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WO2024229087A1 - Inhibiteurs d'egfr pour le traitement d'une maladie - Google Patents

Inhibiteurs d'egfr pour le traitement d'une maladie Download PDF

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Publication number
WO2024229087A1
WO2024229087A1 PCT/US2024/027195 US2024027195W WO2024229087A1 WO 2024229087 A1 WO2024229087 A1 WO 2024229087A1 US 2024027195 W US2024027195 W US 2024027195W WO 2024229087 A1 WO2024229087 A1 WO 2024229087A1
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Prior art keywords
alkyl
membered heterocycloalkyl
pharmaceutically acceptable
compound
acceptable salt
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PCT/US2024/027195
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English (en)
Inventor
Jingrong Jean Cui
Eugene Yuanjin Rui
Evan W. ROGERS
Anindya SARKAR
Dayong Zhai
Wei Deng
Jane Ung
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Blossomhill Therapeutics Inc
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Blossomhill Therapeutics Inc
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Priority to AU2024266587A priority Critical patent/AU2024266587A1/en
Publication of WO2024229087A1 publication Critical patent/WO2024229087A1/fr
Priority to IL324276A priority patent/IL324276A/en
Priority to MX2025013034A priority patent/MX2025013034A/es
Anticipated expiration legal-status Critical
Priority to CONC2025/0016647A priority patent/CO2025016647A2/es
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • EGFR INHIBITORS FOR TREATING DISEASE RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 63/463,498, filed May 2, 2023, U.S. Provisional Application No. 63/627,624, filed January 31, 2024, and U.S. Provisional Application No.63/636,734, filed April 20, 2024, the entire disclosures of all of which are incorporated herein by reference.
  • TECHNICAL FIELD [0002] The present disclosure relates to compounds targeting kinases such as EGFR, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.
  • Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli.
  • the human genome encodes approximately 518 protein kinases (Manning G, et al., The protein kinase complement of the human genome. Science.2002, 298:1912–34).
  • Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A., Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462–469).
  • the molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29).
  • the critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molecule kinase inhibitors have been approved and 55 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463).
  • kinase inhibitors have achieved dramatic success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment.
  • Non-small-cell lung cancer is the leading cause of cancer mortality worldwide (World Health Organisation.
  • the first-generation reversible EGFR inhibitors, erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this setting.
  • advanced EGFR mutation-positive (Del19 or L858R) NSCLC have been used as first-line standard of care in this setting.
  • most patients will develop resistance to gefitinib or erlotinib with 50% to 70% of tumors developing EGFR T790M gatekeeper mutation with time of treatment (Sequist LV, et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26).
  • EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D, et al., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9:5641-53).
  • afatinib and dacomitinib are more potent EGFR inhibitors approved as first- line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression free survival time (PFS) in comparison with gefitinib and erlotinib
  • PFS progression free survival time
  • EGFR T790M has been developed with time of treatment with afatinib (Tanaka K, et al., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30).
  • EGFR T790M confers resistance to dacomitinib In vitro studies (Kobayashi Y, et al., EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31).
  • the third-generation EGFR inhibitor Osimertinib is also an irreversible inhibitor targeting both EGFR activating mutations (Del19 and L858R) and T790M resistant double mutations, with selectivity over the wild-type EGFR (Finlay MR, et al., Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67).
  • Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and later approved in the first-line setting for patients with EGFR mutation-positive NSCLC following the phase III FLAURA trial with head-to-head trials comparing with erlotinib or gefitinib (Soria JC, et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25).
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, m, n, p, and q are as described herein.
  • the disclosure relates to a compound of the formula II, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, [0011] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, m, n, p, and q are as described herein.
  • the disclosure relates to a compound of the formula III, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, [0013] wherein X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, p, and q are as described herein.
  • the disclosure relates to a compound of the formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, [0015] wherein X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, and B are as described herein.
  • the compound of Formula (I)-(IV) is a compound selected from those species described or exemplified in the detailed description below.
  • the disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I)-(IV) or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.
  • Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.
  • the disclosure relates to a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, for use as a medicament.
  • the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.
  • the disclosure relates to use of a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.
  • the disclosure relates to a method of inhibiting a tyrosine kinase, such as EGFR, including the certain mutations as described herein, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound of Formula (I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • each R 1 and R 2 when present, is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -S(O)2NR a R b , -S(O)2NR a R b , -S(O)2NR a R
  • each “ ” is independently a carbon-carbon single bond or a carbon-carbon double bond;
  • each “ ” represents a point of covalent attachment; [0055] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.
  • ring A is selected from the group consisting of [0057] [0058] wherein each “ ” represents a point of covalent attachment; [0059] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.
  • ring A is selected from the group consisting of
  • each “ ” represents a point of covalent attachment; [0062] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [0063] 9. The compound of any one of clauses 1 to 4 or 6, wherein ring B is selected from the group consisting of
  • each “ ” represents a point of covalent attachment; [0065] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [0066] 10. The compound of any one of the preceding clauses, wherein ring B is selected from the group consisting of [0067] wherein each “ ” represents a point of covalent attachment; [0068] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [0069] 11.
  • each R 3 and R 4 is independently H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a
  • R 3 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f ,
  • each “ ” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium; [0091] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [0092] 21. The compound of any one of the preceding clauses, wherein R 8 is H or C 1 -C 6 alkyl; [0093] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [0094] 22.
  • DETAILED DESCRIPTION [0106]
  • each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure.
  • A-B where A and B are joined by a covalent bond
  • the portion of A-B defined by the group or chemical structure A can be represented by , ” represents a bond to A and the point of covalent bond attachment to B.
  • the portion of A-B defined by the group or chemical structure B can be represented by , represents a bond to B and the point of covalent bond attachment to A.
  • alkyl refers to a straight- or branched-chain monovalent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain divalent hydrocarbon group.
  • an “alkyl” or “alkylene” can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or C 1 -C 6 alkyl or C 1 -C 6 alkylene.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH 2 -) 3 ), iso-propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -) 4 ), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C 2 -C 20 alkenyl, C 2 -C 12 alkenyl, or C 2 -C 6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein.
  • alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C 2 -C 12 alkynyl, or C 2 -C 6 alkynyl.
  • alkynyl groups include acetylenyl (-C ⁇ CH) and propargyl (-CH2C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH2CH2-), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0119]
  • the term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkyl In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities:
  • a cyclopropyl moiety can be depicted by the structural formula be appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein.
  • a cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • halogen or “halo” represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF 3 , -(CH 2 )F, -CHF 2 , -CH 2 Br, -CH 2 CF 3 , and -CH2CH2F.
  • aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6- C 10 aryl).
  • aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • ring atoms such as from 3 to 12 ring atoms (3- to 12- membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered).
  • heterocycloalkyl it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine.
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5- diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane.
  • heterocycloalkyl groups include monovalent radicals of the following entities:
  • a three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
  • a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane.
  • a five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one.
  • a six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide.
  • a “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.
