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WO2025222187A1 - Composés et leurs utilisations - Google Patents

Composés et leurs utilisations

Info

Publication number
WO2025222187A1
WO2025222187A1 PCT/US2025/025477 US2025025477W WO2025222187A1 WO 2025222187 A1 WO2025222187 A1 WO 2025222187A1 US 2025025477 W US2025025477 W US 2025025477W WO 2025222187 A1 WO2025222187 A1 WO 2025222187A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
attorney docket
patent attorney
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/025477
Other languages
English (en)
Inventor
Shawn E.r. SCHILLER
Wesley Francis Austin
Md Imran Hossain
Paige Justine MONSEN
Solymar NEGRETTI EMMANUELLI
Molly Madeline WILSON
Darshan Singh SAPPAL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Foghorn Therapeutics Inc
Original Assignee
Foghorn Therapeutics Inc
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Filing date
Publication date
Application filed by Foghorn Therapeutics Inc filed Critical Foghorn Therapeutics Inc
Publication of WO2025222187A1 publication Critical patent/WO2025222187A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings

Definitions

  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, 40 melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, 404 PATENT Attorney Docket No.: 51121-100WO2 rcoma, clear id sarcoma, senchymoma a), non-small 5 er.
  • a sarcoma e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma
  • the cancer e.g., 10 the cancer is a is synovial lung cancer, astric cancer, 15 cells contain o not contain 20 cells contain cancer.
  • cancer. 25 a subject in the foregoing n thereof.
  • bowel cancer breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, 40 esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; 405 PATENT Attorney Docket No.: 51121-100WO2 which may be ample, acute emia (AML), r, anaplastic 5 mphoma, bile r, brain stem uble negative of estrogen, cer, estrogen 10 east cancer, e or negative sitive breast drosarcoma, er, colorectal 15 toma, ductal geal cancer, a, gallblad
  • l carcinoma 30 rcin dder, bowel, ervi and stomach; l as; on-Hodgkin's l a; ding Ewing's , he oepithelioma, 35 synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; 40 carcinosarcoma, Hodgkin's disease, Wilm
  • Additional cancers which may be 407 PATENT Attorney Docket No.: 51121-100WO2 ample, acute emia (AML), r, anaplastic mphoma, bile 5 r, brain stem uble negative of estrogen, cer, estrogen east cancer, 10 e or negative sitive breast drosarcoma, er, colorectal toma, ductal 15 geal cancer, a, gallbladder stinal stromal ead and neck al carcinoma 20 , intrahepatic coma, kidney liposarcoma, r, lymphoma, Merkel cell 25 east cancer, toma, mouth elodysplastic uroendocrine ancer, ocular 30 geal cancer, m cell tumor, reatic cancer, er, peripheral toma, pineal 35 ) lymphoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small
  • the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation.
  • the cancer does not have, or has been determined not to 409 PATENT Attorney Docket No.: 51121-100WO2 r does not of the astic ds, the 5 of the to CBP (e.g., cell with an ereof, or any 10 nfection is an nodeficiency ukemia virus patitis C virus omegalovirus 15 V-2), human (e.g., Human mily (e.g., JC ubella virus).
  • EGFR epidermal growth factor receptor
  • te-to-severe ermediate- 30 que 25 ated by itis (e.g., te-to-severe ermediate- 30 ) t-essential eroid- urse juvenile i 35 ated by catricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • This method includes administering to the subject an effective amount of any of the foregoing 40 compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical 412 PATENT Attorney Docket No.: 51121-100WO2 viridae family .g., human T family (e.g., (e.g., Human 5 virus, herpes rpesvirus K*, , HPV E1)), d BK virus), 10 ancer, breast f, the method i mpounds or ma, prostate 15 bject in need he foregoing ogression of gic cancer in 20 ompounds or lonization of gic cancer in ompounds or 25 tivity of CBP ll carcinoma, hod including armaceutical 30 reast cancer, hematologic ound reduces 35 , 30%, 35%, 4 , , , , , , , , , or ) as compare o a reference.
  • human T family e.g.,
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of CBP by 40 at least 90% e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).
  • PATENT Attorney Docket No.: 51121-100WO2 ound reduces %, 45%, 50%, n of the level el of CBP by 5 to percent of that reduces as compared /or activity of 10 %, 55%, 60%, .g., 14 hours, or more).
  • ity of CBP by 60%, 65%, 15 days, 6 days, ound reduces , 30%, 35%, reference.
  • vity of EP300 a reference.
  • the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A 40 lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute 414 PATENT Attorney Docket No.: 51121-100WO2 l tic leukemia), cer is breast st cancer, or g’s sarcoma).
  • a hematologic cancer e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A 40 lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute 414 PATENT Attorney Docke
  • 5 ription Factor is metastatic ration and/or i iogenesis.
  • the cell 10 ancer spread rnatively, the atogenously.
  • f CBP and/or 15 ontacting the apy, surgery, therapy is a , asparagine- bitor, histone 20 ciated kinase i se inhibitor.
  • otoxic agents ts such as by a cancer that 35 e cancer has s, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) 415
  • 51121-100WO2 i nhibitor e.g., 5 ents and is dicates that be n, may be 10 2 alkyl group ber of e carbonyl nitrogen, or c ring.
  • arylalkyl 15 aturated bon atoms, to a straight 20 carbon 20 to a straight 0 carbon endently, H, 25 , arylalkyl, e recited alkylene, and escribed 30 al of 6 to 12 t limited to, yl group.
  • Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, 35 such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl.
  • the alkyl and the aryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.
  • a carbocyclylene is a divalent carbocyclyl group.
  • PATENT Attorney Docket No.: 51121-100WO2 valent mono- fully erm is heptyl, 5 ups (e.g., (bromo), or i which one or 10 ome roups as sed herein, in, in which 15 ur.
  • ch as used n, in which 20 ur.
  • ch as used al of 5 to 12 25 n, oxygen, heteroaryl azoyl, a heteroaryl 30 r from 7 to 0 alkyl C2- d with 1, 2, to 12 atoms 35 o ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.
  • a heterocyclylene is a divalent heteroocyclyl group.
  • hydroxyl as used herein, represents an –OH group.
  • thiol represents an –SH group.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the40 conformers.
  • the compounds described herein may be prepared as individual isomers by either isomer- 418 PATENT Attorney Docket No.: 51121-100WO2 nclude d (followed m of each n and 5 eric pair emoval of duct using pound is 0%, 90%, 10 med or %, or 99.9% depicted or nt optical e weight of 15 er or over med or 99%, or named or %, or 99.9% 20 picted or Percent ntiomer plus oles of the losed 25 compound either f the r.
  • ncer %, 5%, 10%, 30 lastic cells, t two (or ent regimen of 35 administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a 40 symptom, or other parameter related to the disorder is greater than what would be observed with one 420 PATENT Attorney Docket No.: 51121-100WO2 agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially dditiv wh ll dditiv r r t r th n dditiv ( n r i ti ) S nti l r b t nti lly simulta ding, but not 5 mucou rent routes. injectio by method ess 10 (e.g., p to obtain t ue from an value).
  • immun 15 immun ent polariza desorpt s spectro cytome 20 activity t. ient amount d herein r remedi 25 thereto cer, it is an ent respon level and/or describ h 30 as the disorde ut can ne cally effective amount” of an agent that reduces the level and/or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an agent that reduces the level and/or activity of CBP of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • inhibitor refers to any agent which reduces the level and/or activity of a protein (e.g., CBP).
