Lysophosphatidic acid receptor antagonists

A compound of Formula (II):

• or a pharmaceutically acceptable salt thereof, wherein:
• A is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when A is a ring system, it is optionally substituted;
• B is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when B is a ring system, it is optionally substituted;
• C is a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 5-11 membered heterocyclyl, and 5-11 membered carbocyclyl, wherein C is optionally substituted;
• D is selected from —OH,
• —NR13SOpR14, —C(O)—NR13SOpR14,
• —SOpR15, —SOpNR16R17, or carboxylic acid isosteres;
• E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
• L4 is selected from
• or alternatively,
• wherein
• is selected from:
• or optionally substituted variants thereof;
• L1 is selected from a single bond, a —CH2— linker,
• a —C≡C— linker, a —CH═CH— linker, or a ═C(R11)— linker;
• L2 is selected from a single bond, a —CH2— linker,
• a —C≡C— linker, or a —CH═CH— linker;
• L3 is absent or selected from
• or a ═C(R11)— linker;
• L5 is selected from
• or a —C≡C— linker;
• W is selected from C(R6)2, NR6, or O;
• X is selected from —C(O) or S(O)p;
• each Y is independently selected from CR6 or N;
• Y1 is selected from C(R6)2, NR6, or O;
• each Y4 is independently absent, CR9, C(R9)2, N, or NH, provided that only one Y4 can be absent;
• each Z is independently selected from C(O), O, S, S(O)2, NR6a, C(O)NR6b, or S(O)2NR6c;
• R1 is selected from hydrogen;
• alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl;
• or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
• R2 and R3 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each of cycloalkyl, heterocyclyl, aryl, and heteroaryl of R2 or R3 is optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
• or R2 and R3 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• or R2 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl and R3 is joined to an atom alpha to a point of attachment of L5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
• or R3 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R2 is joined to an atom alpha to a point of attachment of L5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
• each R4 and R5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• or R4 and R5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
• each R6, R6a, R6b, and R6c is independently selected from hydrogen;
• alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• aryl;
• or C3-6 cycloalkyl;
• each R7 and R8 is independently selected from hydrogen or C1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• or R7 and R8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
• each R9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen;
• or two adjacent R9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
• each R10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• aryl;
• C3-6 cycloalkyl;
• or cyano;
• each R11 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• haloalkyl;
• or cyano;
• each R13 and R14 is independently selected from hydrogen, alkyl, haloalkyl, aryl, or C3-6 cycloalkyl;
• R15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C3-6 cycloalkyl;
• each R16 and R17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C3-6 cycloalkyl;
• or R16 and R17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• each R2a, R3a, R2b, R3b, R2c, and R3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• or each of R2a and R3a, R2b and R3ab, or R2c and R3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• m is independently an integer from 0-3;
• n is an integer from 0-3;
• k is an integer from 0-3;
• p is an integer from 1-2;
• q is an integer from 1-6;
• each s and u is independently an integer from 0 to 6;
• and
• represents a single or double bond, provided that
• when A is
• B is
• D is —C(O)OH;
• m is 0;
• E is absent;
• L5 is —CH2SCH2CH2—;
• L1 is a single bond;
• L2 is a single bond;
• and
• wherein R9 is selected from H or halogen and R4 is methyl;
• then C is not

A compound of Formula (XI):

