• and
• (a) G is cyclopentyl;
• then ring A is not selected from the group consisting of cycloheptylene,
• wherein R is 2-thienyl;
• or
• (b) G is cyclohexyl;
• then ring A is not cyclopentylene;
• (ii) L is methylene;
• and G is 1,3-benzodioxol-5-yl;
• then ring A is not cycloheptylene;
• (iii) and -LG is 3-methylbutan-1-yl;
• then ring A is not cycloheptylene;
• (iv) and -LG is tert-butyl;
• then ring A is not
• (8) when ring B is
• (i) L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (ii) and -LG is tert-butyl;
• then ring A is not cyclopentylene;
• (9) when ring B is
• and -LG is tert-butyl;
• then ring A is not cyclopentylene;
• (10) when ring B is
• (i) L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (ii) and -LG is tert-butyl;
• then ring A is not cyclohexylene;
• (11) when ring B is
• L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene or
• (12) when ring B is
• L is a bond;
• and G is cyclohexyl or cyclopentyl;
• then ring A is not cyclohexylene;
• (13) when ring B is
• L is a bond;
• and G is cyclohexyl;
• then ring A is not cyclohexylene;
• (14) when ring B is
• and -LG is tert-butyl;
• then ring A is not
• (15) when ring B is
• and -LG is 2,4,4-trimethylpentan-2-yl;
• then ring A is not
• wherein R is tert-butoxy;
• (16) when ring B is N
• (i) L is a bond;
• and G is cyclopentyl;
• then ring A is not selected from the group consisting of
• (a)
• wherein R is 1-butyl, 3,5-difluorophenyl, 3-chlorophenyl, 2-thienyl, 3-pyridinyl, or 3-methylphenyl;
• (b)
• wherein R is tert-butyl, 3-furanyl, 2-phenylethyl, (3-ethylphenyl)amino, 3,5-dimethoxyphenyl, 2-chlorophenyl, 2-methylphenyl, 1-iso-quinolinyl, (5-trifluoromethyl)-2-thienyl, (2,4-dimethylphenyl)amino, (4-chloro-phenyl)methyl, (2-chloro-6-fluorophenyl)methyl, (2-phenylethyl)amino, [4-(methylthio)phenyl]amino, 1,3-benzodioxol-5-yl, (2-chlorophenyl)amino, (2-methylphenoxy)methyl, 6-methyl-3-pyridinyl, phenyl, (2,3-dihydro-1H-inden-5-yl)amino, 2-(2-methoxyphenyl)ethyl, (4-methoxy-2-methylphenyl)amino, 6-methoxy-3-pyridinyl, 6-quinolinyl, (2-methoxy-5-methylphenyl)amino, 1-methyl-1H-indazol-3-yl, (2-furanylmethyl)amino, 3-thienyl, [(3-fluorophenyl)methyl]amino, 4-ethoxyphenyl, 2-furanyl, (4-chloro-2-fluorophenyl)amino, 5-methyl-2-thienyl, or 4-methoxy-2-methylphenyl;
• (c)
• wherein R is 2-furanyl, 4-ethoxyphenyl, (1H-indol-3-yl)methyl, 3-methyl-2-thienyl, 3-fluoro-4-methoxyphenyl, 2-methoxyethyl, (phenylthio)methyl, (2-methoxy-5-methylphenyl)amino, (2-methylphenoxy)methyl, 2,4-dimethoxyphenyl, cyclohexylamino, 2-(3-methoxyphenyl)ethyl, 2-methylphenyl, benzyl, 3-chlorophenyl, 4-methoxy-2-methylphenyl, [(4-methoxyphenyl)methyl]amino, 2-chlorophenyl, 3-thienyl, (2-phenylethyl)amino, 5-chloro-2-thienyl, (2-methoxyphenyl)methyl, 2-pyridinyl, (3-methoxyphenyl)methyl, 3-furanyl, 3,5-dimethoxyphenyl, (4-ethoxy-phenyl)methyl, 6-methoxy-3-pyridinyl, (4-methoxy-2-methylphenyl)amino, 4-cyanophenyl, 2-(2-methoxyphenyl)ethyl, 3-thienylmethyl, [(tetrahydro-2-furanyl)methyl]amino, butan-2-yl, (2,4-dimethylphenyl)amino, [(3-fluorophenyl)methyl]amino, (3,5-dimethyl-1H-pyrazol-1-yl)methyl, 2,4-difluorophenyl, [(3-methoxyphenyl)methyl]amino, (3-methylphenyl)methyl, 2-phenylethyl, 3-fluoro-4-methylphenyl, 1,3-benzodioxol-5-yl, 2-thienylmethyl, cyclopentylmethyl, (4-methoxyphenoxy)methyl, tetrahydro-2-furanyl, 1H-benzimidazol-6-yl, (2-methoxyphenyl)amino, or 3,4-dimethoxyphenyl;
