Compounds for inhibition of alpha 4 beta 7 integrin

A method for treating an inflammatory disease or condition associated with α4β7 integrin, comprising administrating to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 and X2 are each independently selected from C, and N;
• wherein the bond between X1 and X2 is a single or a double bond;
• X3 and X4 are each independently selected from CR10, and N;
• X6 and X7 are each independently selected from CR10R10, CR10, S, S(O), S(O)2, N, NR11, C(O), and O;
• each X6 is independently selected from CR10R10, CR10, S, S(O), S(O)2, N, NR11, C(O), and O;
• wherein the bond between X5 and X6, X6 and X6, or X6 and X7 is a single or a double, provided that at least one is a double bond;
• R1 is selected from -L-A1, -L-A2, -L-A3, and -L-A4;
• L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and —N(H)—C(O)—*;
• wherein * indicates a point of attachment of L to A1, A2, A3, or A4;
• A1 is C6-10aryl optionally substituted with one to six Ra;
• A2 is 5-10 membered heteroaryl containing one to five heteroatoms independently selected from S, N, and O, and optionally one or two C(O);
• wherein A2 is optionally substituted with one to six Ra;
• A3 is 5-10 membered cycloalkyl or 5-14 membered heterocyclyl;
• wherein A3 is optionally substituted with one to six Ra;
• and
• A4 is —NRa1Ra2;
• wherein each Ra is independently selected from halo, cyano, hydroxyl, —NRa1Ra2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, —S(O)m—C1-6alkyl, C3-8cycloalkyl, 3-6 membered heterocyclyl, C6-10aryl, 5-6 membered heteroaryl, —O-(3-6 membered heterocyclyl), —O—C1-4alkylene-C3-8cycloalkyl, —O-phenyl, and —O—C3-8cycloalkyl;
• each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and —S(O)m—C1-6alkyl of Ra are optionally substituted with one to three Ra3;
• wherein each Ra3 is independently selected from hydroxyl, cyano, —NRa1Ra2, C1-6alkoxyl, C3-8cycloalkyl, phenyl, and 3-6 membered heterocyclyl;
• wherein each C3-8cycloalkyl, phenyl, and 3-6 membered heterocyclyl of Ra3 is independently optionally substituted with one to three Ra4;
• wherein each Ra4 is independently selected from halo, cyano, hydroxyl, —NRa1Ra2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxyl, C1-6haloalkoxyl, C3-8cycloalkyl, and 3-6 membered heterocyclyl;
• and
• each C3-8cycloalkyl, 3-6 membered heterocyclyl, C6-10aryl, 5-6 membered heteroaryl, —O-(3-6 membered heterocyclyl), —O—C1-4alkylene-C3-8cycloalkyl, —O-phenyl, and —O—C3-8cycloalkyl of Ra is independently optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NRa1Ra2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxyl, and C1-6haloalkoxyl;
• each R2, R3, R4, R5, and R6 is independently selected from H, halo, cyano, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, C1-8haloalkyl, C1-8haloalkoxyl, —NRb1Rb2, —Rb3S(O)mRb4, —S(O)mRb4, —NRb1S(O)yRb4, —COORb1, —CONRb1Rb2, —NRb1COORb2, —NRb1CORb4, —Rb3NRb1Rb2, —S(O)yNRb1Rb2, C3-12cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 3-12 membered heterocyclyl;
• each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, C1-8haloalkyl, and C1-8haloalkoxyl of R2, R3, R4, R5, and R6 is independently optionally substituted with one to two Rc;
• wherein each Rc is independently selected from azido, oxo, cyano, halo, hydroxyl, —NRa1Ra2, C1-4alkoxyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;
• wherein each C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of Rc is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NRa1Ra2, C1-4alkyl, C1-6haloalkyl, C1-4alkoxyl, and C3-6cycloalkyl;
• each C6-10aryl and 5-6 membered heteroaryl of R2, R3, R4, R5, and R6 is independently optionally substituted with one to five Rb;
• and
• each C3-12cycloalkyl and 3-12 membered heterocyclyl of R2, R3, R4, R5, and R6 is independently optionally substituted with one to six groups independently selected from ═CRb1Rb2, and Rb;
• wherein each Rb is independently selected from azido, cyano, halo, hydroxyl, —NRa1Ra2, C1-6alkyl, C1-8haloalkyl, C1-6alkoxyl, C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;
• wherein each C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of Rb is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NRa1Ra2, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxyl;
• each Rb1 and Rb2 is independently selected from H, C1-8alkyl, C1-8haloalkyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 3-8 membered heterocyclyl;
• each C1-8alkyl and C1-6haloalkyl of Rb1 and Rb2 is optionally substituted with one to two Rb5;
• and
• each C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 3-8 membered heterocyclyl of Rb1 and Rb2 is independently optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NRa1Ra2, C1-8alkyl, C1-8haloalkyl, C1-6alkoxyl, C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;