  • certain embodiments can include a heteroatom-C 2 -C 6 alkylene moiety (e.g., -N(C 2 -C 6 alkylene) or -P(O)2(C 2 -C 6 alkylene)).
  • -heteroatom-(C 2 -C 6 alkylene) represents a cyclic group wherein the heteroatom atom (e.g., nitrogen, phosphorus, etc.) forms two covalent bonds with the C 2 -C 6 alkylene group (e.g., example, -OC(O)N(C 2 -C 6 alkylene) can be depicted by the structural formula .
  • a heterocycloalkyl group can be unsubstituted or substituted as described herein.
  • a heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • heteroarylene refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle.
  • a five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • Non-limiting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • bicyclic heteroaryl or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring.
  • bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of azaindazole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin- 3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • a pyrazolyl moiety can be depicted by the structural formula particular, an example of a pyrazolylene moiety can be depicted by the structural formula .
  • an azaindazolylene or pyrazolopyridylene moiety such as 1H- pyrazolo[3,4-c]pyridylene moiety can be depicted by the structural formula .
  • a heteroaryl group can be unsubstituted or substituted as described herein.
  • a heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • the phrase “taken together with the atoms to which each is attached” means that two substituents (e.g., R 7 and one of R 3 , R 4 , R 5 , or R 6 ) attached to two separate atoms combine to form a 4- to 7-membered heterocycloalkyl that are defined by the claim, such as .
  • the phrase “taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl” means R 7 and one of R 3 , R 4 , R 5 , or R 6 , for example, on different ring atoms , form a 4- to 7-membered ring with those ring atoms.
  • the phrase “taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl” used in connection with the embodiments described herein includes the compound represented as follows: .
  • the term “substituted” means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0136] As used herein, “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
  • the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
  • the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. [0138] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(IV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyra
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
  • an organic acid such as ace
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(IV), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(IV).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(IV), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(IV) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • EGFR inhibitor includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the EGFR gene.
  • EGFR inhibitors include, but are not limited to compounds that are capable of inhibiting the protein that is encoded by the classical EGFR mutations, uncommon mutations, and secondary resistance mutations.
  • Examples of EGFR mutations include, but are not limited to L858R, ⁇ 746-750, ⁇ 746- 750/C979S, L858R/T790M, L858R/T790M/C979S, and D770_N771insNPG, other emerging and established resistance mutations, and the like.
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof I [0148] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, m, n, p, and q are as described herein.
  • the disclosure relates to a compound of the formula II, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, II [0150] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, m, n, p, and q are as described herein.
  • the disclosure relates to a compound of the formula III, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, III [0152] wherein X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, p, and q are as described herein.
  • the disclosure relates to a compound of the formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, IV [0154] wherein X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, and B are as described herein.
  • X 2 N- or -N(R 1 )-
  • ring A is a 5-membered heteroarylene.
  • X 2 N- or -N(R 1 )-
  • ring A is a 5-membered heteroarylene.
  • Y 2 N-
  • ring B is a 5-membered heteroarylene.
  • ring A and ring B are each independently a 5-membered heteroarylene.
  • ring A is selected from the group consisting of represents a point of covalent attachment.
  • ring A is a pyrazolylene.
  • ring A is selected from the group consisting of , wherein each “ ” represents a point of covalent attachment.
  • ring A is selected from the group consisting of wherein each “ ” represents a point of covalent attachment. In some embodiments, ring wherein each “ ” represents a point of covalent attachment. In some embodiments, ring wherein each “ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting of
  • ring A is selected from the group consisting of wherein each “ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting of
  • ring B is selected from the group consisting of
  • each “ ” represents a point of covalent attachment.
  • ring B is a pyrazolylene.
  • ring B is selected from the group consisting of , wherein each “ ” represents a point of covalent attachment.
  • ring “ ” represents a point of covalent attachment.
  • ring erein each “ ” represents a point of covalent attachment.
  • ring B is , wherein each “ ” represents a point of covalent attachment.
  • ring B is selected from the group consisting of , wherein each “ ” represents a point of covalent attachment. In some embodiments, ring B is selected from the group consisting of wherein each “ ” represents a point of covalent attachment. In some embodiments, wherein each “ ” represents a point of covalent attachment. [0159] In some embodiments, ring A and ring B are each a pyrazolylene. [0160] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0.
  • m is 1. In some embodiments, m is 2. In some embodiments, m is 3. [0161] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • each R 1 and R 2 when present, is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O) 2NR a R b , -OS(O) 2NR a R b , -OS(O) 2NR a R
  • each R 1 and R 2 when present, is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O) 2NR a R b , -OS(O) 2NR a R b , -OS(O) 2NR a R
  • each R 1 and R 2 when present, is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a
  • each R 1 and R 2 when present, is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -OR a , -OC(O)R a , -OC(O)NR a R b , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR c , -CN, or -NO 2
  • each R 1 and R 2 when present, is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -OR a , or –CN, wherein each hydrogen atom in C 1 -C 6 alkyl and C 2 -C 6 alkynyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR c , or -CN.
  • each R 1 and R 2 when present, is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -OR a , or –CN, wherein each hydrogen atom in C 1 -C 6 alkyl or C 2 -C 6 alkynyl is independently optionally substituted by -OR c or -CN.
  • each R 1 when present, is independently C 1 -C 6 alkyl, -OR a , or -CN, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by -OR c or -CN.
  • each R 1 when present, is independently C 1 -C 6 alkyl, -OR a , or –CN, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by -OH or -CN.
  • each R 2 when present, is independently halogen, C 1 -C 6 alkyl, or C 2 -C 6 alkynyl. In some embodiments, each R 2 , when present, is independently halogen, methyl, ethyl, or ethyne.
  • each R a is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium or –CN. In some embodiments, each R a is methyl, ethyl, or propyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium or –CN. [0169] In some embodiments, each R c is H.
  • each R 3 , R 4 , R 5 , and R 6 is independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O) 2NR a R b , -OS(O) 2NR a R b , -
  • each R 3 , R 4 , R 5 , and R 6 is independently H or C 1 -C 6 alkyl. In some embodiments, each R 3 , R 4 , R 5 , and R 6 is independently H, methyl, or ethyl. In some embodiments, each R 3 , R 4 , R 5 , and R 6 is independently H or methyl. [0171] In some embodiments, each R 3 and R 4 is independently H, methyl, or ethyl. In some embodiments, each R 3 and R 4 is independently H or methyl. In some embodiments, one instance of R 3 is methyl, and any remaining R 3 and R 4 are H or deuterium.
  • one instance of R 3 is C 1 -C 6 alkyl; R 7 and one instance of R 4 , taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl; and any remaining R 3 and R 4 are H or deuterium.
  • R 5 and R 6 are each H.
  • R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or -C(O)R c ; or R 7 and one instance of R 3 or R 4 , taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl.
  • R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl.
  • R 7 and one of R 3 , R 4 , R 5 , or R 6 taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl.