• (d)
• wherein R is 3-fluorophenyl, 3-methylphenyl, 2-methylphenyl, or 2-thienyl;
• (e)
• (f)
• wherein R is (3,5-difluorophenyl)amino, (2-methoxy-5-methylphenyl)amino, 5-methyl-2-thienyl, 6-methyl-3-pyridinyl, 3-fluoro-4-methoxyphenyl, (4-methoxyphenoxy)methyl, ethyl, (2,4-difluorophenyl)amino, 3-thienyl, 2-furanyl, (2,4-dimethylphenyl)amino, 5-chloro-2-thienyl, 3-methyl-2-thienyl, (3-methoxyphenyl)amino, (4-ethoxyphenyl)methyl, 2-pyridinyl, (2-methoxyphenyl)methyl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, (4-methoxy-2-methylphenyl)amino, (phenylthio)methyl, 4-pyridinyl, 1-ethyl-1H-pyrazol-5-yl, (3,5-dimethyl-1H-pyrazol-1-yl)methyl, 6-methoxy-3-pyridinyl, benzyl, 2-(2-methoxyphenyl)ethyl, 1-methyl-1H-indazol-3-yl, 1-methyl-1H-pyrrol-2-yl, (1H-indol-3-yl)methyl, [(3-fluorophenyl)methyl]amino, 3,5-dimethoxyphenyl, 3-furanyl, [(3-methoxyphenyl)methyl]amino, 3-chlorophenyl, (3,5-dimethyl-4-isoxazolyl)methyl, 2-(4-methoxyphenyl)ethyl, 2-methylphenyl, 2-chlorophenyl, phenyl, 2-phenylethyl, 3-fluoro-4-methylphenyl, 4-ethoxyphenyl, 1,3-benzodioxol-5-yl, (2-chlorophenyl)amino, or 2-thienylmethyl;
• (g)
• wherein R is 2-thienyl, dimethylamino, cyclopropyl, 2-methylphenyl, 3-fluorophenyl, 3-pyridinyl, 3,5-dimethyl-4-isoxazolyl, phenyl, or 4-fluorophenyl;
• (ii) L is a bond;
• and G is cyclohexyl;
• then ring A is not selected from the group consisting of
• (a)
• wherein R is 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, (2,5-dimethoxyphenyl)amino, or (2-methoxyphenyl)amino;
• (b)
• wherein R is 1-propyl;
• (iii) and -LG is tert-butyl;
• then ring A is not selected from the group consisting of
• (a)
• wherein R is 5-(2-thienyl)-1H-pyrazol-3-yl, 3-thienyl, (3-methoxypropyl)amino, (3-chlorophenoxy)methyl, 2-(2-methoxyphenyl)ethyl, 3,5-dimethoxyphenyl, (2-methylphenoxy)methyl, 2-phenylethyl, (3,5-difluorophenyl)amino, 1-butyl, 2,3-dihydro-1,4-benzodioxin-2-yl, butan-2-yl, 4-methoxy-2-methylphenyl, phenyl, 2-furanyl, (1,1-dimethylethyl)amino, 3-fluoro-4-methylphenyl, 1,3-benzodioxol-5-yl, (4-methoxyphenoxy)methyl, 4-ethoxyphenyl, (3-methylphenyl)methyl, 2-(3-methoxyphenyl)ethyl, 3-furanyl, (3-chlorophenyl)amino, 3-methyl-2-thienyl, methyl, or 5-methyl-2-thienyl;
• (b)
• wherein R is 5-(2-thienyl)-1H-pyrazol-3-yl, (2-methylphenoxy)methyl, (3-methylphenyl)methyl, 2-pyridinyl, benzyl, 3-pyridinylmethyl, (phenylthio)methyl, methyl, phenyl, 4-pyridinyl, (1H-indol-3-yl)methyl, (2-fluorophenyl)methyl, 2-thienyl, 3-chlorophenyl, 1-ethyl-1H-pyrazol-5-yl, 2-furanyl, or (4-methoxyphenoxy)methyl;
• (c)
