US 2017/0362227 A1 · NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

Abstract

The present invention discloses compounds according to Formula I: Wherein R1a, R1b, R2, R4, R5, R6a, R6b, R7, R8, W, X, Cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

1) A compound according to Formula I:

wherein
R1a is H, halo or C1-4 alkyl;
R1b is:
halo,
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected halo), or
C1-4 alkoxy (which alkoxy is optionally substituted with one or more independently selected halo);
X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—;
W is N, or CR3
when W is N, R2 is:
H,
—CN,
halo,
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected OH, or CN)
—C(═O)CH3,
—C(═O)CF3,
—C(═O)OCH3,
—C(═O)NH2, or
—NHC(═O)CH3, or
when W is CR3, one of R2 or R3 is:
H,
—CN,
halo,
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected OH, or CN)
—C(═O)CH3,
—C(═O)CF3,
—C(═O)OCH3,
—C(═O)NH2, or
—NHC(═O)CH3,
and the other is H, or C1-4 alkyl;
R4 is C1-4 alkyl;
R5 is C1-4 alkyl optionally substituted with one or more independently selected CN, OH, halo, or —C(═O)NH2;
one of R6a or R6b is selected from H, —CH3, and halo, and the other is H;
Cy is:
C4-10 cycloalkyl,
4-10 membered mono or bicyclic heterocycloalkyl containing one or more heteroatoms independently selected from O, N, and S, or
4-7 membered heterocycloalkenyl containing 1 double bond, containing one or more heteroatoms independently selected from O, N, and S;
each R7 is independently selected from:
OH,
oxo,
halo, and
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected OH, or C1-4 alkoxy);
the subscript a is 0, 1 or 2;
R8 is -(L1-W1)m-L2-G1,
wherein
L1 is absent, or is —O—, —C(═O)—, —NRi, —NRhC(═O)—, or —SO2—;
W1 is C1-4 alkylene;
the subscript m is 0, or 1;
L2 is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)—C(═O)—, —C(═O)—C(═O)NRa—, —NRb—, —C(═O)NRc—, —NRdC(═O)—, —NRjC(═O)O—, —SO2—, —SO2NRe— or —NRfSO2—;
G1 is
H,
—CN,
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected —CN, OH, halo or phenyl),
C3-7 cycloalkyl (which cycloalkyl is optionally substituted with —NH2),
5-6 membered heterocycloalkenyl containing 1 double bond containing one or more heteroatoms independently selected from O, N, and S (which heterocycloalkenyl is optionally substituted with one or more independently selected R9 groups),
4-10 membered mono, bi or spirocyclic heterocycloalkyl containing one or more heteroatoms independently selected from O, N, and S (which heterocycloalkyl is optionally substituted with one or more independently selected R9 groups), or
5-6 membered heteroaryl containing one or more heteroatoms independently selected from O, N, and S (which heteroaryl is optionally substituted with one or more independently selected R10 groups),
each R9 is oxo, or R10
each R10 is:
—OH,
halo,
—CN,
C1-4 alkyl (which alkyl is optionally substituted with one or more independently selected OH, halo, or phenyl),
C1-4 alkoxy,
C3-7 cycloalkyl,
phenyl,
—SO2CH3,
—C(═O)C1-4 alkoxy,
—C(═O)C1-4 alkyl, or
—NRgC(═O)C1-4 alkyl;
and
each Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and R is independently selected from H and C1-4 alkyl;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.

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Abstract

Claims20