  • Non-limiting examples of inhibitors include small molecule inhibitors, degraders, 40 antibodies, enzymes, or polynucleotides (e.g., siRNA).
  • 421 PATENT Attorney Docket No.: 51121-100WO2 referen “increa A level, a %, 5 about 2 t 60%, a %, about 1 of more th s compar out 10 0.1-fold fold, about 1 old, about 5 about 1 L, mg/mL 15 , or a relate n the art, a compo for 20 admini manufa regime or exampl for topical s a 25 sterile s ny other p the compo compo t.
  • disinteg fragran dispers ited to: buty , 35 croscar gelatin, , mannit , polyvin n dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), 40 stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
  • PATENT Attorney Docket No.: 51121-100WO2 accept le salts of medica 5 toxicity, Pharm le salts ar Salts:
  • P lts can be r 10 separat n as pharma ic acids o inorgan 15 accept le pharma e well-kn ases includin adipate 20 camph ethane hydrob lauryl s te, oleate, 25 pivalate , and val m, calcium includin dimeth 30 referen .
  • the ref le can be, ” or a prior al 35 cell or om a subje mple from a or RNA (e meant ed 40 value indicative of non-disease state, e.g., a value expected in a healthy control subject.
  • a 423 PATENT Attorney Docket No.: 51121-100WO2 normal X” or a low lue for a pa referen ase 5 or disor ed embodi t least o e of levels o also be use 10 ce with the therape , non-hu , be receivin y a 15 trained measur disease t are not ase; 20 stabiliz conditio favoursi t necess se.
  • Fig.2d is a graph illustrating the effect on % MYC on the tumor model LU99, in response in response to Compound 1a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 30 mg/kg QID for 3 weeks, 10mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • Fig.2d is a graph illustrating the effect on % MYC on the tumor model LU99, in response in response to Compound 1a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 30 mg/kg QID for 3 weeks, 10mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • FIG. 3a is a graph illustrating the effect on tumor volume on the tumor model A549, in response to Compound 1a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 35 871.
  • Fig.3b is a graph illustrating the effect on body weight on the tumor model A549, in response to Compound 1a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871.
  • Fig.3c is a graph illustrating the effect on % CBP on the tumor model A549, in response in response to 40 Compound 1a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg/kg QID for 5 weeks, 3 425 PATENT Attorney Docket No.: 51121-100WO2 mg/kg mple 871.
  • Fig.3d se to Compo ks, 3 5 mg/kg mple 871.
  • Fig.4A d DMSO Fig.4B nM 10 25nM
  • describ Fig.5A d DMSO Fig.5B nM 15 2.5nM
  • describ 20 related ds useful f cer e.g., s Compo 25 downst herein wherei A is a C B is a d L has t wherein A 1 is a bond between the linker and A; A 2 is a bond between B and the linker, 426 PATENT Attorney Docket No.: 51121-100WO2 or a ph eutic CBP a us in ki 5 differen , org among . Pr er.
  • the dis int ial thromb mia vera or sse itini ved 25 for use acto use in mod o-se e or high-ris lofib st- essenti mbo st disease nic t of 30 COVID com pus erythe s an cortico s.
  • the inflammatory and/or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or 40 chronic graft-versus-host disease.
  • myelofibrosis including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis
  • polycythemia vera steroid-refractory acute graft-versus-host disease, or 40 chronic graft-versus-host disease.
  • the inflammatory and/or autoimmune disorder 428 PATENT Attorney Docket No.: 51121-100WO2 is a res autoim rdi- Goutièr iatic 5 arthritis ar course tofacitin nib for trea inhibito 10 inflamm arthritis active a a result o e disorde 15 an.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia 40 areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, 430 PATENT Attorney Docket No.: 51121-100WO2 Aicardi dermat adminis baricitin 5 r medica tive amoun embodi ritis, psoriati , 10 alopeci erythe uveitis, r medica g to 15 the sub salt thereof e embodi tion (STAT) membe s, 20 axial sp s disease Sjogren psorias a 25 subject compo autoim an effectiv 30 T cell res method , or a phar se
  • myelofi 15 CDK4/ d CDK6 myelofi 15
  • rs disrupt used in y 20 and me nd abema aromat shown 25 inhibito re genera ore precise 30 Palboci break.
  • ed continu toleran d to 150 mg 35 maximi most ef including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4/6 inhibitor, or a 432 PATENT Attorney Docket No.: 51121-100WO2 pharma e embodi cancer, myelofi 5 cancer subject thod includin pharma 10 pharma e embodi s of functiono Pharm 15 und by theo , and/or h as can 20 amoun ore of): (a) ed tumor p tumor r subject 25 treatme , 90%, o reprodu ter of the t 30 treatme 0%, 90%, o reprodu rs visible 35 organs nodule ter) relative reprodu ed 433 PATENT Attorney Docket No.: 51121-100WO2 by coun or 50x).
  • t ced inflamm subject ell 10 (e.g., C activity er) relative measur 15 inflamm , 30%, 4 may be ine signalin ion, 20 or a do a JAK pa lso phosph me phosph - CSF, IL ct 25 the imm 10, IL-22, t , and/or subject s.
  • a JAK pa lso phosph me phosph - CSF IL ct 25 the imm 10, IL-22, t , and/or subject s.
  • 10 sympto inflamm or more o e For exa be deduce ges 15 of the c cytotox ng agents, vinca a s, 20 platinu adreno antiand leucovo s of chemot 25 sulfona meture triethyl ine; acetog e topotec ic 30 analog (includi yin; spongi ine, ifosfam phenes ocin, 35 fotemu , caliche Intl.
  • Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); 40 SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® 436 PATENT Attorney Docket No.: 51121-100WO2 (trastuz (ibritum I- 131); R (nataliz 5 SOLIRI (canaki NUMA (ipilimu trastuz s.
  • 10 e second tumor t int is an in 15 may be protein ent, such a checkp some e 20 molecu ipilimu bitor (e.g., a pembro t is an inhi 46; 25 MEDI4 inhibito fusion ., an inhi 3, GAL9, 30 combin some e antigen art.
  • a checkp some e 20 molecu ipilimu bitor e.g., a pembro t is an inhi 46; 25 MEDI4 inhibito fusion ., an inhi 3, GAL9, 30 combin some e antigen art.
  • these preparations may 40 contain a preservative to prevent the growth of microorganisms.
  • Conventional procedures and ingredients 438 PATENT Attorney Docket No.: 51121-100WO2 for the Pharm Formul include ion 5 of steril he extent t conven de a soluti aqueou 10 contain y, the sea aerosol age form in as compre can 15 also ta include as sugar, ntly in the f compo tion. 20 Intratu r discret .
  • a compo le injectio interve r 25 subject by implant in combin determ d 30 standar Dosag describ he 35 compo tent of the s clearan approp ed initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In 40 general, satisfactory results may be obtained when the compounds described herein are administered to 439 PATENT Attorney Docket No.: 51121-100WO2 a huma m).
  • Dose r exampl may 5 range f Kits t that red sert 10 with ins es (a) a ph cell or subj packag 15 20 25 30 35 40 45 50 440 PATENT Attorney Docket No.: 51121-100WO2 5 10 Unless t further nitroge 15 Prepar Interm (tetrah 20 Step 1.
  • tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure, diluted with water (1.5 L) and 25 extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4.