• wherein R is (4-chloro-2-fluorophenyl)amino, [2-(tri-fluoromethyl)phenyl]amino, (1,1-dimethylethyl)amino, [(4-methoxyphenyl)methyl]amino, (3-chloro-4-fluorophenyl)amino, [3-(methylthio)phenyl]amino, [3-(trifluoromethyl)phenyl]amino, (3-fluoro-4-methoxyphenyl)amino, 3,4-dimethoxyphenyl, (4-chloro-2-methylphenyl)amino, (5-chloro-2-methoxyphenyl)amino, [(3-fluorophenyl)methyl]amino, [(3-methoxyphenyl)methyl]amino, (2,3-dihydro-1H-inden-5-yl)amino, (3-chloro-4-methoxyphenyl)methyl, cyclopentylamino, 2,4-dimethoxyphenyl, 2-methylphenyl, 2-chloro-5-fluorophenyl, (3-chloro-4-methoxyphenyl)amino, (3,5-difluorophenyl)amino, 4-methoxy-2-methylphenyl, (3-methoxyphenyl)amino, (4-methoxyphenoxy)methyl, (3-methylphenyl)methyl, 2-phenylethyl, (2-methoxy-phenyl)methyl, (1-methylethyl)amino, 1,3-benzodioxol-5-yl, 4-methylphenyl, cyclohexylamino, 2-(2-methoxyphenyl)ethyl, 3-methyl-2-thienyl, (4-chlorophenyl)methyl, 4-ethoxyphenyl, (2-ethylphenyl)amino, (3-methoxyphenyl)methyl, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl, (3-ethylphenyl)amino, (2-furanylmethyl)amino, 5-chloro-2-methoxyphenyl, 3-thienylmethyl, 2-(3-methoxyphenyl)ethyl, 6-methyl-3-pyridinyl, or 5-methyl-2-thienyl;
• (d)
• wherein R is 3,5-difluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 5-fluoro-2-methoxyphenyl, 2-chlorophenyl, 1-butyl, ethyl, or 2-fluorophenyl;
• and
• (e)
• (iv) L is methylene;
• and G is phenyl;
• then ring A is not selected from the group consisting of
• (a)
• (b)
• wherein R is (2-furanylmethyl)amino, 2-pyridinyl, cyclo-pentylmethyl, 1-ethyl-1H-pyrazol-3-yl, 2-furanyl, phenyl, morpholin-4-ylmethyl, tetrahydro-2-furanyl, 3-methoxyphenyl, [(tetrahydro-2-furanyl)methyl]amino, cyclopentyl, (3-fluorophenyl)amino, (4-methylphenyl)amino, 4-methoxyphenyl, 1-butyl, 1-methyl-1H-pyrrol-2-yl, 6-methyl-3-pyridinyl, diethylamino, butan-2-yl, methylamino, methyl, 3-furanyl, 2-methoxyphenyl, 2-thienyl, (2-methoxyethyl)amino, phenoxymethyl, 4-pyridinyl, 3-thienyl, 1-ethyl-1H-parazol-5-yl, methoxymethyl, tert-butyl, or 2-methoxyethyl;
• (c)
• wherein R is 1-butyl, 3-pyridinyl, or phenyl;
• (d)
• wherein R is 3-methoxyphenyl, 1-ethyl-1H-pyrazol-3-yl, (3-fluorophenyl)amino, morpholin-4-ylmethyl, 3-thienyl, 1-ethyl-1H-pyrazol-5-yl, 4-methoxyphenyl, (3,5-dimethyl-1,2-oxazol-4-yl)methyl, —CH2NHC(O)CH3, 6-methyl-3-pyridinyl, methyl, 2-furanyl, (2-methylimidazol-1-yl)methyl, 2-pyridinyl, phenoxymethyl, methylamino, (2-furanylmethyl)amino, 3-pyridinylmethyl, 1,5-dimethyl-1H-pyrazol-3-yl, 2-pyrazinyl, methoxymethyl, phenyl, 2-methoxyphenyl, or 6-methoxy-3-pyridinyl;
• (e)
• wherein R is 1-butyl, 3-pyridinyl, or dimethylamino;
• (f)
• wherein R is [(4-fluorophenyl)methyl]amino, tert-butyl, 3-furanyl, 5-methyl-2-thienyl, 3-thienyl, 2,5-difluorophenyl, (4-methoxyphenyl)amino, (2-methylphenoxy)methyl, 3-fluoro-4-methoxyphenyl, 2-furanyl, (3-methylphenyl)amino, 1,3-benzodioxol-5-yl, (2-furanylmethyl)amino, (2-methoxyphenyl)amino, 2-methylphenyl, or phenyl;
• (g)
• wherein R is 2-methylphenyl, 3-pyridinyl, benzyl, or 2-thienyl.