  • R 7 is H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 7 is H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl. In some embodiments, R 7 and one instance of R 3 or R 4 , taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, R 7 and one instance of R 3 or R 4 , taken together with the atoms to which they are attached, combine to form 5-membered heterocycloalkyl.
  • p is 2 or 3 and the portion is an ethylene or propylene, wherein each R 3 and R 4 is independently H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O)NR a R b
  • the portion i attachment, and each hydrogen is independently optionally substituted with deuterium.
  • the portion i represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium.
  • the portion i ” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium.
  • p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 3 or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. [0183] In some embodiments, the portion i , attachment and each hydrogen is independently optionally substituted with deuterium. [0184] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 1.
  • R 8 is H or C 1 -C 6 alkyl.
  • R 8 is H or C 1 -C 6 alkyl. In some embodiments, R 8 is H.
  • R 9 is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -OS(O)NR a R b , -OS
  • R 9 is H, deuterium, halogen, C 1 -C 6 alkyl, or -OR a , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted with deuterium.
  • R 9 is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -OS(O)NR a R b , -OS(O
  • R 9 is H, deuterium, halogen, C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted with deuterium. In some embodiments, R 9 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, is independently optionally substituted by deuterium. In some embodiments, R 9 is H, deuterium, halogen, -CH3, or -CD 3 . In some embodiments, R 9 is H, deuterium, halogen, -OCH 3 , -CH 3 , or -CD 3 .
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkylene-C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and C 1 -C 6 alkylene-5- to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f , taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alken
  • R 9 is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -OS(O)NR a R b , -OS(
  • R 9 is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R
  • R 9 is halogen, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a S(O)NR a R
  • each of R 8 and R 9 is H.
  • R 8 is H and R 9 is not H.
  • R 8 is H and R 9 is as described herein and may be deuterium, optionally substituted C 1 -C 6 alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (i.e., -O-C 1 -C 6 alkyl) (e.g., methoxy).
  • R 8 is H
  • R 9 is as described herein and may be deuterium, optionally substituted C 1 -C 6 alkyl (e.g., methyl or -CD 3 ) or optionally substituted alkoxy (e.g., -O-C 1 -C 6 alkyl such as methoxy)
  • m is 2
  • one R 1 is optionally substituted C 1 -C 6 alkyl (e.g., unsubstituted such as methyl, hydoxy substituted such as -CH(CH 3 )(CH 2 OH) or ethanol, or heterocyloalkyl substituted such as -ethylene-pyrrolidinyl)
  • the other R 1 is either optionally substituted C 1 -C 6 alkyl (e.g., ethyl, optionally substituted -N(H or C 1 -C 6 alkyl)-C 1 -C 6 alkyl) or optionally substituted -O-C 1 -
  • R 8 is H
  • R 9 is optionally substituted C 1 -C 6 alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (e.g., -O-C 1 -C 6 alkyl such as methoxy)
  • m is 2
  • one R 1 is optionally substituted C 1 -C 6 alkyl (e.g., unsubstituted such as methyl, hydoxy substituted such as -CH(CH3)(CH2OH) or ethanol, or heterocyloalkyl substituted such as -ethylene- pyrrolidinyl)
  • the other R 1 is either optionally substituted C 1 -C 6 alkyl (e.g., ethyl, optionally substituted -N(H or C 1 -C 6 alkyl)-C 1 -C 6 alkyl) or optionally substituted -O-C 1 -C 6 alkyl (e.g., ethoxy
  • each of ring A and ring B are a pyrazole, and both of m and n are independently 1, 2, or 3.
  • m can be 1 or 2
  • n can be 1 or 2.
  • each of ring A and ring B are a pyrazole, m is 1 or 2, and n is 2.
  • each of ring A and ring B are a pyrazole, m is 1, and n is 2.
  • each of ring A and ring B are a pyrazole, m is 2 and n is 2.
  • p is 2 or 3, q is 1 or 2, and R 7 is as described herein except is not H.
  • p is 2 or 3
  • q is 1 or 2
  • R 7 is C 1 -C 6 alkyl (e.g., methyl, ethyl, or isopropyl) or C 3 -C 6 cycloalkyl (e.g., cyclopropyl).
  • each of ring A and ring B are a pyrazole, each of m and n are independently 1, 2, or 3; R 8 is H; and R 9 is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, and C 1 -C 6 alkyl.
  • the disclosure provides a compound of the formula (I)-(IV) selected from the group consisting of 2-[(10R,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2- yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; [0202] 2-[(11S,17E)-16-ethoxy-6,8,11-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopent
  • the disclosure provides a compound of the formula (I)-(IV) selected from the group consisting of 2-[(10S,17E)-16-ethoxy-12-ethyl-8,10,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; [0295] 2-[(10S,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-30n][1,4]oxazacyclopentadecin-14-yl]ethan-1
  • each R 1 and R 2 when present, is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -S(O)2NR a R b , -S(O)2NR a R b , -S(O)2NR a R
  • a pharmaceutical composition comprising a compound of any one of the preceding embodiments, and optionally one or more excipients.
  • 26. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of embodiments 1 to 24, or a pharmaceutical composition of embodiment 25.
  • 27. A compound according to any one of embodiments 1 to 24, for use in a method of treating disease in a subject.
  • 28. Use of a compound according to any one of embodiments 1 to 24, in the manufacture of a medicament for the treatment of disease in a subject.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the disclosure are sterile compositions.
  • compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.
  • the pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • a suitable route of delivery such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the term “subject” refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • cancer includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congen
  • cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.
  • Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources.
  • Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR, including EGFR having one or more mutations, such as L858R, ⁇ 746-750, ⁇ 746-750/C979S, L858R/T790M, L858R/T790M/C979S, and D770_N771insNPG .
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases.
  • methods of treating a target cancer are described.
  • an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a cancer cell with abnormal signaling due to upregulation of EGFR, including a cancer cell having one or more EGFR mutations, such as L858R, ⁇ 746-750, ⁇ 746-750/C979S, L858R/T790M, L858R/T790M/C979S, and D770_N771insNPG, while maintaining good selectivity over wild-type EGFR.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • Additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the disclosure, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids.
  • ALK inhibitors e.g., crizotinib
  • Raf inhibitors e.g., vemurafenib
  • VEGFR inhibitors e.g., sunitinib
  • standard chemotherapy agents such as alkylating agents, antimetabolites, anti-t
  • suitable combination agents include anti-inflammatories such as NSAIDs.
  • the pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • CHEMICAL SYNTHESIS METHODS [0467] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(IV). [0468] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
  • the proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below.
  • the following starting materials and intermediates can be obtained from commercial sources or using known literature procedures: (2S)-2-methyloxirane, (2R)-2-methyloxirane, propan-2-amine, iodoethane, 2-bromoethoxy-tert-butyl-dimethyl-silane, (2R)-1- (isopropylamino) propan-2-ol, 5-bromo-1H-pyrazolo[3,4-c]pyridine, 2,5-dimethylpyrazol-3- ol, 2,4-dimethylpyridin-3-amine, 2,6-dimethylpyridine, 2-methylpyrazol-3-ol, methyl 3- methyl-1H-pyrazole-5-carboxylate (a.k.a.
