Gamma secretase modulators

A compound of the Formula I:

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• G, G1, G2, G3, R1, R9, R10, R21, U, V and W are each independently selected;
• (A) and (B) in the rings in Formula I are reference letters to identify the ring;
• either ring A is a 5-membered heteroaryl-, cycloalkyl-, cycloalkenyl-, heterocyclyl- or heterocyclenyl-ring, and ring B is a 6-membered heterocyclyl- or heterocyclenyl-ring which contains at least one N atom, or ring A is a 6-membered aryl-, heteroaryl-, cycloalkyl-, cycloalkenyl-, heterocyclyl- or heterocyclenyl-ring, and ring B is a 5-membered heterocyclyl- or heterocyclenyl-ring which contains at least one N atom;
• each dotted line (----) represents an optional bond;
• U is selected from the group consisting of:
• N, C (if the optional double bond attached to U is present), —CH— or —CR21—;
• G1 is selected from the group consisting of:
• a direct bond (when ring A is a 5-membered ring), —O—, —C(R21)2—, —CHR21—, —CH2—, —CR21— (if the optional double bond to G1 is present), CH (if the optional double bond to G1 is present), —NR2—, —N═ (if the optional double bond to G1 is present), —C(O)—, —C(═NR2)—, —S(O)2— and —S(O)—, with the proviso that when the optional double bond between (3) and (4) is present then G1 is not —O—, —C(R21)2—, —CHR21—, —CH2—, —NR2—, —C(O)—, —C(═NR2)—, —S(O)2—, or —S(O)—;
• G2 is selected from the group consisting of:
• —O—, —C(R21)2—, —CHR21—,
• —CH2—, —CR21— (if the optional double bond to G2 is present), CH (if the optional double bond to G2 is present), —NR2—, —N═ (if the optional double bond to G2 is present),
• —C(O)—, —C(═NR2)—, —S(O)2— and —S(O)—, with the proviso that when the optional double bond between (3) and (4) is present then G2 is not —O—, —C(R21)2—, —CHR21—,
• —CH2—, —NR2—, —C(O)—, —C(═NR2)—, —S(O)2—, or —S(O)—;
• G3 is selected from the group consisting of:
• —C(R21)2—, —CHR21—,
• —CH2—, —CR21— (if the optional double bond to G3 is present), CH (if the optional double bond to G3 is present), —NR2—, and —N═ (if the optional double bond to G3 is present), with the proviso that when the optional double bond between (1) and (2) is present then G3 is not —C(R21)2—, —CHR21—, —CH2—, or —NR2—;
• W is selected from the group consisting of:
• —O—, —S—, —C(R21)2—, —CHR21—,
• —CH2—, —NR2—, —C(O)—, —C(═NR2)—, —S(O)2— and —S(O)—;
• V is selected from the group consisting of:
• a direct bond (when ring (B) is a 5-membered ring), —O—, —C(R21)2—, —CHR21—, —CH2—, —NR2—, —C(O)—, —C(═NR2)—,
• —S(O)2— and —S(O)—;
• G is selected from the group consisting of:
• —C(O)—, —(C═NR2)—, —(C═C(R4)2)—,
• —C(R4)2—, —CF2—, —N(R2)— (and in one example, —NH—), —O—, —S—, —S(O)t, —CR4 (OH)—,
• —CR4 (OR4)—, —C═C—, alkynyl, —C(O)NR5—, —O—C(O)—NR5—, —NR5C(O)—,
• —NR5S(O)t—, —S(O)tNR5—, —NR5—C(O)—O—, —NR5—C(O)—NR5—, —NR5—S(O)t—NR5—,
• —NR5—C(═NR2)—NR5—, —NR5—C(═NR2)—O—, —O—C(═NR2)—NR5—,
• —C(R4)═N—O—, —O—N═C(R4)—, —O—C(R4)═N—, —N═C(R4)—O—, —(CH2)2-3— (i.e., 2 to 3
• —CH2— groups), cycloalkyl, and heterocycloalkyl (comprising 1 to 4 heteroatoms independently selected from the group consisting of:
• —O—, —NR2—, —S—, —S(O)—, and
• —S(O)2);
• R1 is selected from the group consisting of:
• alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, arylalkyl-, alkylaryl-, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), fused benzocycloalkyl (i.e., benzofusedcycloalkyl), fused benzoheterocycloalkyl (i.e., benzofusedhetero-cycloalkyl), fused heteroarylcycloalkyl (i.e., heteroarylfusedcycloalkyl), fused heteroarylheterocycloalkyl (i.e., heteroarylfusedheterocycloalkyl), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), fused benzocycloalkylalkyl- (i.e., benzofusedcycloalkylalkyl-), fused benzoheterocycloalkylalkyl- (i.e., benzofusedheterocycloalkylalkyl-), fused heteroarylcycloalkylalkyl- (i.e., heteroarylfusedcycloalkylalkyl-), fused heteroarylheterocycloalkylalkyl- (i.e., heteroarylfusedheterocycloalkylalkyl-), fused cycloalkylarylalkyl- (i.e., cycloalkyfusedlarylalkyl-), fused heterocycloalkylarylalkyl- (i.e., heterocycloalkylfusedarylalkyl-), fused cycloalkylheteroarylalkyl- (i.e., cycloalkylfusedheteroarylalkyl-), and fused heterocycloalkylheteroarylalkyl- (i.e., heterocycloalkylfusedheteroarylalkyl-), and wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl, fused benzocycloalkyl (i.e., benzofusedcycloalkyl), fused benzoheterocycloalkyl (i.e., benzofusedhetero-cycloalkyl), fused heteroarylcycloalkyl (i.e., heteroarylfusedcycloalkyl), fused heteroarylheterocycloalkyl (i.e., heteroarylfusedheterocycloalkyl), fused cycloalkylaryl, fused
• heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-, fused benzocycloalkylalkyl-, fused benzoheterocycloalkylalkyl-, fused heteroarylcycloalkylalkyl-, fused heteroarylheterocycloalkylalkyl-, fused cycloalkylarylalkyl-, fused heterocycloalkylarylalkyl-, fused cycloalkylheteroarylalkyl-, and fused heterocycloalkylheteroarylalkyl-R1 groups is optionally substituted with 1-5 independently selected R21 groups;
• R6 is selected from the group consisting of:
• H, —C(O)R15, —C(O)OR15,
• —C(O)N(R15)(R16), —C(═NOR15)R16, —CN, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, benzofusedcycloalkyl (i.e., fused benzocycloalkyl), fused benzoheterocycloalkyl, fused heteroarylcycloalkyl, and fused heteroarylheterocycloalkyl;
• and wherein each of said R6 alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclyalkyl-, benzofusedcycloalkyl, fused benzoheterocycloalkyl, fused heteroarylcycloalkyl, and fused heteroarylheterocycloalkyl group is optionally substituted with 1-5 independently selected R21 substituents;
• or
• R1 and R6, taken together with the carbon atom to which they are bound, form a spirocyclic carbocyclic moiety or a spirocyclic heterocyclic moiety, and:
• (a) optionally, said spirocyclic carbocyclic moiety is substituted with 1-4 independently selected R21 substituents,
• (b) optionally, said spirocyclic heterocyclic moiety is substituted with 1-4 independently selected R21 substituents,
• (c) optionally, said spirocyclic carbocyclic moiety is fused with an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring to form a fused ring moiety, and optionally, each ring of said fused ring moiety is substituted with 1-4 independently selected R21 substituents,
• (d) optionally, said spirocyclic heterocyclic moiety is fused with an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring to form a fused ring moiety, and optionally, each ring of said fused ring moiety is substituted with 1-4 independently selected R21 substituents;
• R2 is selected from the group consisting of:
• H, —OH, —O-alkyl (i.e., alkoxy), —O-(halo substituted alky) (such as, for example, —O-fluoroalkyl), —NH(R4), —N(R4)2 (wherein each R4 is independently selected), —NH2, —S(R4), —S(O)R4, —S(O)(OR4),
• —S(O)2R4, —S(O)2 (OR4), —S(O)NHR4, —S(O)N(R4)2 (wherein each R4 is independently selected), —S(O)NH2, —S(O)2 NHR4, —S(O)2 N(R4)2 (wherein each R4 is independently selected), —S(O)2 NH2, —CN, —C(O)OR4, —C(O)NHR4, —C(O)N(R4)2 (wherein each R4 is independently selected), —C(O)NH2, —C(O)R4, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-, substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, and substituted cycloalkyl, wherein said substituted aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl and cycloalkyl groups are substituted with 1 to 5 independently selected R21 groups;
• R3 is selected from the group consisting of:
• H, —OH, halo, —O-alkyl (i.e., alkoxy), —O-(halo substituted alkyl), —NH(R4), —N(R4)2 (wherein each R4 is independently selected), —NH2, —S(R4), —S(O)R4, —S(O)(OR4), —S(O)2R4,
• —S(O)2 (OR4), —S(O)NHR4, —S(O)N(R4)2, —S(O)NH2, —S(O)2 NHR4, —S(O)2 N(R4)2,
• —S(O)2 NH2, —CN, —C(O)OR4, —C(O)NHR4, —C(O)N(R4)2, —C(O)NH2, —C(O)R4, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-, substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, and substituted cycloalkyl, wherein said substituted aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl and cycloalkyl groups are substituted with 1 to 5 independently selected R21 groups;
• each R4 is independently selected from the group consisting of:
• unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-, substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, and substituted cycloalkyl, wherein said substituted aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl and cycloalkyl groups are substituted with 1 to 5 independently selected R21 groups;
• each R5 is independently selected from the group consisting of:
• H, unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl;
• wherein said substituted groups are substituted with 1 to 5 substituents independently selected from R21;
• R9 is selected from the group consisting of:
• aryl, heteroaryl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl-, wherein each of said R9 aryl, heteroaryl, heterocyclyl, heterocyclenyl, or heterocyclyalkyl- is optionally substituted with 1 to 5 independently selected R21 groups;
• R10 is selected from the group consisting of:
• aryl-, heteroaryl-, fused cycloalkylaryl (i.e., cycloalkylfusedaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), and fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), wherein each of said R10 moieties is optionally substituted with 1 to 5 independently selected R21 groups;