  • Step 2 2-benz tetrahy HF at -78 ° time T 20 remove n mixture resultin with brine (1 reduce 0.0 25 mL), co rtion and stir extract
  • Step 3 30 benzyl NaBH4 (148 mg, 3.91 mmol) was added to a solution of 2-benzyl 1-(tert-butyl) (2R)-3-fluoro-4- oxopyrrolidine-1,2-dicarboxylate (1.32 g, 3.91 mmol) in THF (9.24 mL) and EtOH (9.24 mL) at rt.
  • Step 2 NaIO4 ( en- 1-amin ture.
  • the res 10 combin and concen M in PE) to 219.9
  • Step 3 DAST ( chlorop d overnig aqueou rs 20 were w .
  • Step 5 din- 25 3-amin XPhos (difluor yl)pyra as stirred f L) 30 and ext then dri uct was pu 2- yl)-1-(te (ESI) m 35
  • Step 5 pyrazol Pentam ed solution of N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3- 40 c]pyridin-3-amine (290 mg, 0.764 mmol) in TEA (2.8 mL) and formic acid (2 mL).
  • Step 1 5 4-(pyrid nitropyr mmol) i g mixture nic layers 10 concen in PE) to Step 2: NBS (5 (6 15 g, 32.6 re. The res u ng mxure was quenc e w sa. a2 2 3 ( m ) an exrace w c ( m x 3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the organic te 10 was co (colum in 10 min; [M+H]+ 15 Interm oro- 1-[4-(2- Step 1: Titaniu o- 20 benzal HF (60 mL thyl acetate mixture concen was 25 used in Step 2: t-BuOK methyl 30 mmol) i .
  • the res combined organic layers were washed with brine (200 mL), then dried over anhydrous sodium sulfate, 484 PATENT Attorney Docket No.: 51121-100WO2 filtered fford the title Step 3: de 5 XPhos )- 2,2-difl yl- 1,3-dio dioxan atmosp x 10 3).
  • Step 1 4-(chlo 3.153 mmol) i resultin d 10 organic ate was co EA in P Step 2: 15 XantPh methox mg, 1.133 (6 mL). Th mixture ic 20 layers concen chroma a brow 25
  • Step 3 ine NaH (3 yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine (310 mg, 0.821 mmol) in DMF (4 mL) in portions at 0 °C. The resulting mixture was stirred for 0.5 h at room temperature.
  • Step 5 butoxyc 25 TEA (9 (497.84 as stirred - dihydro (480 m 30 temper x 3).
  • the co filtratio h C18-fla the title co 35
  • Step 6 (metho TFA (0 ht hyridin-1-yl]-1-[(1s,3s)-3-(tert-butoxycarbonyl)cyclobutyl]-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 40 (105 mg, 0.190 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at room temperature.
  • Step 7 (methyl HATU ( (difluor c]pyridi 1 10 mg, 0.3 d for 1 h at r Ac (30 mL Na2SO purified % 15 FA)) to Interm (difluo 20 Step 1: Cs2CO mmol) i chlorod ted with DC 25 anhydr desired purifica Step 2: 30 Pd(OA 3 g, 22.046 mmol), tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (6.62 g, 22.046 mmol) and AcOK (6.49 g, 66.138 mmol) in 1,4-dioxane (30 mL).
  • Step 4 PATENT Attorney Docket No.: 51121-100WO2 Step 4: mate Pd(OA tert- butyl (R -1- methyl for 5 overnig h EtOAc er anhydr chroma e compo 10 Step 5: HCl in -(4- fluoro-1 e resultin nder 15 reduce ext step dir Step 6: yl)phen 20 HATU ( azol- 3-yl)ph butoxyc mmol) and DI ature for 1 h.
  • Step 7 methyl HCl in (dimeth n-1- yl)-3,3- xture 35 was sti ssure to affor without 495 PATENT Attorney Docket No.: 51121-100WO2 Interm - fluoro- carbox 5
  • Step 1 Tetrabu [(1R)- 1-(4-br 97 g, 15.815 temper mL) 10 and ext , dried over an rude product s a light ye 15
  • Step 2 ethyl]ca Pd(OA enyl)- 2-(2-m 2.084 mmol) 0°C 20 for 4 h cted with Et r anhydr product a light yellow 25
  • Step 3 de HCl (4.
  • Step 1 K2CO3 (8.06 g, 58.302 mmol) was added to a stirred solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3- 30 dicarboxylate (5 g, 19.434 mmol) and oxane-4-carboximidamide hydrochloride (3.20 g, 19.434 mmol) in 497 PATENT Attorney Docket No.: 51121-100WO2 DMF (50 mL). The resulting mixture was stirred at 80°C for 3 h under nitrogen atmosphere.
  • the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
  • the invention features a method of decreasing the levels and/or activity of a CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the invention features a method of decreasing the levels of or activity of a MYC in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the invention features a method of decreasing the levels of or activity of a AR, i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • a AR i.e. androgen receptor
  • the cell is a cancer cell.
  • the invention features a method of treating a CBP-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the CBP-related disorder is cancer.
  • the invention features a method of inhibiting CBP, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the disclosure features a method of inhibiting the level and/or activity of CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the invention features a method of treating a disorder related to a EP300 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the disorder related to a EP300 loss of function mutation is cancer.
  • the subject is determined to have a EP300 loss of function disorder, for example, is determined to have a EP300 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of EP300 function).
  • the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesen
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma).
  • the sarcoma is synovial sarcoma.
  • the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer.
  • the cancer is gastric cancer.
  • the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors.
  • the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors.
  • the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors.
  • the prostate cancer is CRPC i.e. castration-resistant prostate cancer.
  • the prostate cancer is CRPC i.e. castration-sensitive prostate cancer.
  • the disclosure features a method of treating a CBP-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the CBP-related disorder is cancer.
  • the CBP-related disorder is infection.
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
  • the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demci
  • a prior therapy e.g.,
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma).
  • the sarcoma is synovial sarcoma.
  • the cancer has or has been determined to have CBP mutations. In some embodiments of any of the foregoing methods, the GBP mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, a EP300 mutation.
  • EGFR epidermal growth factor receptor
  • the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation.
  • ALK anaplastic lymphoma kinase
  • the cancer has, or has been determined to have, a KRAS mutation.
  • the CBP mutation is chromosomal translocation.
  • the disclosure provides a method of treating a disorder related to CBP (e.g., cancer or viral infections) in a subject in need thereof.
  • This method includes contacting a cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1 ), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Pap
  • the disclosure provides a method of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile id
  • the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound of the present disclosure.
  • the member of the JAK-STAT pathway is a janus kinase (JAK).
  • the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate-to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109/L, polycythemia vera, steroid- refractory acute graft-versus-host disease, chronic
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is non-infectious non-anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the disclosure provides a method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of suppressing a memory CD8 + T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • An aspect of the present invention relates to a method of treating a disorder related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced T cell (e.g., CD8 + memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in T cell (e.g., CD8 + memory T cells) activity.
  • T cell e.g., CD8 + memory T cells
  • T cell activity is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in inflammation.
  • inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation).
  • inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL- 1 1 , IL-13, IL-25, IL-27, and/or IL-31 , which in turn can affect the immune system response.
  • cytokines that interact with JAK1 , JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs (a/p) , IL-2, IL-4, IL- 7, IL-9, IL-15, and IL-21 .