  • Step 1 A solution of commercially available (2R)-2-methyloxirane (5.00 g, 86.0 mmol, 1 eq) and commercially available propan-2-amine (15.2 g, 258 mmol, 3 eq) in MeOH (80 mL) was stirred at 25 °C for 14 hours. On completion, the mixture was concentrated to give (2R)- 1-(isopropylamino) propan-2-ol (8.60 g, 73.3 mmol, 85% yield) as a yellow oil.
  • Step 4 To a solution of methyl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy- pyrazole-3-carboxylate (12 g, 36.53 mmol, 1 eq) in THF (120 mL) was added LiAlH 4 (1.39 g, 36.53 mmol, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was quenched with MeOH (150 mL) at 0 °C, and the mixture was concentrated to give a residue.
  • Step 7 To a solution of (2R)-1-(isopropylamino) propan-2-ol (4.00 g, 34.1 mmol, 1.5 eq) in ACN (260 mL) was added K2CO3 (6.29 g, 45.5 mmol, 2 eq) and 5-(bromomethyl)-1-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (11.1 g, 22.8 mmol, 1 eq). The mixture was stirred at 50 °C for 12 h. On completion, the mixture was filtered and concentrated to give a residue.
  • Step 1 To a solution of MeNH 2 (41.1 g, 397 mmol, 30% purity, 20 eq) in acetone (800 mL) was added K2CO3 (8.24 g, 59.6 mmol, 3 eq) at 0°C.Then 2-[5-(bromomethyl)-4-iodo-3- isopropoxy-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.3/Ex. 4, (10 g, 19.8 mmol, 1 eq) in acetone (200 mL) was added dropwise at 0 °C.
  • reaction mixture was diluted with H2O (15 mL) and extracted with EA (20 mL ⁇ 3). The combined organic layers were washed with H 2 O (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl] methyl-ethyl-amino] propan-2-ol (1.00 g, 1.95 mmol, 1.00 eq) and DIEA (758 mg, 5.86 mmol, 3.00 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (511 mg, 2.93 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h.
  • Step 5 To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl) silyl] oxyethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl]methyl]-N-ethyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo [3,4-c]pyridin-5-yl)pyrazol-3-yl] oxy-propan-1-amine (830 mg, 1.01 mmol, 1.00 eq) in DMF (8 mL) was added Pd(OAc)2 (34.1 mg, 152 ⁇ mol, 0.15 eq), TBAC (563 mg, 2.03 mmol, 2.00 eq) and KOAc (497 mg, 5.07 mmol, 5.00 eq).
  • Step 4 To a solution of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (710 mg, 838 ⁇ mol, 1 eq) in DMF (35 mL) was added NaHCO3 (176 mg, 2.10 mmol, 2.5 eq) and TBAC (233 mg, 838 ⁇ mol, 1 eq) and Pd(OAc) 2 (37.6 mg, 167 ⁇ mol, 0.2 eq).
  • Step 4 SFC separation: the product above was purified by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO 2 -MeOH];B%:40%, isocratic elution mode) to give Ex.11 (32.97 mg, 65.08 ⁇ mol, 54.95% yield) as a white solid and Ex. 12 (8.41 mg, 16.60 ⁇ mol, 14.02% yield) as a white solid.
  • Ex. 11 LCMS: (M+1:507.1). 1 H NMR for Ex. 11 can be found in the below NMR table.
  • Ex. 12 LCMS: (M+1:507.2). 1 H NMR for Ex.
  • Step 8 To a solution of (10S,17E)-14-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-12- ethyl-6,8,10,16-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (200 mg, 296 ⁇ mol, 1 eq) was added DCM (2.5 mL) and TFA (0.5 mL).
  • the mixture was stirred at 140 °C for 1 h under nitrogen atmosphere. On completion, the mixture was added brine (100 mL) and extracted with EA (50 mL ⁇ 3). The combined organic layer was washed with brine (50 mL ⁇ 2). The organic layer was concentrated in vacuum to give the residue.
  • Step 1 To a solution of commercially available (2S)-2-aminopropan-1-ol (553 mg, 7.36 mmol, 3 eq) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazole, which was prepared according to the method described in Ex. 1, (1.20 g, 2.45 mmol, 1 eq) in DMF (15 mL) was added K2CO3 (1.02 g, 7.36 mmol, 3 eq). The mixture was stirred at 70 °C for 2 h. On completion, the crude mixture was used for next step.
  • Step 5 SFC purification: The product obtained above was separated by SFC (condition: column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO 2 - MeOH(0.1%NH 3 H 2 O)];B%:40%, isocratic elution mode) to give Ex.20 (7.38 mg, 14.53 ⁇ mol, 13.85% yield, 96.6% purity) as an orange solid and Ex. 21 (28.43 mg, 57.60 ⁇ mol, 54.90% yield, 99.4% purity) as an orange solid.
  • Step 1 To a solution of [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1- yl]propoxy]-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.19, (960 mg, 1.91 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (791 mg, 5.72 mmol, 3 eq) and commercially available (2S)-2-aminopropan-1-ol (430 mg, 5.72 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hr.
  • Step 4 A mixture of the product from Step 3 (460 mg, 0.543 mmol, 1 eq), diacetoxypalladium (24.4 mg, 0.109 mmol, 0.2 eq), tetrabutylammonium chloride (151 mg, 0.543 mmol, 1 eq) and NaHCO 3 (114 mg, 1.36 mmol, 2.5 eq) in DMF (5 mL) was degassed and purged with N 2 for 3 times, and then stirred at 140 °C for 1 h under N 2 atmosphere. On completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (15 mL ⁇ 3).
  • Step 5 To a solution of the product from Step 4 (260 mg, 0.362 mmol, 1 eq) in DCM (1 mL) was added TFA (3.22 g, 28.2 mmol, 2.10 mL, 78.1 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 1 To a solution of commercially available (2R)-1-tert-butoxycarbonylpyrrolidine- 2-carboxylic acid (20.0 g, 92.9 mmol, 1 eq), commercially available N-methoxymethanamine (6.24 g, 102 mmol, 1.10 eq), DIEA (24.0 g, 185 mmol, 2.00 eq), HATU (38.8 g, 102 mmol, 1.10 eq) in DCM (200 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with water (300 mL) and extracted with DCM (60 mL ⁇ 3).
  • Step 4 To a solution of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (1.00 g, 4.64 mmol, 1.00 eq) in DCM (10 mL) was added HCl/dioxane (4 M, 2.00 mL, 1.72 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated to give 1-((R)-pyrrolidin-2-yl)ethan-1-ol (700 mg, crude) as a white oil. [0579] Step 5.
