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EP-4735112-A1 - NEW TREATMENTS FOR PAIN

EP4735112A1EP 4735112 A1EP4735112 A1EP 4735112A1EP-4735112-A1

Abstract

New Treatments for Pain The Application describes new SOS1 inhibitors for use in the treatment of pain and cancer.

Inventors

  • MENEAR, KEITH

Assignees

  • Sevenless Therapeutics Limited

Dates

Publication Date
20260506
Application Date
20240628

Claims (12)

  1. Claims 1. A Compound of formula (I) Or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N or CR 25 R 1 is selected from a N containing 4-7 membered saturated heterocycle, optionally containing an additional O, N or S atom, or S(O) 2 moiety. Said heterocycle optionally containing: (i) an ether bridge, or (ii) joining another 4-7membered, N containing, saturated heterocycle to form a spiro bicyclic group; or (iii) joining with another 3-6 membered N containing saturated heterocycle, such that the rings share two atoms in common, said saturated heterocycle optionally incorporating a C(O) moiety; said monocyclic or bicyclic heterocycle optionally substituted by 1-3 substituents, each independently selected from NC(O)C 1-6 alkyl, H, N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl, C(O)C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, OH and O-C 1-6 alkyl , HC(O)C 1-6 alkyl, halo and Ph. R 2 is selected from R 3 is H or NH 2 R 4 is CF 3 , CF 2 CH 2 OH, CN R 5 is halo R 6 is H R 7 is H R 8 is Ph, ortha substituted by CH 2 NHCH 3 R 25 is selected from H, OCH 3 , F and CN 2. A compound according to claim 1 wherein R 2 is R 3 is H or NH 2 R 4 is CF 3 , CF 2 CH 2 OH, CN R 5 is F
  2. 3. A compound according to claim 1 wherein R 2 is R 6 is H R 7 is H R 8 is Ph, ortha substituted by CH 2 NHCH 3 4. A compound according to claims 1-3 wherein R 1 is selected from:
  3. And NR 17 R 18 , Wherein R 10 is selected from NC(O)C 1-6 alkyl, H, N(C 1-6 alkyl)(C 1-6 alkyl) R 11 is selected from C 1-6 alkyl, C(O)C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, OH and O-C 1-6 alkyl R 12 is selected from NHC(O)C 1-6 alkyl, C 1-6 alkyl, H R 13 is selected from NHC(O)C 1-6 alkyl, C 1-6 alkyl, H R 14 is selected from halo, OH, OC 1-6 alkyl, H R 15 is selected from halo, OH, OC 1-6 alkyl, H R 16 is selected from C(O)C 1-6 alkyl R 17 is selected from C 1-6 alkyl, H, Ph R 18 is selected from C 1-6 alkyl, H, Ph R 19 is selected from C(O)C 1-6 alkyl R 20 is OH R 21 is selected from CH 3 or H R 22 is selected from C 1-6 alkyl, H, C(O)C 1-6 alkyl and C(O)NHC 1-6 alkyl R 23 is selected from C 1-6 alkyl and H R 24 is C(O)C 1-6 alkyl 5. A compound according to claim 4 wherein R 1 is selected from:
  4. And NR 17 R 18 , Wherein R 10 is selected from NC(O)CH 3 , H, N(CH 3 ) 2 R 11 is selected from CH 3 , C(O)CH 3 , CH 2 -OCH 3 , OH, R 12 is selected from NHC(O)CH 3 , CH 3 , H. R 13 is selected from NHC(O)CH 3 , CH 3 , H. R 14 is selected from F, OH and H. R 15 is selected from F, OH and H. R 16 is selected from C(O)CH 3 R 17 is selected from CH 3 , H & Ph R 18 is selected from CH 3 , H & Ph R 19 is selected from C(O)CH 3 R 20 is OH
  5. R 21 is selected from CH 3 or H R 22 is selected from CH 3 , H, C(O)CH 3 and C(O)NHCH 3 R 23 is selected from CH 3 and H R 24 is C(O)CH 3 6. A compound according to claim 5 wherein R1 is selected from R14 is H R 15 is OH
  6. 7. A compound according to any preceeding claim wherein X is N or CR 25 , wherein R 25 is H.
  7. 8. A compound according to claims 1-7 for use as a medicament
  8. 9. Use of a compound according to claims 1-7 in the treatment of pain
  9. 10. Use according to claim 9 wherein pain includes acute pain, chronic pain, inflammatory pain, nociceptive pain, neuropathic pain, hyperalgesia, allodynia, central pain, cancer pain, post-operative pain, visceral pain, musculo-skeletal pain, heart or vascular pain, head pain, orofacial pain and back pain.
  10. 11. Use of a compound according to claims 1-7 in the treatment of cancer.
  11. 12. Use according to claim 11 wherein cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.
  12. 13. Use of a compound according to claims 1-7 for the treatment of neurofibromatosis.