  • the disclosure provides a method for treating a viral infection in a subject in need thereof.
  • This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr
  • HIV Human
  • the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of reducing the level and/or activity of CBP and/or EP300 in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophagael, stomach, or hematologic cell is in a subject.
  • the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 90% e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • the effective amount of the compound reduces the level of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to the percent of reduction of the level of EP300.
  • the effective amount of the compound that reduces the level of CBP by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to percent of reduction of the level of EP300.
  • the effective amount of the compound that reduces the level of CBP by at least 90% e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
  • the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).
  • the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of EP300 by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).
  • 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%
  • the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • the effective amount of the compound that reduces the level and/or activity of EP300 by at least 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).
  • the subject has cancer.
  • the cancer expresses CBP and/or EP300 protein and/or the cell or subject has been identified as expressing CBP and/or EP300.
  • the cancer expresses CBP protein and/or the cell or subject has been identified as expressing CBP.
  • the cancer expresses EP300 protein and/or the cell or subject has been identified as expressing EP300.
  • the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma).
  • the cancer is prostate cancer.
  • the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
  • a hematologic cancer e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphom
  • the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer).
  • the cancer is a bone cancer (e.g., Ewing’s sarcoma).
  • the cancer is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)).
  • the cancer is metastatic (e.g., the cancer has spread to the liver).
  • the metastatic cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis.
  • the migrating cancer is a cell migration cancer.
  • the cell migration cancer is a non-metastatic cell migration cancer.
  • the metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces.
  • the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously.
  • the effective amount of an agent that reduces the level and/or activity of CBP and/or EP300 is an amount effective to inhibit metastatic colonization of the cancer to the liver.
  • the method further includes administering to the subject or contacting the cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
  • an anticancer therapy e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
  • the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparaginespecific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.
  • an anticancer therapy is a chemo
  • Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • alkylating agents include, but are not limited to, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • paclitaxel paclitaxel
  • taxol docetaxel
  • taxotere cis-platinum
  • the anticancer agent is a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is abemaciclib, ribociclib, or palbociclib.
  • the method further comprises administering hormone therapy.
  • the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject.
  • the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents.
  • the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp O, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and/or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).
  • a CTLA-4 inhibitor e.g., ipilimumab
  • a PD-1 inhibitor e.g., Nivolumab or pembroli
  • a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety.
  • other atoms such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms.
  • an unsubstituted C2 alkyl group has the formula -CH2CH3.
  • a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups.
  • a reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • An alkylene is a divalent alkyl group.
  • alkenyl refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynyl refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • amino represents -N(RN1 )2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl.
  • the amino groups of the compounds described herein can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2).
  • aryl refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -C6 alkyl C6-C10 aryl, C1 -C10 alkyl C6-C10 aryl, or C1 -C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl.
  • the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.
  • Carbocyclyl refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms.
  • Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.
  • a carbocyclylene is a divalent carbocyclyl group.
  • cycloalkyl refers to a saturated, non-aromatic, and monovalent monodi-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms.
  • the cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic.
  • cycloalkoxy refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy).
  • halo means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy).
  • a heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O- A heteroalkenylene is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O-.
  • a heteroalkynylene is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • Unsubstituted heteroarylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -C6 alkyl C2-C9 heteroaryl, C1 -C10 alkyl C2-C9 heteroaryl, or C1 -C20 alkyl C2- C9 heteroaryl).
  • the alkyl and the heteroaryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.
  • heterocyclyl refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
  • a heterocyclylene is a divalent heteroocyclyl group.
  • hydroxyl represents an -OH group.
  • thiol represents an -SH group.
  • carbonyl represents an -C(O)- group.
  • thiocarbonyl represents an -C(S)- group.
  • sulfonyl represents an -S(O)2- group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol.
  • alkyl e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo,
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms.
  • Stereoisomers are compounds that differ only in their spatial arrangement.
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e. , they do not rotate the plane of polarized light.
  • Geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
  • Atoms (other than H) on each side of a carboncarbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • "R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds described herein may be prepared as individual isomers by either isomer- specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described.
  • the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
  • bronchial including by bronchial instillation
  • CBP refers to the Creb-binding protein in a human cell.
  • CBP-related disorder refers to a disorder that is caused or affected by the level of activity of CBP.
  • CBP loss of function mutation refers to a mutation in CBP that leads to the protein having diminished activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).
  • Exemplary CBP loss of function mutations include, but are not limited to, a homozygous CBP mutation and chromosomal translocations.
  • CBP loss of function disorder refers to a disorder (e.g., cancer) that exhibits a reduction in CBP activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).
  • cancer refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • determining the level of a protein or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners.
  • Methods to measure RNA levels are known in the art.
  • the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and/or activity of CBP (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and/or activity of CBP sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and/or activity of CBP.
  • a “therapeutically effective amount” of an agent that reduces the level and/or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an agent that reduces the level and/or activity of CBP of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • inhibitor refers to any agent which reduces the level and/or activity of a protein (e.g., CBP).
  • Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA).
  • level is meant a level of a protein, or mRNA encoding the protein, as compared to a reference.
  • the reference can be any useful reference, as defined herein.
  • a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01 -fold, about 0.02-fold, about 0.1 -fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1
  • decreasing the activity of CBP is meant decreasing the level of an activity related to CBP, or a related downstream effect.
  • the activity level of a CBP may be measured using any method known in the art, e.g., HIBit assay.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human.
  • a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • any other pharmaceutically acceptable formulation e.g., for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as
  • a “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I.
  • Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • a “reference” is meant any useful reference used to compare protein or RNA levels.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes.
  • the reference can be a normal reference sample or a reference standard or level.
  • a “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration.
  • a control e.g., a predetermined negative control value such as
  • reference standard or level is meant a value or number derived from a reference sample.
  • a “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”).
  • a subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker.
  • a normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.
  • the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • animal e.g., mammals such as mice, rats, rabbits, non-human primates, and humans.
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • the terms “treat,” “treated,” or “treating” mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.
  • variants and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein.
  • a variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.
  • the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., CBP) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.
  • a protein e.g., CBP
  • degradation moiety refers to a moiety whose binding results in degradation of a protein, e.g., CBP. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., CBP.
  • Fig. 1a is a graph illustrating the effect on tumor volume on the tumor model AGS, in response to Compound 1 a (10 mg/kg, BID for 5weeks, subcutaneous) and Compound 1 (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg QD for 5 weeks, subcutaneous) over 55 days as described in Example 869.
  • Fig. 1b is a graph illustrating the effect on body weight on the tumor model AGS, in response to Compound 1 a (10 mg/kg, BID for 5weeks, subcutaneous) and Compound 1 (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg QD for 5 weeks, subcutaneous) over 55 days as described in Example 869.
  • Fig. 1c is a graph illustrating the effect on % CBP on the tumor model AGS, in response to Compound 1 (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg for 5 weeks, subcutaneous) as described in Example 869.
  • Fig. 1d is a graph illustrating the effect on % MYC on the tumor model AGS, in response to Compound 1 (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg for 5 weeks, subcutaneous) as described in Example 869.