  • Step 7 A mixture of tert-butyl-[2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1-tetrahydropyran- 2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]pyrrolidin-1-yl]methyl]-3- ethoxy-4-iodo-pyrazol-1-yl]ethoxy]-dimethyl-silane (420 mg, 497 ⁇ mol, 1 eq), diacetoxypalladium (22.3 mg, 99.4 ⁇ mol, 0.2 eq), TBAC (138 mg, 497 ⁇ mol, 1 eq) and NaHCO 3 (104 mg, 1.24 mmol, 2.5 eq) in DMF (10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stir
  • Step 3 To the solution of N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-ethanamine (114 mg, 141.64 ⁇ mol) in DMF (1.40 mL), was added sodium bicarbonate (36 mg, 424.9 ⁇ mol) and TBAC (43.3 mg, 155.8 ⁇ mol).
  • the mixture was stirred as argon was bubbled through and palladium acetate (6.4 mg, 28.3 ⁇ mol) was then added.
  • the vessel was sealed and heated to 140 °C for 1.5 hr. Reaction was diluted with DCM and water (4 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 ⁇ 4 mL). The combined organic layer was washed with brine and dried over sodium sulfate.
  • reaction mixture was stirred while Argon was bubbled through, and palladium acetate (2.19 mg, 9.75 ⁇ mol, 1 ⁇ L) was added. Argon was bubbled through for an additional 5 minutes.
  • the vessel was sealed, and the reaction heated to 140 °C for 1.5 hr. Reaction was diluted with DCM and water (5 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 ⁇ 3mL). The combined organic layer was washed with brine and dried over sodium sulfate.
  • Step 1 To a solution of commercially available (2S)-1-(isopropylamino)propan-2-ol (600 mg, 5.12 mmol, 1.5 eq) in ACN (6 mL) was added commercially available 5- (bromomethyl)-4-iodo-1,3-dimethyl-pyrazole (,1.08 g, 3.41 mmol, 1 eq) and K2CO3 (1.42 g, 10.2 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered to remove K2CO3 and then was concentrated in vacuum.
  • Step 4 To a solution of the product from Step 3 (1.20 g, 1.75 mmol, 1 eq) in DMF (12 mL) was added NaHCO3 (734 mg, 8.74 mmol, 5 eq) and TBAC (971 mg, 3.50 mmol, 2 eq) and Pd(OAc) 2 (58.9 mg, 262 ⁇ mol, 0.15 eq) was degassed and purged with N 2 for 3 times. The mixture was stirred at 130 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was diluted with H 2 O (100 mL) and extracted with EA (100 mL ⁇ 3).
  • Step 2 To a solution of the product from Step 1 (400 mg, 744 ⁇ mol, 1 eq) in DCM (4 mL) was added TEA (225 mg, 2.23 mmol, 3 eq) and methylsulfonyl methanesulfonate (324 mg, 1.86 mmol, 2.5 eq). The mixture was stirred at 25 °C for 2 hours.
  • Step 4 A mixture of the product from Step 3 (60.0 mg, 69.8 ⁇ mol, 1 eq), Cs2CO3 (68.2 mg, 209 ⁇ mol, 3 eq), ditert-butyl(cyclopentyl)phosphane, and dichloropalladium;iron (Pd(dtbpf)Cl2) (22.7 mg, 34.9 ⁇ mol, 0.5 eq) in dioxane (1 mL) was degassed and purged with N 2 for 3 times. Then the mixture was stirred at 80 °C for 10 min under N 2 atmosphere. On completion, the mixture was filtered, and the filtrate concentrated.
  • Step 5 To a solution of the product from Step 4 (5.00 mg, 6.84 ⁇ mol, 1 eq) in DCM (1 mL) was added HCl/EtOAc (4 M, 0.5 mL, 3 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered, and filtrate concentrated to give a residue. The crude product was purified by reversed-phase HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:26%-56% B over 10 min) to give Ex. 107 (0.98 mg, 23% yield) as a yellow solid.
  • Step 2 Step 3 and Step 4 were carried out in the same manner as in Ex.108 using 2,5- dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- ol in Step 3 as prepared according to the method described in Ex.47. [0610] Step 5.
  • Step 5 was carried out in the same manner as in Ex.109 to afford Ex.110 and byproduct Ex.111.
  • 1 H NMR for Ex.110 and Ex. 111 are in the below NMR table.
  • [0613] Preparation of 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.
  • Step 6 To a solution of the product from Step 5 (1.40 g, 2.84 mmol, 1 eq) in DCM (14 mL) was added DIEA (1.10 g, 8.51 mmol, 1.48 mL, 3 eq) and methylsulfonyl methanesulfonate (988 mg, 5.67 mmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with water (40 mL) and extracted with DCM (15 mL ⁇ 3).
  • Step 8 To a solution of the product from Step 7 (220 mg, 0.265 mmol, 1 eq) in DMF (20 mL) was added Na 2 CO 3 (84.4 mg, 0.796 mmol, 3 eq) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (Pd(dppf)Cl2) (19.4 mg, 0.0265 mmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. On completion, the mixture was poured into H2O (80 mL) and extracted with EA (100 mL ⁇ 3).
  • Step 9 To a solution of the product from Step 8 (70.0 mg, 99.8 ⁇ mol, 1 eq) in MeOH (1.5 mL) was added HCl (12 M, 0.5 mL, 60.08 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give a residue.
  • the mixture was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 8 min ), followed by further SFC separation (column: REGIS (R,R)WHELK-O1 (250mm*25mm, 10 um); mobile phase: [CO 2 - ACN/MeOH(0.1% NH3H2O)];B%:45%, isocratic elution mode ) to give Ex.127 (7.70 mg) as brown solid and a byproduct Ex.128 (5.02 mg) as brown solid.
  • 1 H NMR for Ex.127 and Ex. 128 can be found in the below NMR table.
  • Steps 2 through 4 were performed in a similar manner to steps 7 through 9 in the synthesis of Ex.127/128, with DMF used as the solvent in step 7 rather than ACN.
  • 1 H NMR for Ex.139 and Ex.140 can be found in the below NMR table.
  • Step 3 A solution of 1-((R)-1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazol-5-yl)methyl)pyrrolidin-2-yl)ethan-1-ol (926 mg, 1.77 mmol, 1 eq), 1,3- dimethyl-4-(7-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5- yl)-1H-pyrazol-5-ol, which was prepared according to the method described in Ex.47 (500 mg, 1.41 mmol, 0.8 eq), and PPh 3 (927 mg, 3.54 mmol, 2 eq) in 2-methyltetrahydrofuran (10 mL) was degassed and purged with N2 atmosphere for 3 times.
  • Ex. 179 and Ex. 180 were synthesized following the procedure described for the synthesis of Ex. 177/Ex. 178, using (S)-5-(bromomethyl)-1-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole (which was prepared following the method described in Ex.19) in Step 2.
  • 1 H NMR for Ex.179 and Ex.180 can be found in the below NMR table.
  • General Method B using Ex.22 as example.