• Rb3 is C1-4alkylene;
• Rb4 is selected from C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;
• wherein each C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and the 4-6 membered heterocyclyl of Rb4 is optionally substituted with one to three Rb6;
• each Rb5 is independently selected from cyano, hydroxyl, C1-4alkoxyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;
• wherein each C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of Rb5 is optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NRa1Ra2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxyl, and phenyl;
• and
• each Rb6 is independently selected from halo, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxyl, C3-6cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl;
• wherein each C3-6cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of Rb6 is independently optionally substituted with one to three groups independently selected from halo, cyano, —NRa1Ra2, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxyl;
• or
• R2 and R3, R3 and R4, or R5 and R6 together with the atoms to which they are attached may form a C6-10aryl, 5-6 membered heteroaryl, C3-6cycloalkyl, or 5-6 membered heterocyclyl;
• wherein each C6-10aryl, 5-6 membered heteroaryl, C3-6cycloalkyl, or 5-6 membered heterocyclyl is optionally substituted with one to three groups independently selected from halo, cyano, —NRa1Ra2, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C3-8cycloalkyl, 3-6 membered heterocyclyl, C6-10aryl, 5-6 membered heteroaryl, C1-4alkylene-C3-8cycloalkyl, C1-4alkylene-C6-10aryl, and C1-4alkylene-(5-6 membered heteroaryl);
• R7 is selected from H, C1-4alkyl, and C1-4haloalkyl;
• R8 is selected from H, C1-4alkyl, and C1-4haloalkyl;
• R9 is selected from H, C1-6alkyl, —C1-4alkylene-NRa1Ra2, —C1-4alkylene-C(O)NRa1Ra2, —C1-4alkylene-O—C(O)—C1-4alkyl, —C1-4alkylene-O—C(O)—O—C1-4alkyl, —C1-4alkylene-O—C(O)—C1-4alkylene-NRa1Ra2, —C1-4alkylene-O—C1-4alkyl, C3-8cycloalkyl, —C1-4alkylene-C3-8cycloalkyl, 4-6 membered heterocyclyl, and —C1-4alkylene-(4-6 membered heterocyclyl);
• wherein each C3-8cycloalkyl, —C1-4alkylene-C3-8cycloalkyl, and 4-6 membered heterocyclyl of R9 is optionally substituted with one to three groups independently selected from halo, C1-4alkyl, C1-4alkoxyl, and C1-4haloalkyl;
• or
• R9 together with the N that attaches to R8 forms a 5 membered heterocyclyl;
• wherein the 5 membered heterocyclyl is optionally substituted with one to two groups independently selected from halo, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, and C6-10aryl;
• wherein C6-10aryl is optionally substituted with one to three groups independently selected from halo, C1-6alkyl, C1-6alkoxyl, and C1-6haloalkyl;
• each R10 is independently selected from H, halo, cyano, hydroxyl, —C(O)Rb1, —NRa1Ra2, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, C1-4haloalkoxyl, C3-10cycloalkyl, 3-8 membered heterocyclyl, C6-10aryl, and 5-6 membered heteroaryl;
• wherein each C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, C1-4haloalkoxyl, C3-10cycloalkyl, 3-8-membered heterocyclyl, C6-10aryl, and 5-6 membered heteroaryl is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NRa1Ra2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxyl, and C3-6cycloalkyl;
• or
• two R10 either attached to the same or adjacent atoms form C3-12cycloalkyl or 3-10 membered heterocyclyl;
• wherein each C3-12cycloalkyl and 3-10 membered heterocyclyl is optionally substituted with one to three groups independently selected from H, halo, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, and C1-4haloalkoxyl;
• each R11 is independently selected from H, C1-4alkyl, and C1-4haloalkyl;
• wherein each C1-4alkyl, —C(O)Rb1, and C1-4haloalkyl of R11 is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NRa1Ra2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxyl, and C3-6cycloalkyl;
• or
• R10 and R11, or two R11 together with the atoms to which they are attached to form 3-12 membered heterocyclyl;
• wherein 3-12 membered heterocyclyl is optionally substituted with one to three groups independently selected from H, halo, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, and C1-4haloalkoxyl;
• each Ra1 and Ra2 is independently selected from H, C1-6alkyl, and C1-6haloalkyl;
• p is selected from 1, 2, and 3;
• m is selected from 0, 1, and 2;
• v is selected from 1 and 2;
• provided that the ring formed by Y and Z is not one of
• wherein * indicates a point of attachment to R1;
• and
• at least one pharmaceutically acceptable carrier.