  • Fig. 2a is a graph illustrating the effect on tumor volume on the tumor model LU99, in response to Compound 1 a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 mg/kg QID for 3 weeks, 10 mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • Fig. 2b is a graph illustrating the effect on body weight on the tumor model LU99, in response to Compound 1 a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 mg/kg QID for 3 weeks, 10mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • Fig. 2c is a graph illustrating the effect on % CBP on the tumor model LU99, in response to Compound 1 a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 mg/kg QID for 3 weeks, 10mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • Fig. 2d is a graph illustrating the effect on % MYC on the tumor model LU99, in response in response to Compound 1 a (50mg/kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg/kg QID for 3 weeks, 10 mg/kg QID for 3 weeks, 10mg/kg BID for 3 weeks or 50 mg/kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.
  • Fig. 3a is a graph illustrating the effect on tumor volume on the tumor model A549, in response to Compound 1 a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .
  • Fig. 3b is a graph illustrating the effect on body weight on the tumor model A549, in response to Compound 1 a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .
  • Fig. 3c is a graph illustrating the effect on % CBP on the tumor model A549, in response in response to Compound 1 a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .
  • Fig. 3d is a graph illustrating the effect on % MYC on the tumor model A549, in response in response to Compound 1 a (50mg/kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg/kg QID for 5 weeks, 3 mg/kg QID for 5 weeks, 10mg/kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .
  • Fig. 4A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in MCF7 cells.
  • Fig. 4B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 12.5nM, 25nM, or 50nM), fulvestrant (e.g. 0 nM, 0.05nM, 0.1 nM), and 1 nM Compound 140 over 14 days as described in Example 867 in MCF7 cells.
  • abemaciclib e.g, 0 nM, 12.5nM, 25nM, or 50nM
  • fulvestrant e.g. 0 nM, 0.05nM, 0.1 nM
  • 1 nM Compound 140 over 14 days as described in Example 867 in MCF7 cells.
  • Fig. 5A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in T47D cells.
  • Fig. 5B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 1 ,25nM, 2.5nM, or 5.0nM), fulvestrant (e.g. 0 nM, 0.05nM, 0.1 nM), and 1 nM Compound 140 over 14 days as described in Example 867 in T47D cells.
  • abemaciclib e.g, 0 nM, 1 ,25nM, 2.5nM, or 5.0nM
  • fulvestrant e.g. 0 nM, 0.05nM, 0.1 nM
  • 1 nM Compound 140 over 14 days as described in Example 867 in T47D cells.
  • compositions and methods useful for the treatment of CBP- related disorders e.g., cancer and infection.
  • the disclosure further features compositions and methods useful for inhibition of the level and/or activity of CBP, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.
  • disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.
  • A is a CBP binding moiety
  • B is a degradation moiety
  • a 1 is a bond between the linker and A;
  • a 2 is a bond between B and the linker, or a pharmaceutically acceptable salt thereof.
  • Protein kinases regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.
  • JAKs Janus kinase family
  • STATs Signal Transducers and Activators of Transcription
  • JAK1 Janus kinase- 1
  • JAK2, JAK3 also known as Janus kinase, leukocyte; JAKL; and L- JAK
  • TYK2 protein-tyrosine kinase 2
  • STAT1 STAT1
  • STAT2, STAT3, STAT4, STAT5 STAT5A and STAT5B
  • STAT6 STAT6.
  • JAK2 Janus kinase 2
  • JAK-STAT pathway plays a role in transduction of cytokines and growth factor signals in inflammatory and autoimmune diseases.
  • Globally approved JAK inhibitors include abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, and upadacitinib.
  • JAK inhibitors include AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, and ritlecitinib.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the JAK inhibitor is AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • Filgotinib, oclacitinib, and upadacitinib are JAK1 inhibitors.
  • Filgotinib e.g., Jyseleca, Europe
  • Upadacitinib e.g., Rinvoq
  • moderate-to-severe rheumatoid arthritis psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, and refractory, moderate-to-severe atopic dermatitis.
  • the JAK inhibitor is a JAK1 inhibitor.
  • the JAK inhibitor is filgotinib, oclacitinib, or upadacitinib.
  • the JAK inhibitor is filgotinib or upadacitinib.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, and refractory, moderate-to-severe atopic dermatitis.
  • Fedratinib and pacritinib are JAK2 inhibitors.
  • Fedratinib e.g., Inrebic
  • Pacritinib e.g., Vonjo
  • Pacritinib acts as an inhibitor of both JAK2 and FLT3 that could be used to overcome resistance in existing acute myeloid leukaemia (AML) treatments. Pacritinib was tested in glioblastoma multiforme in combination with temozolomide.
  • the JAK inhibitor is a JAK2 inhibitor.
  • the JAK2 inhibitor is fedratinib or pacritinib.
  • the disorder is intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis or intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 10 9 /L.
  • Abrocitinib, baricitinib, and ruxolitinib are JAK1/2 inhibitors.
  • Abrocitinib e.g., Cibinqo
  • Baricitinib e.g., Olumiant
  • Ruxolitinib (e.g., Jakafi) is approved for use in intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and postessential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease. Baricitinib was authorized for emergency use for treatment of COVID-19 in combination with remdesivir.
  • Baricitinib was shown to improve symptoms of systemic lupus erythematosus and decrease inflammation/pruritus in atopic dermatitis when used with topical corticosteroids. Baricitinib is being studied in Aicardi-Goutieres syndrome and primary Sjogren’s syndrome. The combination of ruxolitinib and ERBB1/2/4 inhibitors also displayed synergistic anticancer activity against lung, breast, and ovarian cancer cells.
  • the JAK inhibitor is a JAK1/2 inhibitor.
  • the JAK1/2 inhibitor is abrocitinib, baricitinib, or ruxolitinib.
  • the inflammatory and/or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or chronic graft-versus-host disease.
  • the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung.
  • the inflammatory and/or autoimmune disorder is systemic lupus erythematosus, inflammation/pruritus in atopic dermatitis, Aicardi- Goutieres syndrome or primary Sjogren’s syndrome.
  • Tofacitinib is a JAK1/2/3 inhibitor.
  • Tofacitinib e.g., Xeljanz
  • Tofacitinib is approved for use in active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis.
  • Trials are underway to study tofacitinib in COVID-19 related lung problems.
  • Tofacitinib is being studied in combination with abrocitinib for treatment of toxic epidermal necrolysis.
  • the JAK inhibitor is a JAK1/2/3 inhibitor.
  • the JAK1/2/3 inhibitor is tofacitinib.
  • the inflammatory and/or autoimmune disorder is active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis.
  • the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung.
  • the inflammatory and/or autoimmune disorder is toxic epidermal necrolysis.
  • Delgocitinib is a non-selective JAK inhibitor that is approved for use in atopic dermatitis in Japan. Delgocitinib was tested and showed improvement in psoriasis and chronic hand eczema.
  • the JAK inhibitor is delgocitinib.
  • the inflammatory and/or autoimmune disorder is atopic dermatitis. In some embodiments, the inflammatory and/or autoimmune disorder is psoriasis or chromic hand eczema.
  • Peficitinib is a pan-JAK inhibitor approved for use in rheumatoid arthritis in Japan.
  • the pan-JAK inhibitor is peficitinib.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis.
  • Brepocitinib is being evaluated in active non-infectious non-anterior uveitis, dermatomyositis, and cicatricial alopecia.
  • Cerdulatinib is being evaluated for relapsed/refractory peripheral T-cell lymphoma, chronic lymphcytic leukemia, small lymphocytic lymphoma, B-cell non-hodgkin lymphoma, follicular lymphoma, T- cell lymphoma and vitiligo.