  • Step 1 To a solution of commercially available ethyl 3-hydroxy-1H-pyrazole-5- carboxylate (1.00 g, 6.40 mmol, 1 eq) in DMF (10 mL) was added imidazole (1.31 g, 19.2 mmol, 3 eq), and then TBSCl (1.45 g, 9.61 mmol, 1.5 eq) was added at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was partitioned between EA (30 mL ⁇ 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
  • Step 8 To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]carbamate (232 mg, 467 ⁇ mol, 1 eq) in DMF (5 mL) was added NaH (37.4 mg, 934 ⁇ mol, 60% purity, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, then CH3I (99.5 mg, 701 ⁇ mol, 1.5 eq) was added.
  • Step 11 To a mixture of 2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[[(2S)-2-[2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- yl]oxyprop yl]-methyl-amino]methyl]-4-iodo-pyrazol-3-yl]oxyacetonitrile (309 mg, 372 ⁇ mol, 1 eq) in DMF (15 mL) was added NaHCO 3 (78.2 mg, 931 ⁇ mol, 2.5 eq), Pd(OAc) 2 (16.7 mg, 74.5 ⁇ mol, 0.2 eq) and TBAC (103 mg, 372 ⁇ mol, 1 eq) degassed and purged with N2 for 3 times, then
  • Step 1 A mixture of 2-methyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.
  • Step 1 A mixture of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.
  • Step 3 To a solution of tert-butyl N-[(1S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-1-methyl-ethyl]-N-methyl-carbamate (1.00 g, 1.96 mmol, 1 eq) in DCM (10 mL) was added ZnBr 2 (2.21 g, 9.79 mmol, 5 eq). The mixture was stirred at 25 °C for 12 h.
  • Step 4 A mixture of (2S)-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-2-amine (350 mg, 852 ⁇ mol, 1 eq), 2-[5-(bromomethyl)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-pyrazol-3- yl]oxyacetonitrile, which was prepared according to the method described in Ex.22, (426 mg, 852 ⁇ mol, 1 eq), K 2 CO 3 (353 mg, 2.56 mmol, 3 eq) in ACN (5 mL) was stirred at 60 °C for 2 h.
  • Step 1 A mixture of 2-methyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 28, (750 mg, 2.21 mmol, 1 eq), commercially available tert-butyl N-[(2S)-2- hydroxypropyl]carbamate (774 mg, 4.42 mmol, 2 eq), DBAD (1.12 g, 4.86 mmol, 2.2 eq), PPh 3 (1.28 g, 4.86 mmol, 2.2 eq) was degassed and purged with N 2 for 3 times.
  • Step 3 To a solution of tert-butyl N-methyl-N-[(2S)-2-[2-methyl-4-(7-methyl-1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl] carbamate (350 mg, 685 ⁇ mol, 1 eq) in DCM (5 mL) was added ZnBr2 (463 mg, 2.06 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hr.
  • Step 5 A mixture of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- isopropoxy-pyrazol-3-yl]methyl]-N-methyl-2-[2-methyl-4-(7-methyl-1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine (330 mg, 396 ⁇ mol, 1 eq), diacetoxypalladium (17.7 mg, 79.2 ⁇ mol, 0.2 eq), TBAC(110 mg, 396 ⁇ mol, 1 eq) and sodiumbicarbonate (83.2 mg, 990 ⁇ mol, 2.5 eq) in DMF (6 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 130 °C for 1 h under N 2 atmosphere.
  • Step 1 To a solution of (2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-1-amine, which was prepared according to the method described in Ex.22, (190 mg, 462 ⁇ mol, 1 eq) , 2-[5-(bromomethyl)- 4-iodo-3-methyl-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.
  • Step 2 A mixture of methyl 3-(2-trimethylsilylethoxymethoxy)-1H-pyrazole-5- carboxylate (10.0 g, 36.7 mmol, 1.00 eq), commercially available 2-[tert- butyl(dimethyl)silyl]oxyethanol (14.2 g, 80.7 mmol, 2.20 eq), and PPh3 (21.1 g, 80.7 mmol, 2.20 eq) in THF (100 mL) was degassed and purged with N 2 for 3 times, and then DIAD (16.3 g, 80.7 mmol, 2.20 eq) was added at 0 °C.
  • Step 7 A mixture of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-(2- trimethylsilylethoxymethoxy)pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2- yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-1-amine (290 mg, 315 ⁇ mol, 1 eq) in DMF (14.5 mL) was added NaHCO3 (66.1 mg, 787 ⁇ mol, 2.5 eq), TBAC (87.5 mg, 315 ⁇ mol, 1 eq) and Pd(OAc) 2 (14.14 mg, 62.9 ⁇ mol, 0.2 eq).
  • Step 8 To a solution of (10R,17E)-14-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)- 6,8,10,12-tetramethyl-2-(oxan-2-yl)-16- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ - 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (223 mg, 281 ⁇ mol, 1 eq) in THF (1.69 mL) was added TBAF (1 M, 1.69 mL, 6 eq).
  • Step 10 To a solution of ⁇ [(10R,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy ⁇ acetonitrile (57.0 mg, 97.0 ⁇ mol, 1 eq) in DCM (0.5 mL) was added TFA (11.0 mg, 97.0 ⁇ mol, 1 eq).
  • Step 1 To a solution of (2S)-N-methyl-2-[2-methyl-4-(7-methyl-1-tetrahydropyran-2- yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine, which was prepared according to the method described in Ex. 29, (200 mg, 487 ⁇ mol, 1 eq) in DMF (3 mL) was added [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]propoxy]-tert-butyl- dimethyl-silane, which was prepared according to the method described in Ex.
  • Step 1 A mixture of (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol, which was prepared according to the method described in Ex.19, (7.00 g, 36.7 mmol, 1 eq), commercially available methyl 3-methyl-1H-pyrazole-5-carboxylate (10.3 g, 73.5 mmol, 2 eq), PPh3 (14.4 g, 55.1 mmol, 1.5 eq), DIAD (55.1 mmol, 11 mL, 1.5 eq) in THF (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 12 hours under N2 atmosphere.
  • reaction mixture was quenched by addition of H2O (20 mL) and extracted with EA (10mL ⁇ 3). The combined organic layers were washed with the saturated solution of NaCl (30 mL), concentrated under reduced pressure to give a residue.
  • Step 4 To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]-N-methyl- carbamate (1.70 g, 3.24 mmol, 1 eq) in DCM (17 mL) was added ZnBr 2 (3.65 g, 16.2 mmol, 811 ⁇ L, 5 eq). The mixture was stirred at 25 °C for 2 h.
  • Step 1 A solution of commercially available methyl 3-bromo-1H-pyrazole-5- carboxylate (2.00 g, 9.76 mmol, 1 eq), (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol, which was prepared according to the method described in Ex. 19, (1.86 g, 9.76 mmol, 1 eq) and PPh 3 (5.12 g, 19.51 mmol, 2 eq) in THF (40 mL) was stirred at 25 °C for 30 mines. Then DIAD (3.95 g, 19.51 mmol, 2 eq) was added at 0 °C, the mixture and stirred at 25 °C for 2 h.
