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EP-4212523-B1 - PYRAZOLE AMIDE COMPOUNDS AS IRAK INHIBITORS

EP4212523B1EP 4212523 B1EP4212523 B1EP 4212523B1EP-4212523-B1

Inventors

  • TSO, KIN
  • CHEN, YAN
  • YEN, ROSE
  • TAYLOR, VANESSA
  • HECKRODT, THILO
  • SINGH, RAJINDER
  • SHAW, SIMON
  • LI, HUI

Dates

Publication Date
20260506
Application Date
20171025

Claims (14)

  1. A compound having a structure according to formula 2 or a salt thereof, wherein: ring A is 6-membered heterocycloaliphatic; R 1 is H or C 1-6 alkyl; R 2 is H, aliphatic, heteroaliphatic, or heterocyclyl; each of R 5 , R 6 , and R 7 independently is H or C 1-6 alkyl; and R 4 is pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, indolyl, furanyl, or pyrrolopyridinyl.
  2. The compound of claim 1, wherein R 2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic.
  3. The compound of claim 1, wherein R 2 is H, CH 3 ,
  4. The compound of any one of claims 1-3, wherein R 1 is H.
  5. The compound of any one of claims 1-4, wherein each of R 5 , R 6 , and R 7 is H.
  6. The compound of any one of claims 1-5, wherein R 4 is pyridinyl.
  7. The compound of any one of claims 1-5, wherein: y is 0, 1 or 2; and each R p independently is -CH 3 , -OCH 3 , -NH 2 , -CF 3 , F, -CN,
  8. The compound of any one of claims 1-7, wherein ring A is piperidin-1-yl, or morpholino.
  9. The compound of claim 1, selected from: I-73: N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-74: N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-76: 5'-methyl-N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; or I-77: 5'-methyl-N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide.
  10. A composition, comprising a compound of any one of claims 1-9, and a pharmaceutically acceptable excipient.
  11. A compound according to any one of claims 1-9, or a composition of claim 10, for use in a method of treatment of a disease or condition.
  12. The compound or composition for use according to claim 11, wherein the disease or condition is a disease or condition for which an IRAK inhibitor is indicated.
  13. The compound or composition for use according to claim 12, wherein the disease or condition is an auto-immune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulatory disorder, a proliferative disease, or a combination thereof.
  14. The compound or composition for use according to claim 13, wherein the proliferative disease is selected from benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, colon carcinoma, colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88 driven disorder, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, chronic lymphocytic leukemia, smoldering or indolent multiple myeloma; preferably wherein the proliferative disease is a hematological malignancy; more preferably wherein the hematological malignancy is selected from leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma; more preferably still, wherein the hematological malignancy is a myelodysplastic syndrome.

Description

FIELD This disclosure concerns amide compounds, and embodiments of a method for making and using the compounds, such as for inhibiting interleukin receptor-associated kinase (IRAK), and for treating diseases and conditions related to IRAK. BACKGROUND Interleukin-1 receptor-associated kinases (IRAKs) are important mediators of signaling processes, such as toll-like receptors (TLR) and interleukin-1 receptor (IL-1R) signaling processes. IRAKs have been implicated in modulating signaling networks that control inflammation, apoptosis, and cellular differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), and studies have revealed distinct, non-redundant biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity. WO2015/068856 discloses IRAK inhibitors. SUMMARY The invention is as defined in the claims. Accordingly, the invention provides a compound having a formula 2 or a salt thereof, wherein: ring A is 6-membered heterocycloaliphatic;R1 is H or C1-6alkyl;R2 is H, aliphatic, heteroaliphatic, or heterocyclyl;each of R5, R6, and R7 independently is H or C1-6 alkyl; andR4 is pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, indolyl, furanyl, or pyrrolopyridinyl. The invention also provides a composition comprising a compound as defined above, and a pharmaceutically acceptable excipient. The claimed compounds represent a subclass within the group of compounds having a formula 1 and/or a salt thereof. Formula 1 is included for reference purposes. A person of ordinary skill in the art will appreciate that compounds within formula 1 also can be solvates, including hydrates, N-oxides thereof. With reference to formula 1, ring A is aromatic or heterocycloaliphatic. Ring A may be aryl, heteroaryl, 5-membered heterocycloaliphatic, or 6-membered heterocycloaliphatic, such as phenyl, pyridinyl, pyrazinyl, pyrrolidinyl, piperidinyl, or morpholino, and in certain embodiments, ring A is heteroaryl, 5-membered heterocycloaliphatic, or 6-membered heterocycloaliphatic, such as pyridinyl, pyrazinyl, pyrrolidinyl, piperidinyl, or morpholino. In particular embodiments, ring A is pyridin-2-yl. In other examples, ring A is where X is a bond, O, or CH2, such as and where each Q independently is CH, CRm or N, Rm is Rb, and x is 0, 1, or 2. In some embodiments, at least one Q is N. Rb is independently for each occurrence -OH, -CF3, -CN, -ORc, -SO2Rc, -NRdRd, -N(H)SO2Rc, - C(O)OH, -N(H)C(O)Rc, -C(O)ORc, -C(O)NRdRd, =O, or halogen. Rc is independently for each occurrence C1-6alkyl, C3-6cycloalkyl, C3-6heteroalicyclyl, aralkyl, C1-6alkyl substituted with 1, 2 or 3 Re, C5-10aromatic, C5-10aromatic substituted with 1, 2 or 3 Re. Rd is independently for each occurrence H, C1-6alkyl optionally substituted with 1, 2 or 3 Re, C3-6cycloalkyl optionally substituted with 1, 2 or 3 Re, C3-6heteroalicyclyl optionally substituted with 1, 2 or 3 Re, C5-10aromatic optionally substituted with 1, 2 or 3 Ra or Rb, or two Rd groups together with the nitrogen bound thereto form a C3-6heteroalicyclyl moiety optionally substituted with C1-6alkyl and optionally interrupted with one or two -O- or -N(Rg) wherein Rg is R70. Ra is independently for each occurrence H, D, C1-6alkyl, C3-6cycloalkyl, C5-10aromatic, or C3-6heterocycloaliphatic. And Re is independently for each occurrence halogen, C1-6alkyl, C3-6cycloalkyl, or -ORa. R1 may be H, aliphatic, or heteroaliphatic, and in some embodiments, R1 is H or C1-6 alkyl. R2 is H, aliphatic, heteroaliphatic, or heterocyclyl, and may be H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C1-6 alkyl, or C1-6alkyl substituted with - OH, amino, alkoxy, or heterocycloaliphatic. In some embodiments, R2 is Ra, Ra substituted with Rb, Ra substituted with 1 or 2 Rc, or Ra substituted with Rd. And in particular embodiments, R2 is H, CH3, In certain embodiments of formula 1, ring A is pyridinyl, pyrazinyl, pyrrolidinyl, piperidinyl, or morpholino; R1 is H; and/or R2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C1-6 alkyl, or C1-6alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic. Also with respect to formula 1, each Z1, Z2, Z3, and Z4 independently is N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N and each R3 independently is H, aliphatic, or heteroaliphatic. R4 may be halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl. In some embodiments, the moiety is pyridinyl, pyrimidinyl, or pyrazinyl. In some examples, Z1 is N. In other examples, Z1 is N, and Z2, Z3, and Z4 are CR3; Z1 and Z2 are N, and Z3 and Z4 are CR3; Z1 and Z3 are N, and Z2 and Z4 are CR3; Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and