  • Decernotinib is a JAK3 inhibitor being evaluated for rheumatoid arthritis.
  • Deucravacitinib is being evaluated in pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pstulosis, Crohn’s disease, ulcerative colitis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, and systemic lupus erythematosus, among others.
  • Gandotinib is a JAK2 inhibitor being evaluated for myeloproliferative disorders including myelofibrosis, graft-versus host disease, and rheumatoid arthritis.
  • Itacitinib is a JAK1 inhibitor being evaluated for acute graft-versus-host disease.
  • Momelotinib is being evaluated for primary myelofibrosis, polycythemia vera myelofibrosis, postessential thrombocytopenia myelofibrosis, and non-small cell lung cancer, among others.
  • Nezulcitinib is being evaluated in COVID-19 related lung problems.
  • Ritlecitinib is a JAK3 inhibitor being evaluated for nonsegmental vitiligo, cutaneous T-cell lymphoma, cicatricial alopecia, and alopecia areata.
  • the JAK inhibitor is brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, icacitinib, momelotinib, nezulcitinib.or ritlecitinib.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a compound as described herein is administered as a replacement therapy for treating a disease associated with JAK activity.
  • the disease associated with JAK activity is an inflammatory and/or autoimmune disorder.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile id
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis.
  • the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the present disclosure provides a method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.
  • the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by JAK activity, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the disease, disorder, or medical condition mediated by JAK activity is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the member of the JAK-STAT pathway is a janus kinase (JAK).
  • the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).
  • the treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the present disclosure provides a method of inducing immune tolerance in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
  • the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is a skin disorder. In some embodiments, the skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. In some embodiments, the cancer is lymphoma, leukemia, or multiple myeloma.
  • the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).
  • the myeloproliferative disorder is myelofibrosis.
  • the myeloproliferative disorder is primary myelofibrosis (PMF).
  • the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF).
  • CDK4/6 inhibitors are a class of drugs that target cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), enzymes crucial for cell division and proliferation. By inhibiting these kinases, CDK4/6 inhibitors disrupt the cell cycle, preventing cancer cells from growing and dividing. These inhibitors are primarily used in the treatment of hormone receptor-positive (HR+), HER2-negative breast cancer, both in early and metastatic stages. Common CDK4/6 inhibitors include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).
  • CDK4/6 inhibitors are often administered in combination with hormone therapy, such as aromatase inhibitors or fulvestrant, to enhance their effectiveness. This combination therapy has been shown to improve progression-free survival and overall survival in patients. Side effects of CDK4/6 inhibitors can include fatigue, gastrointestinal disturbances, and bone marrow suppression, but they are generally less severe than those associated with traditional chemotherapy.
  • hormone therapy such as aromatase inhibitors or fulvestrant
  • inhibitors represent a significant advancement in targeted cancer therapy, offering a more precise approach to treating certain types of breast cancer and improving patient outcomes.
  • CDK4/6 inhibitors The dosing of CDK4/6 inhibitors varies depending on the specific drug and clinical setting.
  • Palbociclib is typically administered at a dose of 125 mg once daily for 21 days, followed by a 7-day break. Ribociclib is given at 600 mg once daily for 21 days, with a 7-day off period.
  • Abemaciclib is dosed continuously at 200 mg twice daily. Dose adjustments are often necessary based on the patient's tolerance and side effects, such as neutropenia or diarrhea. For instance, abemaciclib may be reduced to 150 mg or 100 mg twice daily if adverse reactions occur. These dosing schedules are designed to maximize therapeutic efficacy while managing potential side effects, ensuring that patients receive the most effective treatment with minimal discomfort.
  • the present disclosure provides a method of treating cancer the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4/6 inhibitor, or a pharmaceutically acceptable salt thereof (see e.g., Figs. 4A/4B and 5A/5B and Example 867).
  • the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer.
  • the cancer is gastric cancer.
  • the cancer is metastatic.
  • the subject or cancer has a EP300 loss of function mutation.
  • the present disclosure provides a method of treating gastric cancer the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4/6 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the cancer is gastric cancer.
  • the cancer is metastatic.
  • the subject or cancer has a EP300 loss of function mutation.
  • the compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of CBP, e.g., by inhibiting the activity or level of the CBP in a cell within a mammal.
  • An aspect of the present invention relates to methods of treating disorders related to CBP such as cancer in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject.
  • Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
  • Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • the number of metastatic nodules may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
  • An aspect of the present invention relates to methods of treating disorders related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced T cell (e.g., CD8 + memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.
  • T cell e.g., CD8 + memory T cells
  • Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in T cell (e.g., CD8 + memory T cells) activity.
  • T cell e.g., CD8 + memory T cells
  • T cell activity is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • T cell activity may be measured by any reproducible means of measurement.
  • Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in inflammation.
  • inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • T cell activity may be measured by any reproducible means of measurement.
  • Treating inflammatory disorders and/or autoimmune disorders can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation).
  • each cytokine receptor is paired with a JAK pair.
  • the JAK pair When the JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, which creates a STAT binding site for a STAT to then also become phosphorylated.
  • inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM- CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL-11 , IL-13, IL-25, IL-27, and/or IL-31 , which in turn can affect the immune system response.
  • cytokines that interact with JAK1 , JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs (a/p), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 .
  • Tereating cancer, inflammatory disorders, and/or autoimmune disorders can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • Treating cancer, inflammatory disorders, and/or autoimmune disorders can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • a method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer, inflammatory disorders, and/or autoimmune disorders or symptoms associated therewith, or in combination with other types of therapies to treat cancer, inflammatory disorders, and/or autoimmune disorders.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.
  • the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer).
  • chemotherapeutic agents e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer.
  • alkylating agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
  • 5-fluorouracil 5-FU
  • leucovorin LV
  • irenotecan oxaliplatin
  • capecitabine paclitaxel
  • doxetaxel Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
  • Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein.
  • Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041 -1047 (2000).
  • the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
  • the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®).
  • the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer.
  • Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (pan
  • the second agent may be a therapeutic agent which is a non-drug treatment.
  • the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
  • the second agent may be a checkpoint inhibitor.
  • the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody).
  • the antibody may be, e.g., humanized or fully human.
  • the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011 ).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof.
  • B7-H3 e.g., MGA271
  • B7-H4 BTLA
  • HVEM TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof.
  • the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy.
  • the T cell is an activated T cell.
  • the T cell may be modified to express a chimeric antigen receptor (CAR).
  • CAR modified T (CAR-T) cells can be generated by any method known in the art.
  • the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject.
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466;
  • a desirable protein e.g., a CAR
  • the second agent may be a Janus Kinase (JAK) inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after the second therapeutic agent.
  • compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • the compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound described herein may also be administered parenterally. Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form includes an aerosol dispenser
  • a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • a compound described herein may be administered intratumorally, for example, as an intratumoral injection.
  • Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors.
  • Local, regional, or systemic administration also may be appropriate.
  • a compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals.
  • the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection.
  • Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.
  • the compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the dosage of the compounds described herein, and/or compositions including a compound described herein can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.01 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg).
  • the dosage amount can be calculated using the body weight of the patient.
  • the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg/kg (e.g., 0.25-25 mg/kg).
  • kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of CBP in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein.
