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CN-122029158-A - EGFR inhibitors

CN122029158ACN 122029158 ACN122029158 ACN 122029158ACN-122029158-A

Abstract

The present disclosure provides compounds represented by structural formula (a), or pharmaceutically acceptable salts thereof, useful in the treatment of cancer. (A)

Inventors

  • O. Amad
  • BARVIAN KEVIN KARL
  • CAMPBELL JOHN E.
  • T. A. Tinian
  • M. S. ino
  • D.P. Fernando
  • DOWD HARDWIN
  • V. B. Ribeiro Da Silva
  • Q. Peilong

Assignees

  • 缆图药品公司

Dates

Publication Date
20260512
Application Date
20241010
Priority Date
20231011

Claims (20)

  1. 1.A compound of formula (a): or a pharmaceutically acceptable salt thereof, wherein X is CR x or N; R x is H or F; Ring a is selected from the group consisting of azetidinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, piperidinyl, pyridinyl, piperazinyl, and pyridazinyl, wherein ring a is optionally substituted with 1 to 4 groups selected from deuterium, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy; Ring B is selected from the group consisting of cyclohexyl, phenyl, thiazolyl, isothiazolyl, thienyl, pyridinyl, benzo [ d ] imidazolyl, pyrazolo [3,4-B ] pyridinyl, wherein ring B is optionally substituted with 1 to 5 groups selected from deuterium, halo, OR a , and C 1 -C 4 alkyl, wherein said C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups selected from deuterium, halo, OH, C 1 -C 2 alkoxy, and C 1 -C 2 haloalkoxy; OR ring a is pyrazolyl, indazolyl, indolyl, benzo [ d ] isoxazolyl, OR pyrazolo [1,5-a ] pyridinyl, and ring B is absent, wherein ring a is optionally substituted with 1 to 4 groups selected from deuterium, halo, OR a , and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups selected from deuterium, halo, OH, C 1 -C 2 alkoxy, and C 1 -C 2 haloalkoxy; wherein if ring a is pyrazolyl and ring B is phenyl, then ring a-ring B is selected from: , L 1 is a bond, NH, -NHC (O) 、-NHC(O)O- O or-OC (O) Wherein- Represents the point of attachment to R 1 ; L 2 is a bond or O; R 1 is H or halo, or C 1 -C 4 alkyl OR C 2 -C 4 alkenyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a 、NR a R b 、C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein each of said heterocyclyl and said heteroaryl is optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl, OR C 3 -C 8 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl, or 5 to 12 membered heteroaryl, wherein the cycloalkyl, the phenyl, the heterocyclyl, and the heteroaryl represented by R 1 are each optionally substituted with 1 to 4 groups independently selected from R 11 ; Each R 11 is independently selected from halo, deuterium 、OR a 、C(O)R a 、C(O)NR a R b 、NR a C(O)OR a 、NR a R b 、S(O) 2 R a 、C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, 4 to 12 membered heterocyclyl, and 5 to 12 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by R 11 are each optionally substituted with 1 to 4 groups selected from deuterium, halo, C 1 -C 4 alkyl, OR a , and NR a R b , OR two R 11 attached to the same carbon atom together form =o; R 2 is H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 4 alkenyl OR C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a 、NR a R b and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C 1 -C 4 alkyl, OR R 2 is a 4 to 12 membered heterocyclyl or a 5 to 12 membered heteroaryl, wherein the heterocyclyl and the heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, C 1 -C 4 alkyl, C (O) R a and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups selected from halo, deuterium and C 1 -C 4 alkyl; Each R a is independently selected from H, deuterium, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, and 4 to 6 membered heterocyclyl; Each R b is independently selected from H, deuterium, and C 1 -C 4 alkyl; Each R c is independently selected from H, deuterium, halo, and C 1 -C 4 alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a 、NR a R b 、C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and the heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C 1 -C 4 alkyl, and R d is attached to any nitrogen atom in the pyrazole ring and is selected from H, deuterium, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and 4 to 6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl represented by R d are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a 、NR a R b and C 3 -C 6 cycloalkyl.
