Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension

A method for treating a disease or disorder mediated by the PDGF receptor, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• A is
• R1 is C1-C4 alkyl;
• C1-C4 alkoxy optionally substituted by one or more halogen atoms;
• CN;
• or halogen;
• R1a is H, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
• X is N or CH;
• R2 is H;
• C1-C8 alkyl optionally substituted by one or more OH, —NR9R11 or C1-C4 alkoxy;
• C1-C8 haloalkyl;
• C2-C8 alkynyl substituted by one or more halogen, OH, —NR9R11 or C1-C4 alkoxy;
• C3-C10 cycloalkyl;
• —(C1-C4 alkyl)-C3-C8 cycloalkyl;
• C1-C8 alkoxy optionally substituted by one or more halogen, —NR9R11 or OH;
• OH;
• CN;
• halogen;
• —(C0-C4 alkyl)-NR9R11;
• —(C0-C4 alkyl)-CO2R15;
• —(C0-C4 alkyl)-C(O)NR9R11;
• —(C0-C4 alkyl)-C6-C14 aryl;
• or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl;
• wherein the cycloalkyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl are each optionally substituted by one or more Za substituents;
• R3 is H;
• C1-C8 alkyl optionally substituted by one or more OH, —NR9R11 or C1-C4 alkoxy;
• C1-C8 haloalkyl;
• C2-C8 alkynyl substituted by one or more halogen, OH, —NR9R11, or C1-C4 alkoxy;
• C3-C10 cycloalkyl;
• —(C1-C4 alkyl)-C3-C8 cycloalkyl;
• C1-C8 alkoxy optionally substituted by one or more halogen, —NR9R11 or OH;
• OH;
• CN;
• halogen;
• —(C0-C4 alkyl)-NR9R11;
• —(C0-C4 alkyl)-CO2R15;
• —(C0-C4 alkyl)-C(O)NR9R11;
• —(C0-C4 alkyl)-C6-C14 aryl;
• or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl;
• wherein the cycloalkyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 heterocyclyl are each optionally substituted by one or more Za substituents;
• each Za is independently OH;
• (C0-C4 alkyl)-C6 aryl;
• O—C6 aryl;
• C1-C4 alkyl optionally substituted by one or more OH, CN or —NR19aR21a;
• C1-C4 haloalkyl;
• C1-C4 alkoxy optionally substituted by one or more OH, —CO2R19a, —NR19aR21a or C1-C4 alkoxy;
• —NR18aC(O)R21a;
• —C(O)NR19aR21a;
• —NR18aC(O)NR19aR21a;
• NR19aR21a;
• —(C0-C4 alkyl)-C(O)OR18a;
• —(C0-C4 alkyl)-C(O)R19a;
• oxo;
• CN;
• NO2;
• halogen;
• —(C0-C4 alkyl)-4 to 6 membered heterocyclyl;
• or —O-(4 to 6 membered heterocyclyl);
• wherein the (C0-C4 alkyl)-C6 aryl, O—C6 aryl, —(C0-C4 alkyl)-4 to 6 membered heterocyclyl and —O-(4 to 6 membered heterocyclyl) are each optionally substituted by OH, halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy optionally substituted by one or more halogens;
• R4 is H;
• R5 is H, C1-C4 alkyl or C1-C4 haloalkyl;
• R6 is selected from C1-C8 alkyl optionally substituted by one or more C1-C4 alkoxy or —NR19R21;
• C1-C8 haloalkyl;
• —(C0-C4alkyl)-C3-C8cycloalkyl;
• C1-C8alkoxy optionally substituted by one or more halogen atoms;
• —NR19R21;
• —(C0-C4 alkyl)-C6-C14aryl;
• and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl;
• wherein the —(C0-C4alkyl)-C3-C8cycloalkyl, —(C0-C4 alkyl)-C6-C14aryl and —(C0-C4 alkyl)-3 to 14 heterocyclyl are each optionally substituted by one or more Z substituents;
• each Z is independently selected from (C0-C4 alkyl)-C6 aryl;
• O—C6 aryl;
• C1-C6 alkyl optionally substituted by one or more C1-C6 alkoxy, CN or —NR19R21;
• C1-C6 haloalkyl;
• C1-C6 alkoxy optionally substituted by one or more —NR19R21 or C1-C4 alkoxy;
• —NR19R21;
• (C0-C4 C4 alkyl)-C(O)R19;
• CN;
• halogen and (C0-C4 alkyl)-4 to 6 membered heterocyclyl;
• and wherein the aryl and heterocyclyl are each optionally substituted by one or more halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy optionally substituted by one or more halogens;
• R9 and R11 are each independently selected from H;
• C1-C6 alkyl optionally substituted by one or more C1-C4 alkoxy or OH;
• C1-C6 haloalkyl;
• —(C0-C1alkyl)-C3-C6 cycloalkyl;
• (C0-C4 alkyl)-C6-C14aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen;
• and (C0-C4 alkyl)-3- to 14-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl;
• or
• R9 and R11 together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH;
• halogen;
• phenyl, 5- to 10-membered heterocyclyl;
• C1-C6 alkyl;
• C1-C6 haloalkyl;
• C1-C6 alkoxy optionally substituted by one or more OH or C1-C4 alkoxy;
• and C(O)OC1-C6alkyl;
• wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• R15 is selected from H;
• C1-C8 alkyl;
• C1-C8 haloalkyl;
• C3-C10 cycloalkyl;
• (—C1-C4alkyl)-C3-C8 cycloalkyl;
• —(C0-C4 alkyl)-C6-Ci4aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl group;
• wherein the C3-C10 cycloalkyl, (—C1-C4alkyl)-C3-C8 cycloalkyl, —(C0-C4 alkyl)-C6-C14aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl groups are each optionally substituted by one or more Z substituents;
• R18a is independently H or C1-C6 alkyl;
• R19a and R21a are each independently H;
• C1-C6 alkyl optionally substituted by one or more C1-C4 alkoxy, —NR22R23′, or OH;
• C1-C6 haloalkyl;
• —(C0-C1alkyl)-C3-C6cycloalkyl;
• —(C0-C4 alkyl)- C6-C14aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen;
• or —(C0-C4 alkyl)-3- to 14-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl;
• or
• R19a and R21a together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH;
• halogen;
• phenyl;
• 5- to 10-membered heterocyclyl;
• C1-C6 alkyl;
• C1-C6 haloalkyl;
• C1-C6 alkoxy optionally substituted by one or more OH or C1-C4 alkoxy;
• and C(O)OC1-C6alkyl;
• wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• R18 is independently H or C1-C6 alkyl;
• R19 and R21 are each independently C1-C6 alkyl optionally substituted by one or more C1-C4 alkoxy;
• C1-C6 haloalkyl;
• —(C0-C1alkyl)-C3-C6cycloalkyl;
• —(C0-C4 alkyl)-C6-C14aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen;
• or —(C0-C4 alkyl)-3- to 14-membered heterocyclyl, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl and —C(O)C1-C6 alkyl;
• or
• R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from halogen;
• phenyl;
• 5- to 10-membered heterocyclyl;
• C1-C6 alkyl;
• C1-C6 haloalkyl;
• C1-C6 alkoxy optionally substituted by one or more C1-C4 alkoxy and C(O)OC1-C6alkyl;
• wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by a substituent selected from C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy;
• and
• R22 and R23 are each independently H or C1-C6 alkyl;
• wherein the disease or condition is asthma, allergic rhinitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, type I diabetes or type II diabetes.