  • the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of CBP in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • Step 4 tert-Butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate t-BuONa (2.31 g, 24.1 mmol) and RuPhos Pd 3G (671 mg, 0.80 mmol) were added to a stirred solution of tert-Butyl 3-bromo-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (3.1 g, 8.0 mmol) and 7-(difluoromethyl)-1 ,2,3,4-tetrahydroquinoline (1 .5 g, 8.0 mmol) in 1 ,4- di
  • NBS (1 .0 g, 5.6 mmol) was added in portions at 0 °C to a stirred solution of tert-Butyl 3-(7- (difluoromethyl)-3,4-dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (3.1 g, 6.3 mmol) in ACN (30.0 mL). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure.
  • Step 7 1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
  • NBS (74.7 mg, 0.42 mmol) was added in portions at 0°C to a stirred solution of tert-butyl 3-(3,4- dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (230 mg, 0.52 mmol) in ACN (3 mL).
  • the reaction mixture was stirred for 1 h at room temperature.
  • the reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered and evaporated.
  • Acetic anhydride (37.1 mg, 0.36 mmol) was added dropwise at 0°C to a stirred solution of 6-Bromo-1 -(1 - (tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4-tetrahydroquinoline (138 mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol) in DCM (2 mL). The reaction mixture was stirred for 1 h at room temperature.
  • RuPhos Pd G3 (106 mg, 0.13 mmol) and t-BuONa (365 mg, 3.8 mmol) were added to a stirred solution of tert-butyl 3-bromo-1 -methyl-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 1 .26 mmol) and 7-(difluoromethyl)-1 ,2,3,4-tetrahydroquinoline (232 mg, 1.26 mmol) in dioxane (12 mL). The reaction mixture was stirred for 1 h at 100°C.
  • NBS 29.7 mg, 0.17 mmol
  • tert-butyl 3-(7-(difluoromethyl)-3,4- dihydroquinoli n-1 (2H)-yl)-1 -methyl-1 ,4,6,7-tetrahydro-5H-pyrazoio[4,3-c]pyridine-5-carboxyiate 3 70 mg, 0.17 mmol
  • ACN ACN
  • the reaction mixture was stirred for 1 h at room temperature.
  • the reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL x 2) and brine (30 mL).
  • Acetic anhydride (61 .6 mg, 0.60 mmol) was added at 0°C to a stirred solution of 6-Bromo-7- (difluoromethyl)-l -(1 -methyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4-tetrahydroquinoline (160 mg, 0.40 mmol) and TEA (122 mg, 1 .21 mmol) in DCM (4 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with water (30 mL x 2) and brine (30 mL).
  • Iron powder (17.3 g, 310.8 mmol, 6 eq) was added to a stirred solution of 1 -(2-chloroethoxy)-4- (difluoromethyl)-2-nitrobenzene (13.0 g, 51.8 mmol) in AcOH (60 mL). After stirring for 4 hours, the reaction was quenched with water (150 mL) and extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SC , and concentrated under reduced pressure.
  • CS2CO3 (63.3 g, 203 mmol) was added to a stirred solution of tert-butyl 3-bromo-1 H,4H,6H,7H- pyrazolo[4,3-c]pyridine-5-carboxylate (20.5 g, 67.8 mmol) and oxan-4-yl methanesulfonate (18.3 g, 101 .7 mmol) in DMAc (130 mL). The resulting mixture was stirred for 3.5 h at 80°C. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (400 mL x 2). The organic layers were combined and washed with brine (100 mL).
  • Step 6 1-(3-(6-(Difluoromethyl)-2,3-dihydro-4H-benzo[b][1 ,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4- yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
  • CS2CO3 (20.7 g, 63.6 mmol) and XPhos Pd 3G (2.15 g, 2.5 mmol) was added to a stirred solution of 7- (difluoromethyl)-l ,2,3,4-tetrahydroquinoline 7 (3.94 g, 21 .2 mmol) and 1 -(3-bromo-1 -(tetrahydro-2H- pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1 -one (8.99 g, 27.4 mmol) in nitrogen degassed 1 ,4-dioxane (100 mL).
  • NBS (3.73 g, 21 .0 mmol) was added to a stirred solution of 1 -(3-(6-(difluoromethyl)-2,3-dihydro-4H- benzo[b][1 ,4]oxazin-4-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1 -one (9.07 g, 21 .0 mmol) in MeCN (100 ml_) in 3 portions at 0 °C.
  • Step 8 1- ⁇ 3-[6-(Difluoromethyl)-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1 ,4- benzoxazin-4-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl ⁇ ethanone
  • Step 3 tert-Butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
  • the crude product (1 .9 g) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5pm; Mobile Phase A: Water(0.05% HCI), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 11% B to 127% B in 8 min; Wave Length: 254nm/220nm nm; RT1 (min): 9.68) to afford the title compound (1 .2 g, 4.72 mmols) as a yellow solid.
  • 1 H NMR (300 MHz, DMSO-d6) 5 8.67 - 8.59 (m, 2H), 8.35 - 8.27 (m, 1 H).
  • LCMS (ESI) m/z [M+H] + 254.0.
  • Step 3 Ethyl 6-bromo-8-chloro-1,2,4-benzotriazine-3-carboxylate (2-Ethoxy-2-oxoethyl)dimethylsulfanium bromide (1 .00 g, 4.34 mmol) was added to a stirred solution of 6- bromo-4-chloro-1 -trifluoromethanesulfonyl-1 ,2,3-benzotriazole (1 .32 g, 3.62 mmol) and K2CO3 (0.60 g, 4.34 mmol) in i-PrOH (20 mL). The resulting mixture was stirred for 2 h at room temperature.
  • Step 2 N-(6-chloro-5-(difluoromethyl)pyridin-3-yl)-1 ,1-diphenylmethanimine t-BuONa (9.3 g, 96.5 mmol), XantPhos (8.6 g, 14.8 mmol) and Pd2(dba)s (6.8 g, 7.4 mmol) was added to a stirred mixture of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (18.0 g, 74.2 mmol) and diphenylmethanimine (13.5 g, 74.2 mmol) in toluene (200 mL) under nitrogen atmosphere.
  • NBS (9.37 g, 52.6 mmol) in ACN (50 mL) was added dropwise at 0 °C to a stirred solution of 6-chloro-5- (difluoromethyl)pyridin-3-amine (9.4 g, 52.6 mmol) in ACN (100 mL).
  • the resulting mixture was stirred for 1 h at room temperature.
  • the solvent was removed under reduced pressure.
  • the residue was quenched with saturated Na2S20s (aq.).
  • the resulting mixture was extracted with EtOAc (300 mL x 2).
  • the combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Rh(PPh3)3CI (1 .5 g, 1 .6 mmol) was added to a stirred solution of ethyl (E)-3-(3-amino-6-chloro-5- (difluoromethyl)pyridin-2-yl)acrylate (9.1 g, 32.9 mmol) in MeOH (150 mL). The resulting mixture was stirred for 1 h at room temperature under hydrogen atmosphere. The solvent was removed under reduced pressure. The mixture was filtered, the filter cake was washed with EtOAc (200 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (9.2 g, crude). The crude product was used in the next step directly without further purification.
