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EP-4164634-B1 - 6-(PHENYL)-N-(1-((1-(5-(2-OXO-3-AZABICYCLO[3.1.0]HEXAN-3-YL)PYRIMIDIN-2-YL)ETHYL)-1H-PYRAZOL-4-YL)PYRAZINE-2-CARBOXAMIDE DERIVATIVES AS PLASMA KALLIKREIN INHIBITORS FOR THE TREATMENT OF E.G. IMPAIRED VISUAL ACTIVITY

EP4164634B1EP 4164634 B1EP4164634 B1EP 4164634B1EP-4164634-B1

Inventors

  • JABRI, SALMAN
  • LANG, Simon, B.
  • TAOKA, BRANDON, M.
  • TIAN, Maoqun
  • SHEARN-NANCE, Galen, Paul
  • KUANG, RONGZE
  • LOMBARDO, Matthew, J.
  • WU, ZHICAI
  • ZHAO, ZHIQIANG
  • OGAWA, Anthony, Ken
  • SINZ, Christopher, J.
  • HICKS, JACQUELINE, D.
  • CHENG, ALAN, C.
  • GAO, YING-DUO
  • YANG, SONG
  • BAO, JIANMING
  • HAYES, Donna, A., A., W.

Dates

Publication Date
20260513
Application Date
20210610

Claims (17)

  1. A compound of the formula: wherein is selected from or is selected from V is CH or N; X is CH or N; Y is N, NO, NR x or C=O; Z is NR 4 or CR 4 ; E is N or CH; Q is N or CH; G is N or CR 7 ; J is N or CR 7 ; L is N or CR 7 ; M is N or CR 8 ; R 1 is selected from the group consisting of hydrogen, halo, cyano, R x , OR x and SO 2 R x ; R 2 is hydrogen or halo; R 3 is hydrogen or halo; R 4 is hydrogen, R x , OR x , C 1-3 alkyl-OR x , C 1-3 alkyl-O-C 3-6 cycloalkyl or CH=CH 2 ; R 5 is hydrogen or C 1-3 alkyl, which is optionally substituted with one to three substituents selected from halo and hydroxy; R 6 is hydrogen or C 1-3 alkyl; or R 5 and R 6 can be taken together with the carbon atom between them to form a C 3-6 cycloalkyl group; each R 7 is independently selected from the group consisting of halo, R x , OR x , C 1-3 alkyl-OR x , NH(C=O)OR x and NH 2 ; R 8 is selected from the group consisting of R x or OR x ; or R 7 and R 8 can be taken together with the carbon atoms between them to form a 5-membered cycloalkyl or heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one to two substituents independently selected from the group consisting of halo, methyl and ethyl; R 9 is hydrogen or C 1-3 alkyl; R 10 is hydrogen, hydroxy or C 1-3 alkyl; R x is hydrogen or C 1-6 alkyl, which is optionally substituted with one to four substituents selected from halo and hydroxy; or a pharmaceutically acceptable salt thereof.
  2. The compound of Claim 1 wherein E is CH and Z is CH; or a pharmaceutically acceptable salt thereof.
  3. The compound of Claim 1 or 2 wherein wherein is or a pharmaceutically acceptable salt thereof.
  4. The compound of any of Claims 1-3 wherein R1 is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OCHF2 and SO2CH3; or a pharmaceutically acceptable salt thereof.
  5. The compound of any of Claims 1-4 wherein R4 is selected from the group consisting of cyano, CH3, CHF2, CH2OH, CH2OCH3, CH2OC(CH3)3, CH2O(cyclopropyl), CH(OH)CF3, CH2C(CH3)2OH, CD2OH, CH(CH3)OH and OCH3; or a pharmaceutically acceptable salt thereof.
  6. The compound of any of Claims 1-5 wherein R5 is hydrogen, CH3 or CH2OH; or a pharmaceutically acceptable salt thereof.
  7. The compound of any of Claims 1-6 wherein X is N; Y is N; V is CH; or a pharmaceutically acceptable salt thereof.
  8. The compound of any of Claims 1-7 wherein each R7 is independently selected from the group consisting of hydrogen, chloro, fluoro, CH3, OCH3, CHF2, OCHF2, CH2OH, NH2 and NH(C=O)ORx; or a pharmaceutically acceptable salt thereof.
  9. The compound of Claim 1 selected from any one of compounds 1-255, or a pharmaceutically acceptable salt thereof.
  10. A pharmaceutical composition comprising a compound of any one of Claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  11. A compound according to any one of claims 1-9 or a composition according to claim 10 for use in a method for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal.
  12. A compound according to any one of claims 1-9 or a composition according to claim 10 for use in a method for treating uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal, preferably for use in a method of treating diabetic retinopathy or diabetic macular edema, optionally for use in a method of treating retinal vein occlusion.
  13. The compound according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in therapy.
  14. The composition of Claim 10 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  15. The compound for use or the composition for use according to Claim 11, the method further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  16. A combination comprising a compound according to any one of Claims 1-9, or a pharmaceutically acceptable salt thereof, and one or more additional pharmacologically active agents.
  17. A combination comprising a compound according to any one of Claims 1-9, or a pharmaceutically acceptable salt thereof, and one or more additional pharmacologically active agents for use in therapy.