  2. 2. The compound of claim 1, wherein the compound is represented by one of the following structural formulas: (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (II-18), (II-19), (II-20), (II-21), (II-22), (II-23), (II-24), (II-25), (II-26), (II-27) (II-28), Or a pharmaceutically acceptable salt thereof, wherein, Each Y is CH or N; Each R a1 is selected from H, deuterium, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyclohexyl, thiazolyl, isothiazolyl, thienyl, pyridinyl, benzo [ d ] imidazolyl, and pyrazolo [3,4-b ] pyridinyl, wherein each of said cyclohexyl, said thiazolyl, said isothiazolyl, said thienyl, said pyridinyl, said benzo [ d ] imidazolyl, and said pyrazolo [3,4-b ] pyridinyl is optionally substituted with 1 to 4 groups selected from R b1 ; Each R b1 is independently selected from deuterium, halo, OR a , and C 1 -C 4 alkyl, wherein said C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups selected from deuterium, halo, OH, C 1 -C 2 alkoxy, and C 1 -C 2 haloalkoxy, and N is an integer selected from 0 to 4.
  3. 3. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is CH.
  4. 4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N.
  5. 5. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein R a1 is H, C 1 -C 4 alkyl, or is represented by the formula: 、 、 、 、 、 、 、 、 Or (b) Wherein each R b1 is independently halo or C 1 -C 4 alkyl, and n is 0 or 1.
  6. 6. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein R a1 is selected from-H, -CH 3 , 、 、 、 、 、 、 、 、 、 、 、 And 。
  7. 7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each R c is independently H, C 1-2 alkyl, C 1-2 haloalkyl, halo, or-OH.
  8. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein each R c is independently H, -CH 3 、-CF 3 , -OH, or-F.
  9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R d is attached to a nitrogen atom and is selected from H, deuterium, and C 1 -C 4 alkyl, wherein the alkyl groups represented by R d are each optionally substituted with 1 to 4 groups independently selected from halo and deuterium.
  10. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each R d is independently H or-CH 3 .
  11. 11. The compound of any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein each R b1 is selected from deuterium, halo, and C 1 -C 4 alkyl.
  12. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein each R b1 is independently-F or-Cl.
  13. 13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R b1 and the ring B to which it is attached are selected from 、 、 、 、 、 、 、 、 、 、 、 And 。
  14. 14. The compound of any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  15. 15. The compound of any one of claims 2 to 13, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  16. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein (i) L 1 is-OC (O) room And L 2 is O, (ii) L 1 is a bond and L 2 is a bond, (iii) L 1 is-NHC (O) - And L 2 is a bond, (iv) L 1 is-NHC (O) - And L 2 is O, (v) L 1 is a bond and L 2 is O, (vi) L 1 is O and L 2 is O, or (vii) L 1 is NH and L 2 is O.
  17. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 8 cycloalkyl, phenyl, 6 to 9 membered heterocyclyl, and 5 to 6 membered heteroaryl, wherein each of the cycloalkyl, the heterocyclyl, the phenyl, and the heteroaryl is optionally substituted with 1 to 3 groups independently selected from R 11 .
  18. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, halo, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, cyclopropyl, cyclobutyl, bicyclo [1.1.1] pentyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyranyl, piperazinyl, morpholinyl, and isoindolinone, wherein the cyclopropyl, the cyclobutyl, the bicyclo [1.1.1] pentyl, the phenyl, the pyrazolyl, the thiazolyl, the pyridinyl, the pyranyl, the piperazinyl, the morpholinyl, or the isoindolinone is optionally substituted with 1 to 3 groups selected from R 11 .
  19. 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from-H, -F, -CH 3 , 、 、 、 、 、 、 、 、 、 、 、 、 、 And 。
  20. 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected from halo, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with 1 to 3 groups selected from deuterium and halo.