Description

New treatments for Pain The present invention describes compounds that bind to the Son of Sevenless homolog 1 receptor (SOS1) protein thereby inhibiting a cascade pathway, leading to a reduction in pain. There remains a need for novel treatments for the treatment of pain. Many of the most efficacious and frequently prescribed pain treatments are opioids. These drugs have a high potential for abuse and addiction. However, to date there are no treatments of comparable efficacy to replace them as front-line treatments. To provide a paradigm shift in the treatment of pain requires the identification of new targets and pathways within the body. This application describes novel SOS1 inhibitors suitable for the treatment of Pain and cancer. SOS1 inhibitors have recently been identified capable of mediating several conditions: WO2019/122129 describes benzylamino substituted pyridopyrimidines as SOS1 inhibitors useful in the treatment of cancerous growth in oncology. WO2018/115380 describes benzylamino substituted quinazolines as SOS1 inhibitors, similarly useful in the treatment of cancerous growth in oncology. WO2018/172250 describes a genus of 2 methyl quinazolines for use in treating hyper- proliferative diseases. WO2019/201848 describes a further genus of 2 methyl quinazolines for use in treating hyper-proliferative diseases. Further SOS1 inhibitors are taught in Proceedings of the National Academy of Sciences of the United States of America (2019), 116(7), 2551-2560. The present invention provides novel SOS1 inhibitors, novel SOS1 inhibitors for use in the treatment of Pain and novel SOS1 inhibitors for use in the treatment of cancer. Figures Fig 1. NGF signal transduction pathway leading to pain and the clinical drugs that validate the pathway. NGF binds to TrkA and subsequent signal transduction culminates in the nuclear accumulation of diphopshorylated Extracellular signal-regulated kinase (dppERKnuc) in neurons, upregulating pain genes. Fig 2. Clinical genetic validation of the target. In NF1, patients have a mutation in the neuronal gap protein (NF1). The mutation causes a loss of function, preventing the normal turnover of GTP on RASGTP to GDP in turn increasing the concentration of RASGTP and leading to excess signalling, tumours and pain. Summary of invention This application describes novel SOS1 inhibitors, their use to treat pain and their use to treat cancer. The present invention provides compounds of formula (I) Or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N or CR25 R1 is selected from a N containing 4-7 membered saturated heterocycle, optionally containing an additional O, N or S atom, or S(O)2 moiety. Said heterocycle optionally containing: (i) an ether bridge, or (ii) joining another 4-7membered, N containing, saturated heterocycle to form a spiro bicyclic group; or (iii) joining with another 3-6 membered N containing saturated heterocycle, such that the rings share two atoms in common, said saturated heterocycle optionally incorporating a C(O) moiety; said monocyclic or bicyclic heterocycle optionally substituted by 1-3 substituents, each independently selected from NC(O)C1-6 alkyl, H, N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C(O)C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl, OH and O-C1-6 alkyl , HC(O)C1-6 alkyl, halo and Ph. R2 is selected from R3 is H or NH2 R4 is CF3, CF2CH2OH, CN R5 is halo R6 is H R7 is H R8 is Ph, ortha substituted by CH2NHCH3 R25 is H, OCH3, F and CN The present invention provides SOS1 inhibitors for use in the treatment of Pain. The present invention provides SOS1 inhibitors for use in the treatment of Cancer. The present invention provides novel compounds, uses of the compounds as medicaments, pharmaceutical compositions and pharmaceutical products as set out in the appended claims. Other features of the invention will be apparent from the dependent claims, and the description that follows. Unless otherwise stated, the following terms used in the specification and claims have the meanings set out below. The term “comprising” or “comprises” means including the component(s) specified but not to the exclusion of the presence of other components. The term “consisting essentially of” or “consists essentially of” means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention. The term “consisting of” or “consists of” means including the components specified but excluding other components. Whenever appropriate, depending upon the context, the use of the term “comprises” or “comprising” may also be taken to include the meaning “consists essentially of” or “consisting essentially of”, and may also be taken to include the meaning “consists of” or “consisting of”. The optional features set out herein may be used either i