Description

BACKGROUND OF THE INVENTION Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Proteolyticactivation by factor XIIa at an internal I 389-R390 bond yields a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors, including alpha 2 macroglobulin and Cl-inhibitor. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight kininogen (HMWK). In blood, the majority of plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cleaves HMWK to liberate bradykinin. Bradykinin release results in increase of vascular permeability and vasodilation (for review, Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier A.H., "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). Patients presenting genetic deficiency on C1-esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling throughout the body, including the hands, feet, face, throat, genitals and gastrointestinal tract. Analysis of blisters arising from acute episodes have been shown to contain high levels of plasma kallikrein, and treatment with a protein-based reversible plasma kallikrein inhibitor, Ecallantide (Kalbitor), has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J.Allergy Clin.Immunol., 120: p.416 (2007)). Additionally, the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that plasma kallikrein contributes to observed retinal vascular leakage and dysfunction in diabetic rodent models (A. Clermont, et al., Diabetes, 60:1590 (2011)), and that treatment with a small molecule plasma kallikrein inhibitor ameliorated the observed retinal vascular permeability and other abnormalities related to retinal blood flow. It would be desirable in the art to develop plasma kallikrein inhibitors having utility to treat a wide range of disorders, including hereditary angioedema, diabetic macular edema and diabetic retinopathy. US 2019/218205; Z. Xie et al., Eur. J. Med. Chem., 2020, 190, 112137; WO 2013/111108; and US 10329260 B2 each disclose plasma kallikrein inhibitors. SUMMARY OF THE INVENTION The present invention relates to compounds of Formula I: and pharmaceutically acceptable salts thereof. The compounds of Formula I are inhibitors of plasma kallikrein, and as such may be useful in the treatment, inhibition or amelioration of one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof. The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of Formula I: wherein is selected from or is selected from V is CH or N;X is CH or N;Y is N, NO, NRx or C=O;Z is NR4 or CR4;E is N or CH;Q is N or CH;G is N or CR7;J is N or CR7;L is N or CR7;M is N or CR8;R1 is selected from the group consisting of hydrogen, halo, cyano, Rx, ORx and SO2Rx;R2 is hydrogen or halo;R3 is hydrogen or halo;R4 is hydrogen, Rx, ORx, C1-3 alkyl-ORx, C1-3 alkyl-O-C3-6 cycloalkyl or CH=CH2;R5 is hydrogen or C1-3 alkyl, which is optionally substituted with one to three substituents selected from halo and hydroxy;R6 is hydrogen or C1-3 alkyl;or R5 and R6 can be taken together with the carbon atom between them to form a C3-6 cycloalkyl group;each R7 is independently selected from the group consisting of halo, Rx, ORx, C1-3 alkyl-ORx, NH(C=O)ORx and NH2;R8 is selected from the group consisting of Rx or ORx;or R7 and R8 can be taken together with the carbon a