• optionally, R9 and R10 can be linked together to form a fused tricyclic alkyl ring, a fused tricyclic heteroalkyl ring, a fused tricyclic aryl ring, a fused tricyclic heteroaryl ring, a fused tricyclic alkenyl ring or a fused tricyclic heteroalkenyl ring;
• R15, R16 and R17 are the same or different and each is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)n-alkyl, (R18)n-cycloalkyl, (R18)n-cycloalkylalkyl, (R18)n-heterocyclyl, (R18)n-heterocyclylalkyl,
• (R18)n-aryl, (R18)n-arylalkyl,
• (R18)n-heteroaryl and (R18)n-heteroarylalkyl;
• R15A and R16A are the same or different and each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)n-alkyl, (R18)n-cycloalkyl, (R18)n-cycloalkylalkyl, (R18)n-heterocyclyl, (R18)n-heterocyclylalkyl, (R18)n-aryl, (R18)n-arylalkyl,
• (R18)n-heteroaryl and (R18)n-heteroarylalkyl;
• each R15 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl,
• HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19 —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2 NH2, —S(O)2 NHR19 —S(O)2 NH(heterocyclyl), —S(O)2 N(alkyl)2, —S(O)2 N(alkyl)(aryl), —OCF3,
• —OH, —OR20, —O-heterocyclyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20—NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2 NH(alkyl),
• —NHS(O)2 N(alkyl)(alkyl), —N(alkyl)S(O)2 NH(alkyl) and —N(alkyl)S(O)2 N(alkyl)(alkyl);
• optionally, two R18 moieties on adjacent carbons can be linked together to form a
• R19 is selected from the group consisting of:
• alkyl, cycloalkyl, aryl, arylalkyl and heteroarylalkyl;
• R20 is selected from the group consisting of:
• alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl and heteroarylalkyl;
• each R21 is independently selected from the group consisting of:
• alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15,
• —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —P(O)(CH3)2, —SO(═NR15)R16—, —SF5,
• —OSF5, —Si(R15)3 wherein each R15 is independently selected, —SR15,
• —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16,
• —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15;
• —CH2N(R15)(R16), —N(R15)S(O)R16A, —N(R15)S(O)2R16A, —CH2—N(R15)S(O)2R16A, —N(R15)S(O)2 N(R16)(R7), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R7), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16
• —S(O)R15A, ═NOR15, —N3, —NO2, —S(O)2R15A, —O—N═C(R4)2 (wherein each R4 is independently selected), and —O—N═C(R4)2 (wherein the two R4 groups are taken together with the carbon atom to which they are bound to form a 5 to 10 membered ring, said ring optionally containing 1 to 3 heteroatoms selected from the group consisting of —O—, —S—, —S(O)—, —S(O)2—, and —NR2—), wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl R21 groups is optionally substituted with 1 to 5 independently selected R22 groups;
• each R22 group is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN,
• —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SF5, —OSF5,
• —Si(R15)3 wherein each R15 is independently selected, —SR15, —S(O)N(R15)(R16),
• —S(O)2 N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR6), —N(R15)(R16),
• -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16A,
• —N(R15)S(O)2R16A, —CH2—N(R15)S(O)2R16A, —N(R15)S(O)2 N(R16)(R17),
• —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17),
• —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15A and —S(O)2R15A;
• optionally, one of (a)-(b) below can represent a spiro ring:
• (a) when G1, G2 or G3 represents —C(R21)2—, two R21 groups on one of G1, G2 or G3 can together form a 3 to 8 membered cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl spiro ring attached to ring (A), or
• (b) when W or V represents —C(R21)2—, two R21 groups on one of W or V can together form a 3 to 8 membered cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl spiro ring attached to ring (B);
• d is 0 or 1;
• m is 0 to 6;
• n is 1 to 5;
• p is 0 to 5;
• r is 1 to 3;
• t is 1 or 2;
• and
• provided that:
• (a) rings (A) and (B) do not have two adjacent —O— atoms in the ring;
• and
• (b) rings (A) and (B) do not have two adjacent sulfur groups in the ring (i.e., when there is a —S—, —S(O)— or —S(O)2 group at one position, then the adjacent positions are not —S—, —S(O)— or —S(O)2);
• and
• (c) rings (A) and (B) do not have an —O— atom adjacent to a sulfur group (i.e., rings (A) and (B) do not have an —O— atom adjacent to a —S—, —S(O)— or —S(O)2);
• and
• (d) when G1 is N, then G2 is not —O—;
• and
• (e) when G1 is —O—, then G2 is not N;
• and
• (f) when G1 is N, and G3 is N, then G2 is not N;
• and
• (g) when G2 is N, and G3 is N, then G1 is not N;
• and
• (h) when G1 is N, and G2 is N, then G3 is not N;
• and
• (i) when the double bond between positions 1 and 2 is not present, then G is not —C(O)—, —(C═NR2)— or —(C═C(R4)2)—.