  • Step 7 To a solution of (10S,17E)-16-bromo-14-[(2S)-1- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ propan-2-yl]-6,8,10,12-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (160 mg, 216 ⁇ mol, 1 eq) in DMA (1.6 mL) was added Zn (3.54 mg, 54.0 ⁇ mol, 0.25 eq), dicyanozinc (27.9 mg, 237 ⁇ mol, 1.1 eq), Pd2(dba)3 (6.54 mg, 7.14 ⁇ mol, 0.0
  • Step 8 To a solution of (10S,17E)-14-[(2S)-1- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propan- 2-yl]-6,8,10,12-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-16-carbonitrile (160 mg, 233 ⁇ mol, 1 eq) in DCM (4 mL) was added TFA (10.7 mmol, 800 ⁇ L, 46.2 eq).
  • Step 1 To a solution of commercially available tert-butyl N-[(1R)-2-hydroxy-1- methyl-ethyl]carbamate (309 mg, 1.77 mmol, 1 eq), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (600 mg, 1.77 mmol, 1 eq) in THF (14 mL) was added PPh 3 (927 mg, 3.54 mmol, 2 eq) and DBAD (611 mg, 2.65 mmol, 1.5 eq).
  • Step 3 To a solution of tert-butyl N-[(1R)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-1-methyl-ethyl]-N-methyl-carbamate (1.10 g, 2.15 mmol, 1 eq) in ACN (10 mL) was added TMSI (560 mg, 2.80 mmol, 1.3 eq). The mixture was stirred at 25 °C for 2 h.
  • Step 5 To a solution of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- (2-trimethylsilylethoxymethoxy)pyrazol-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran- 2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-2-amine (1.10 g, 1.19 mmol, 1 eq) in DMF (55 mL) was added TBAC (331 mg, 1.19 mmol, 1 eq), NaHCO3 (250 mg, 2.99 mmol, 2.5 eq) and Pd(OAc) 2 (53.6 mg, 238 ⁇ mol, 0.2 eq).
  • Step 7 To a solution of (11R,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (200 mg, 364 ⁇ mol, 1 eq) and commercially available 2-iodoacetonitrile (73.0 mg, 437 ⁇ mol, 1.2 eq) in DMF (4 mL) was added K2CO3 (101 mg, 729 ⁇ mol, 2 eq).
  • Step 8 To a solution of ⁇ [(11R,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy ⁇ acetonitrile (100 mg, 170 ⁇ mol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol, 79.0 eq).
  • Step 1 Commercially available 5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (10.0 g, 64 mmol, 1 eq), SEM-Cl (42.7 g, 256 mmol, 4 eq), and TEA (38.9 g, 384 mmol, 6 eq) were mixed in DCM (100 mL) at 0 °C and the mixture was stirred at 25 °C for 1 h. On completion, the mixture was diluted with water (500 mL) and extracted with DCM (100 mL ⁇ 3). The combined organic phase was dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give a residue.
  • reaction mixture was quenched by addition of saturated sodium sulfite solution (70 mL) at 0 °C, and then diluted with H2O (260 mL) and extracted with EA (100 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • reaction mixture was quenched by addition H2O (8 mL) at 25 °C and extracted with EA (8 mL ⁇ 3). The combined organic layers were washed with H 2 O (10 mL ⁇ 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition H2O (30 mL) at 25 °C and extracted with EA (15 mL ⁇ 3). The combined organic layers were washed with H 2 O (20 mL ⁇ 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Step 8 To a solution of (10S,17E)-14-[(2S)-1- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propan- 2-yl]-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-16- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ - 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (260 mg, 317 ⁇ mol, 1 eq) in THF (2.6 mL) was added TBAF (1 M, 1.90 mL, 6 eq).
  • Step 9 To a solution of (10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12,20- pentamethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (90.0 mg, 156 ⁇ mol, 1 eq) in DMF (1 mL) was added K2CO3 (43.1mg, 312 ⁇ mol, 2 eq) and commercially available 2-iodoacetonitrile (31.3 mg, 187 ⁇ mol, 1.2 eq).
  • Step 1 To a solution of (2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-1-amine, which was prepared according to the method described in Ex.22, (500 mg, 1.22 mmol, 1 eq), 2-[[5-(bromomethyl)- 1-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo-pyrazol-3- yl]oxymethoxy]ethyl-trimethyl-silane, which was prepared according to the method described in Ex.52, (368 mg, 609 ⁇ mol, 0.5 eq) in DMF (5 mL) was added K2CO3 (505 mg, 3.65 mmol, 3 eq).
  • Step 4 A mixture of tert-butyl-[(2S)-2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]pyrrolidin- 1-yl]methyl]-3-ethoxy-4-iodo-pyrazol-1-yl]propoxy]-dimethyl-silane (360 mg, 419 ⁇ mol, 1 eq), TBAC (116 mg, 419 ⁇ mol, 1 eq), NaHCO3 (88.0 mg, 1.05 mmol, 2.5 eq) and Pd(OAc)2 (18.8 mg, 83.8 ⁇ mol, 0.2 eq) in DMF (4 mL) was degassed and purged with N2 for 3 times, and then
  • reaction mixture was quenched by addition of H 2 O (30 mL) at 25 °C and extracted with EA (15 mL ⁇ 3). The combined organic layers were washed with H2O (50 mL ⁇ 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of tert-butyl N-[2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]carbamate (1.08 g, 2.24 mmol, 1 eq) in DMF (10 mL) was added NaH (179 mg, 4.48 mmol, 60% purity, 2 eq) at 0 °C and stirred at 25 °C for 30 mines.
  • Step 1 To a solution of (2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-1-amine, which was prepared according to the method described in Ex.47, (290 mg, 683 ⁇ mol, 1 eq) in DMF (3 mL) was added 2-[[5-(bromomethyl)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo- pyrazol-3-yl]oxymethoxy]ethyl-trimethyl-silane, which was prepared according to the method described in Ex.
  • Step 2 To a solution of tert-butyl N-[2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]carbamate (1.70 g, 3.52 mmol, 1 eq) in DMF (17 mL) was added NaH (423 mg, 10.6 mmol, 60% purity, 3 eq) at 0 °C for 0.5 h, and then EtI (5.28 mmol, 423 ⁇ L, 1.5 eq) was added at 0 °C.
  • Step 7 To a solution of (17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8-dimethyl- 2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (130 mg, 231 ⁇ mol, 1 eq) in DMF (1.5 mL) was added commercially available 2-iodoacetonitrile (57.9 mg, 346 ⁇ mol, 1.5 eq) and K2CO3 (95.8 mg, 693 ⁇ mol, 3 eq).
  • Step 8 To a solution of ⁇ [(17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8- dimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4- f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy ⁇ acetonitrile (60.0 mg, 99.7 ⁇ mol, 1 eq) in DCM (0.6 mL) was added TFA (1.62 mmol, 120.