• or a pharmaceutically acceptable salt thereof, wherein
• A is selected from the group consisting of
• wherein A is optionally substituted;
• is selected from
• or optionally substituted variants thereof;
• wherein each * is a point of attachment of C to L2;
• D is selected from —OH,
• —NR13SOpR14, —C(O)—NR13SOpR14,
• —SOpR15, —SOpNR16R17, or carboxylic acid isosteres;
• E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
• L4 is selected from
• or alternatively,
• wherein
• is selected from:
• or optionally substituted variants thereof;
• L2 is selected from a single bond, a —CH2— linker,
• a —C≡C— linker, or a —CH═CH— linker;
• L5 is selected from a single bond, a —CH═CH— linker, a —C≡C— linker,
• or a 4-7 membered heterocyclyl;
• W is selected from C(R6)2, NR6, or O;
• X is selected from —C(O) or S(O)p;
• each Y is independently selected from CR or N;
• Y1 is selected from C(R6)2, NR6, or O;
• each Y2 is independently selected from —CH═ or N;
• each Y3 is independently selected from C(R6)2, NR6, O or S;
• each Y4 is independently absent, CR9, C(R9)2, N, or NH, provided that only one Y4 can be absent;
• each Z is independently selected from C(O), O, S, S(O)2, NR6a, C(O)NR6b, or S(O)2NR6c;
• R1 is selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl, or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
• R2 and R3 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each of cycloalkyl, heterocyclyl, aryl, and heteroaryl of R2 or R3 is optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
• or R2 and R3 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• or R2 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl and R3 is joined to an atom alpha to a point of attachment of L5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
• or R3 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R2 is joined to an atom alpha to a point of attachment of L5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
• each R4 and R5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• or R4 and R5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
• each R6, R6a, R6b, and R6c is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, halogen, aryl, or C3-6 cycloalkyl;
• each R7 and R8 is independently selected from hydrogen or C1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or R7 and R8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
• each R9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen, or two adjacent R9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
• each R10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, halogen, aryl, C3-6 cycloalkyl, or cyano;
• each R12 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, acyl, C-carboxy, C-amido, sulfinyl, sulfonyl, or S-sulfonamido.
• each R13 and R14 is independently selected from hydrogen, alkyl, haloalkyl, halogen, aryl, or C3-6 cycloalkyl;
• R15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C3-6 cycloalkyl;
• each R16 and R17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C3-6 cycloalkyl;
• or R16 and R17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• each R2a, R3a, R2b, R3b, R2c, and R3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• or each of R2a and R3a, R2b and R3b, or R2c and R3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• m is independently an integer from 0-3;
• n is an integer from 0-3;
• p is an integer from 1-2;
• q is an integer from 1-6;
• each s and u is independently an integer from 0 to 6;
• and
• represents a single or double bond.

A compound of Formula (XII):

• or a pharmaceutically acceptable salt thereof, wherein:
• A is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when A is a ring system, it is optionally substituted;
• B is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when B is a ring system, it is optionally substituted;
• C is a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 5-11 membered heterocyclyl, and 5-11 membered carbocyclyl, wherein C is optionally substituted;
• D is selected from —OH,
• —NR13SOpR14, —C(O)—NR13SOpR14,
• —SOpR15, —SOpNR16R17, or carboxylic acid isosteres;
• E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
• L4 is selected from
• or alternatively,
• wherein
• is selected from:
• or optionally substituted variants thereof;
• L1 is selected from a single bond, a —CH2— linker,
• a —C≡C— linker, a —CH═CH— linker, or a ═C(R11)— linker;
• L2 is selected from a single bond, a —CH2— linker,
• a —C≡C— linker, or a —CH═CH— linker;
• L3 is absent or selected from
• or a ═C(R11)— linker;
• L5 is selected from a single bond, a —CH═CH— linker, a —C≡C— linker,
• or a 4-7 membered heterocyclyl;
• W is selected from C(R6)2, NR6, or O;
• X is selected from —C(O) or S(O)p;
• each Y is independently selected from CR6 or N;
• Y1 is C(R6)2, NR6, or O;
• each Y4 is independently absent, CR9, C(R9)2, N, or NH, provided that only one Y4 can be absent;
• each Z is independently selected from C(O), O, S, S(O)2, NR6a, C(O)NR6b, or S(O)2NR6c;
• R1 is selected from hydrogen;
• alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl;
• or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
• R2 and R3 are each independently selected from hydrogen, halogen, haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-10 membered heteroaryl;
• wherein each C3-7 cycloalkyl, 3-7 membered heterocyclyl, and 5-10 membered heteroaryl of R2 or R3 is optionally substituted;
• provided that R2 and R3 cannot both be hydrogen;
• or R2 and R3 are joined together with the atom to which they are attached to form a halo-substituted C3-7 cycloalkyl or halo-substituted 3-7 membered heterocyclyl;
• each R4 and R5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• or R4 and R5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
• each R6, R6a, R6b, and R6c is independently selected from hydrogen;
• alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• aryl;
• or C3-6 cycloalkyl;
• each R7 and R8 is independently selected from hydrogen or C1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• or R7 and R8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
• each R9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen;
• or two adjacent R9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
• each R10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• aryl;
• C3-6 cycloalkyl;
• or cyano;
• each R11 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy;
• halogen;
• haloalkyl;
• or cyano;
• each R13 and R14 is independently selected from hydrogen, alkyl, haloalkyl, aryl, or C3-6 cycloalkyl;
• R15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C3-6 cycloalkyl
• each R16 and R17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C3-6 cycloalkyl;
• or R16 and R17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• each R2a, R3a, R2b, R3b, R2c, and R3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• or each of R2a and R3a, R2b and R3b, or R2c and R3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
• m is independently an integer from 1-3;
• n is an integer from 0-3;
• k is an integer from 0-3;
• p is an integer from 1-2;
• q is an integer from 1-6;
• each s and u is independently an integer from 0 to 6;
• and
• represents a single or double bond.