Description

EGFR inhibitors Cross-reference to related patent applications The present application claims priority from U.S. provisional application No. 63/543,608 filed on 10/11 of 2023, the entire contents of which are incorporated herein by reference. Technical Field The present application relates to EGFR inhibitors and methods of use thereof. Background EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. EGFR can form homodimers on cell membranes by binding to its ligands, such as Epidermal Growth Factor (EGF), or heterodimers with other receptors in the family, such as erbB2, erbB3, or erbB 4. The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating many downstream signaling pathways in the cells. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis. Disorders of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and alterations such as mutations, deletions, etc., can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, alterations, such as mutations and deletions, of the EGFR gene are found in non-small cell lung cancer (NSCLC) tumors. The two most common EGFR changes found in NSCLC tumors are the short in-frame deletion in exon 19 (del 19), and the single missense mutation in L858R, exon 21 (Cancer discover 2016 6 (6) 601). These two changes are called priming mutations, which cause ligand independent EGFR activation, and are called primary or activating mutations in EGFR mutant NSCLC (EGFR m+). Clinical experience has shown that in EGFR M+NSCLC patients treated first-line (1L) with EGFR Tyrosine Kinase Inhibitors (TKI) erlotinib, gefitinib, afatinib and Organinib, the Objective Remission Rate (ORR) is about 60% to 85% (Lancet Oncol. 2010 Vol. 11, 121; lancet Oncol. 2016 Vol 17, 577; N.Engl. J. Med. 2017, 11 th 18 Doi:10.1056/NEJMoa1713137; lancet Oncol. 2011, vol. 12, 735), thus demonstrating that EGFR mutant NSCLC tumors survive and proliferate depending on oncogenic EGFR activity, and establishing del19 and L858R mutated EGFR as oncogenic drivers of the disease, thereby validating drug targets and biomarkers for the treatment of NSCLC. Ornitinib is a covalent third (3 rd) generation EGFR TKI, which has been approved as a first line (1L) standard treatment (SOC) for the treatment of NSCLC carrying del19 and L858R mutations. Progression Free Survival (PFS) was 18.9 months (JC Soria et al-NEJM, 1 month 2018; 378 (2): 113-125), which was shown to give patients an revolutionary result compared to the first generation TKI. However, resistance was observed in almost all NSCLC patients following an average of 10 to 12 months of treatment (Lancet Oncol. 2 months 2010; 11 (2): 121-8.; lancet Oncol. 2016, 5 months; 17 (5): 577-89; lancet Oncol. 2011, 8 months; 12 (8): 735-42). Additional 3 rd generation TKIs are in front of line use (e.g., RASER tinib) and rely on the same covalent mechanism of binding to EGFR. The most prominent targeting drug resistance mechanism is due to the secondary mutation of C797X in EGFR (where "X" may be "S" or "G" or "N" or "Y" or "T" or "D"), which occurs in 7% to 22% of patients who develop disease after the anterior line of 3 rd generation EGFR inhibitors (Blakely, 2012; kobayashi, 2005). This secondary C797S mutation reduces the affinity of the drug to the target, thereby creating resistance and leading to tumor recurrence or disease progression. The resulting "double mutant" tumors carry the priming mutation del19 or L858R and the drug resistance mutation C797X (e.g., C797S), which is no longer sensitive to the 2 nd and 3 rd generation TKIs. There is currently no approved drug for the treatment of double mutant patients. Generation 1 TKIs (gefitinib and erlotinib) are active on C797X (e.g., C797S), but they are poorly tolerated due to the activity associated with wild-type EGFR inhibition and are unable to control brain disease due to their low ability to cross the Blood Brain Barrier (BBB). There is an unmet need for selective therapeutic agents for the treatment of double mutant tumors that are brain permeable and can treat brain diseases, and have reduced toxicity (diarrhea, rash) associated with wild-type EGFR inhibition. Disclosure of Invention Applicants have discovered novel compounds that are potent inhibitors of certain mutant forms of EGFR (see synthesis examples 1-92). In particular, compounds of the present disclosure have been shown to be effective in inhibiting certain mutant forms of EGFR. The compounds of the present disclosure (also referred to herein as "disclosed compounds") or pharmaceutically acceptable salts thereof are effective in inhibiting EGFR with one or more alterations, including L858R or exon 19