  • reaction mixture was quenched by addition sat. NH 4 Cl (10 mL) at 0 °C, and then diluted with H 2 O (80 mL) and extracted with EA (30 mL ⁇ 3). The combined organic layers were washed with H2O (30mL ⁇ 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Step 6 To a mixture of (17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,12-trimethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (340 mg, 620 ⁇ mol, 1 eq) and K 2 CO 3 (257 mg, 1.86 mmol, 3 eq) in DMF (4 mL) was added commercially available 2-iodoacetonitrile (103 mg, 620 ⁇ mol, 1 eq).
  • Step 7 To a solution of ⁇ [(17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,12-trimethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy ⁇ acetonitrile (300 mg, 510 ⁇ mol, 1 eq) in DCM (3 mL) was added TFA (20.2 mmol, 1.50 mL, 39 eq).
  • Step 7, Step 8, and Step 9 were carried out in the same manner as in Ex.27, using (2S)- 2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]260yridine-5-yl)pyrazol-3- yl]oxy-N-methyl-propan-1-amine that was prepared according to the method described in Ex. 22.
  • 1 H NMR for Ex.86 can be found in the below NMR table.
  • Steps 1 and 2 were performed in the same manner as steps 1 and 2 in Ex.29, substituting 2-MeTHF for the solvent in step 1 and using 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1 and commercially available tert-butyl N-[(1R)-2-hydroxy-1-methyl- ethyl]carbamate in Step 1. [0843] Step 3.
  • N-methyl-N-[2-(1-methylpyrazol-4-yl)oxyethyl]carbamate (1 g, 3.92 mmol) in Acetonitrile (20 mL) was added NBS (627.4 mg, 3.53 mmol). The mixture was stirred at 22 °C for 3 days. The reaction was quenched with water (5 mL) and the volume decreased by ⁇ 1/3 under reduced pressure. The remaining solution was worked up with water and DCM (10 mL each). The layers were partitioned, and the aqueous layer extracted again with DCM (2 ⁇ 5 mL). The combined organic layer was washed with brine and dried over sodium sulfate.
  • tert-butyl N-[2-(5-bromo-1-methyl-pyrazol-4-yl)oxyethyl]-N-methyl- carbamate (122 mg, 0.365 mmol) was dissolved in anhydrous THF (1 mL) and cooled to -78 °C under argon. To this solution was added n-BuLi (70.2 mg, 1.10 mmol, 0.438 mL of 2.5 M in hexane) dropwise. After stirring at -78 °C for 1 h, commercially available 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135.84 mg, 0.73 mmol) was added under argon.
  • Step 4 To the mixture of [4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl- pyrazol-3-yl]boronic acid (109 mg, 0.364 mmol) in dioxane (0.5 mL) and water (0.5 mL), was added 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine, which was prepared according to the method described in Ex.
  • Step 3 To a solution of the mesylate from Step 2 (65 mg, 0.097 mmol) in dry DMF (0.364 mL) under Argon was added pyrrolidine (103.4 mg, 1.46 mmol, 0.121 mL) and anhydrous potassium carbonate (134.3 mg, 971.9 ⁇ mol). The mixture was stirred under Argon at 60 °C for 20 hr. The reaction mixture was diluted with water (1 mL) and DCM (3 mL), and the aqueous phase was extracted with DCM (3 ⁇ 3 mL).
  • Step 4 To a solution of the product from Step 3 (62 mg, 0.096 mmol) in DCM (0.6 mL) at 0 °C was added TFA (219.6 mg, 1.93 mmol, 0.147 mL) and the reaction mixture stirred for 15 hr. The volatiles were evaporated in vacuo and the residue was purified using preparative HPLC (C18, 40-50% MeCN in water with 0.035% TFA) to provide Ex.116 (28.67 mg) as yellow gum. 1 H NMR for Ex.116 can be found in the below NMR table.
  • Step 2 To a solution of the product from Step 1 (1.30 g, 1.25 mmol, 1 eq) in THF (6 mL), MeOH (6 mL), H 2 O (2 mL) was added LiOH.H 2 O (157 mg, 3.75 mmol, 3 eq). The mixture was stirred at 25 °C for 14 hours. On completion, the mixture was filtered and concentrated to give a residue.
  • Step 4 To a solution of the product from Step 3 (200 mg, 0.290 mmol, 1 eq) in DCM (2 mL) was added TBSCl (65.6 mg, 0.435 mmol, 1.5 eq) and imidazole (29.6 mg, 435 ⁇ mol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was filtered and concentrated to give a residue.
  • Step 5 A mixture of the product from Step 4 (150 mg, 186 ⁇ mol, 1 eq), Pd(OAc) 2 (8.39 mg, 37.3 ⁇ mol, 0.2 eq), TBAC (51.9 mg, 186 ⁇ mol, 1 eq) and NaHCO3 (39.2 mg, 467 ⁇ mol, 2.5 eq) in DMF (1 mL) was degassed and purged with N 2 for 3 times, and then stirred at 130 °C for 0.5 hours under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL ⁇ 3) and water (3 mL).
  • Step 6 To a solution of the product from Step 5 (40.0 mg, 59.2 ⁇ mol, 1 eq) in DMSO (1 mL) was added CsF (45.0 mg, 296 ⁇ mol, 5 eq). The mixture was stirred at 25 °C for 1 hour.
  • Step 7 To a solution of the product from Step 6 (30.0 mg, 53.5 ⁇ mol, 1 eq) in DCM (1 mL) was added TEA (16.2 mg, 160 ⁇ mol, 3 eq) and methanesulfonic anhydride (23.3 mg, 134 ⁇ mol, 2.5 eq). The mixture was stirred at 25 °C for 1 hour.
  • Step 8 To a solution of the product from Step 7 (30.0 mg, 46.9 ⁇ mol, 1 eq) in DMF (1 mL) was added K2CO3 (19.4 mg, 140 ⁇ mol, 3 eq) and pyrrolidine (3.34 mg, 46.9 ⁇ mol, 1 eq). The mixture was stirred at 80 °C for 1 hour.
  • Step 9 To a solution of the product form Step 8 (25.0 mg, 40.7 ⁇ mol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (2 M, 1.25 mL, 61 eq). The mixture was stirred at 25 °C for 0.2 hours. On completion, the mixture was filtered and concentrated to give a residue.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés ciblant des kinases telles que l'EGFR, des compositions pharmaceutiques contenant les composés, et des procédés d'utilisation de tels composés pour traiter une maladie, telle que le cancer.
PCT/US2024/027195 2023-05-02 2024-05-01 Inhibiteurs d'egfr pour le traitement d'une maladie Pending WO2024229087A1 (fr)

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IL324276A IL324276A (en) 2023-05-02 2025-10-27 EGFR inhibitors for the treatment of diseases
MX2025013034A MX2025013034A (es) 2023-05-02 2025-10-30 Inhibidores de egfr para el tratamiento de enfermedades
CONC2025/0016647A CO2025016647A2 (es) 2023-05-02 2025-11-28 Inhibidores de egfr para el tratamiento de enfermedades

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WO2023133375A1 (fr) * 2022-01-05 2023-07-13 Blossomhill Therapeutics, Inc. Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de kinase
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