Gamma secretase modulators

A compound of the formula (I):

• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• Ring (B) is a 4 to 10 membered single ring or fused ring selected from the group consisting of:
• cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, and
• (a) said heterocycloalkyl Ring (B), or said heterocycloalkenyl Ring (B), or said heteroaryl Ring (B), comprises 1 to 4 heteroatoms (including any heteroatoms common to Ring (A) and Ring (C)) selected from the group consisting of —NR2—, —O—, —S—, —S(O)— and —S(O)2, and
• (b) Ring (B) is optionally substituted with 1 to 5 substitutents independently selected from the group consisting of:
• ═O, ═NR2 and R21;
• Ring (C) is an aryl or heteroaryl ring, and said Ring (C) is optionally substituted with 1 to 3 independently selected R21 substitutents;
• the dotted line () between positions (1) and (2) represents an optional bond;
• the dotted line () between positions (3) and (4) represents an optional bond;
• d is 0 or 1;
• f is 1;
• m is 0 to 6;
• n is 1 to 5;
• p is 0 to 5;
• q is 0, 1 or 2, and each q is independently selected;
• W is selected from the group consisting of:
• —C(O)—, —S(O)2—, —S(O)—, and —C(═NR2)—;
• G1 is selected from the group consisting of:
• a direct bond (i.e., the N at (5) is bonded directly to G2, and Ring A is a five membered ring), —O—, —C(R21)q, —N(R2)d—, —C(O)—, —C(═NR2)—, —S—, —S(O)2, and —S(O)—;
• and with the proviso that when the optional double bond between (3) and (4) is present then:
• (a) q for the —C(R21)q group is 0 or 1, and
• (b) d for the —N(R2)d— group is 0;
• and
• (c) G1 is not —O—, —C(O)—, —C(═NR2)—, —S—, —S(O)2, or S(O)—;
• G2 is selected from the group consisting of:
• a direct bond, —O—, —C(R21)q, —N(R2)d—, —C(O)—, —C(═NR2)—, —S—, —S(O)2, and —S(O)—;
• and with the proviso that when the optional double bond between (3) and (4) is present then:
• (a) q for the —C(R21)q group is 0 or 1, and
• (b) d for the —N(R2)d— group is 0;
• and
• (c) G2 is not —O—, —C(O)—, —C(═NR2)—, —S—, —S(O)2, or —S(O)—;
• G3 is:
• (a) carbon when the optional bond between G3 and G4 is present,
• (b) carbon when the optional bond between G3 and G4 is absent, and there is a double bond to G3 in Ring (B), and
• (c) carbon or nitrogen when the optional bond between G3 and G4 is absent, and there is single double bond to G3 in Ring (B);
• G4 is:
• (a) carbon when the optional bond between G3 and G4 is present,
• (b) carbon when the optional bond between G3 and G4 is absent, and there is a double bond to G4 in Ring (B), and
• (c) carbon or nitrogen when the optional bond between G3 and G4 is absent, and there is single double bond to G4 in Ring (B);
• R1 is selected from the group consisting of:
• alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, fused benzocycloalkyl, fused benzoheterocycloalkyl, fused heteroarylcycloalkyl, fused heteroarylheterocycloalkyl, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl, -and heterocyclyalkyl-;
• wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl-, cycloalkylalkyl-, fused benzocycloalkyl, fused benzaheterocycloalkyl, fused heteroarylcycloalkyl, fused heteroarylheterocycloalkyl, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl and heterocyclyalkyl-R1 groups is optionally substituted with 1-5 independently selected R21 groups;
• or
• R2 is selected from the group consisting of:
• H, —OH, —O-alkyl, —O-(halo substituted alky), —NH(R4), —N(R4)2 (wherein each R4 is independently selected), —NH2, —S(R4), —S(O)R4, —S(O)(OR4), —S(O)21R4—S(O)2(OR4), —S(O)NHR4, —S(O)N(R4)2, —S(O)NH2, —S(O)2NHR4, —S(O)2N(R4)2, —S(O)2NH2, —CN, —C(O)2R4, —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;
• R9 is selected from the group consisting of:
• aryl-, arylalkyl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl-, and heterocyclyalkyl-, wherein each of said R9 aryl-, arylalkyl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclyalkyl- and heterocyclyalkyl- is optionally substituted with 1-3 independently selected R21 groups;
• R14 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, heterocyclylalkyl, heterocyclyalkenyl-, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NO15)R16, and —P(O)(OR15)(OR16);
• R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)-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;
• or
• R15, R16 and R17 are independently selected from the group consisting of:
• Each R18 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)2NH2, —S(O)2NHR19, —S(O)2NH(heterocyclyl), —S(O)2N(alkyl)2, —S(O)2N(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)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);
• or
• 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, cycloalkyll, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalky, halo, —ON, —OR15,
• —C(O)R15, —C(O)OR15, —O(O)N(R15)(R16), —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)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(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, —S(O)R15, ═NOR15, —N3, —NO2, —S(O)2R15, —O—N═C(R4)2 (wherein each R4 is independently selected), and —O—N═C(R4)2 wherein R4 is 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 R 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), —SR15, —S(O)N(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, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(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)R15 and —S(O)2R15;
• or two R21 or two R22 moieties on adjacent carbons can be linked together to form a
• and when R21 or R22 is selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(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)R16 and —CH2—N(R15)C(O)OR16, then R15 and R16 together can form a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R18, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by (R23)n;
• Each R23 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;
• and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl R23 groups is optionally substituted with 1 to 5 independently selected R27 groups;
• Each R24, R25 and R26 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, (R27A)n-alkyl, (R27A)n-cycloalkyl, (R27A)n-cycloalkylalkyl, (R27A)n-heterocycloalkyl, (R27A)n-heterocycloalkylalkyl, (R27A)n-aryl, (R27A)n-arylalkyl, (R27A)n-heteroaryl and (R27A)n-heteroarylalkyl;
• Each R27 is independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R28), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;
• Each R27A is independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —ON, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R28, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylakyl), —NHC(O)R29, —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)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);
• R28 is selected from the group consisting of:
• alkyl, cycloalkyl, arylalkyl and heteroarylalkyl;
• and
• R29 is selected from the group consisting of;
• alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
• and
• provided that:
• (a) Ring A does not have two adjacent —O— atoms in the ring;
• and
• (b) Ring A does 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 in Ring A, then the adjacent positions in Ring A are not —S—, —S(O)— or —S(O)2);
• and
• (c) Ring A does not have an —O— atom adjacent to a sulfur group (i.e., Ring A does 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, then G2 is not —S—;
• and
• (g) When G1 is —S—, then G2 is not N;
• and
• (h) When G1 is a direct bond, and G2 is —O—, then G3 is not N;
• and
• (i) When G2 is a direct bond, and G1 is —O—, then G3 is not N;
• and
• (j) When G1 is N, and G3 is N, then G2 is not N;
• and
• (k) When G2 is N, and G3 is N, then G1 is not N;
• and
• (l) When G1 is N, and G2 is N, then G3 is not N.