  • LCMS (ESI) m/z [M+H]+ 279.00
  • Step 8 6-Chloro-7-(difluoromethyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine
  • Acetic anhydride (82.6 mg, 0.810 mmol) was added at 0°C to a stirred solution of N-[4-chloro-3- (difluoromethyl)phenyl]-N-methyl-1 -(oxan-4-yl)-4H,5H,6H,7H-pyrazolo [4,3-c]pyridin-3-amine (292 mg, 0.736 mmol) and TEA (223 mg, 2.21 mmol) in DCM (4 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • GPhos Pd G6 TES (6.63 g, 7.01 mmol) was added to a stirred solution of 1 -[3-bromo-1 -(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 g, 70.08 mmol), 6-chloropyridin-3-amine (9.01 g, 70.08 mmol) and sodium trimethylsilanolate (15.72 g, 140.1 mmol) in THF (300 mL). The mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (1000 mL).
  • Pd(dppf)Cl2CH2Cl2 (1 .44 g, 1 .77 mmol) was added to a solution of 4-bromo-7-fluoroquinoline (2 g, 8.85 mmol) and TEA (2.69 g, 26.54 mmol) in MeOH (60 mL). The resulting mixture was stirred for overnight at 100°C under 20 atm with carbon monoxide atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • XPhos Pd G3 (0.61 g, 0.717 mmol) was added to a stirred solution of methyl 7-fluoro-1 ,2,3,4- tetrahydroquinoline-4-carboxylate (1 .5 g, 7.17 mmol), 3-bromo-1 -(oxan-4-yl) pyrazolo[4,3-c]pyridine (2.02 g, 7.17 mmol) and CS2CO3 (7.01 g, 21 .51 mmol) in dioxane (30 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (150 mL x 3).
  • NBS (191 mg, 1 .07 mmol) was added in portions at 0 °C to a stirred solution of methyl 1 -[5-acetyl-1 - (oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-fluoro-3,4-dihydro-2H-quinoline-4-carboxylate (500 mg, 1 .10 mmol) in MeCN (6 ml_). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with saturated Na2S20s (100 mL) and extracted with EtOAc (100 mL x 3).
  • Benzyl alcohol (850 mg, 7.86 mmol) was added to a stirred solution of 2,3,6-trifluoro-5-nitropyridine (1 .4 g, 7.86 mmol), TBAHS (267 mg, 0.786 mmol) and NaOH (314 mg, 7.86 mmol) in DCM (15 mL). The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous NagSC .
  • BH3-THF 8 mL, 83.59 mmol was added dropwise at 0 °C to a stirred solution of 6-(benzyloxy)-7-fluoro- 1 H,3H-pyrido[2,3-b][1 ,4]oxazin-2-one (840 mg, 3.06 mmol) in THF (8 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with MeOH (50 mL) at 0°C, diluted with H2O (300 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4.
  • XPhos Pd G3 (504 mg, 0.596 mmol) was added to a stirred mixture of 6-(benzyloxy)-7-fluoro-2,3-dihydro- 1 H-pyrido[2,3-b][1 ,4]oxazine (775 mg, 2.98 mmol), 3-bromo-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridine (1 .01 g, 3.57 mmol) and t-BuONa (859 mg, 8.93 mmol) in 1 ,4-dioxane (10 mL). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere.
  • Step 7 1-(3-(6-(Benzyloxy)-7-fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
  • Step 8 1-(3-(7-Fluoro-6-hydroxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
  • Step 1 tert-Butyl 4-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1 -carboxylate
  • XPhos Pd G3 (0.54 g, 0.640 mmol) was added to a stirred mixture of tert-butyl 3,4-dihydro-2H- quinoxaline-1 -carboxylate (1 g, 4.27 mmol), 3-bromo-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridine (1.20 g, 4.27 mmol) and CS2CO3 (2.78 g, 8.54 mmol) in 1 ,4-dioxane.
  • TEA 580.1 mg, 5.73 mmol
  • the resulting mixture was stirred for 2 h at room temperature.
  • the mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3).
  • Step 4 tert-Butyl 4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-bromo-2,3- d ihyd roqu i noxali ne-1 -carboxylate
  • NBS (332.6 mg, 1 .87 mmol) was added in portions to a stirred solution of tert-butyl 4-[5-acetyl-1 -(oxan-4- yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1 -carboxylate (750 mg, 1 .56 mmol) in MeCN (10 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with sat. Na2S20s (100 mL) and extracted with EtOAc (80 mL x 3).
  • Pd(dppf)Cl2-CH2Cl2 (1 .7 g, 2.1 mmol) was added to a solution of 2-bromo-1 -chloro-4-nitrobenzene (5 g, 21 mmol), 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (4.2 g, 21 .1 mmol) and K3PO4 (8.98 g, 42.3 mmol) in 1 ,4-dioxane (80 mL) and H2O (20 mL). The resulting mixture was stirred for 1 h at 80°C under nitrogen atmosphere.
  • Step 5 N-[4-chloro-3-(2,2-difluoroethyl)phenyl]-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine
  • XPhos Pd G3 (662.6 mg, 0.78 mmol) was added to a solution of 4-chloro-3-(2,2-difluoroethyl)aniline (750 mg, 3.9 mmol), 3-bromo-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridine (1 .1 g, 3.9 mmol) and t-BuONa (752.4 mg, 7.8 mmol) in 1 ,4-dioxane (15 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3).
  • Step 6 N-[4-chloro-3-(2,2-difluoroethyl)phenyl]-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c] pyridin-3- amine
  • Step 7 methyl 3- ⁇ [4-chloro-3-(2,2-difluoroethyl)phenyl]amino ⁇ -1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridine-5-carboxylate
  • Step 8 methyl 3- ⁇ [4-chloro-3-(2,2-difluoroethyl)phenyl](methyl)amino ⁇ -1-(oxan-4-yl)-4H,6H, 7H- pyrazolo[4,3-c]pyridine-5-carboxylate
  • Step 1 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-methylbutanoate
  • Step 4 tert-butyl N-[(2R)-3-fluoro-1 -[(2S,4R)-4-hydroxy-2-(methylcarbamoyl)pyrrolidin-1 -yl]-3-methyl-1 - oxobutan-2-yl]carbamate
  • Step 5 (2S, 4R)-1-[(2R) -2-amino-3-fluoro-3-methylbutanoyl]-4-hydroxy-N-methylpyrrolidine-2- carboxamide
  • Step 1 2-benzyl 1 -(tert-butyl) (S)-4-oxopyrrolidine-1,2-dicarboxylate (2S)-1 -tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (12.0 g, 52.4 mmol) was added to DMA (120.0 mL) followed by K2CO3 (7.96 g, 57.6 mmol) and benzyl bromide (8.95 g, 6.2 mL, 52.4 mmol) at 23 °C. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere.
  • Step 2 2-benzyl 1 -(tert-butyl) (2R)-3-fluoro-4-oxopyrrolidine-1 ,2-dicarboxylate
  • Step 3 2-benzyl 1 -(tert-butyl) (2S,3S R)-3-fluoro-4-hydroxypyrrolidine-1,2-dicarboxylate (A) and 2- benzyl 1 -(tert-butyl) (2S,3R,4S)-3-fluoro-4-hydroxypyrrolidine-1,2-dicarboxylate (B)
  • the crude was purified by FCC (Eluent: 0 to 50% EA in heptane) to provide the two products 2-benzyl 1 -(tert-butyl) (2R,3S,4R)-3-fluoro-4-hydroxypyrrolidine-1 ,2-dicarboxylate (A) (152 mg) and 2-benzyl 1 -(tert-butyl) (2R,3R,4S)-3-fluoro-4-hydroxypyrrolidine-1 ,2-dicarboxylate (B) (381 mg).
  • FCC Eluent: 0 to 50% EA in heptane
  • Step 4 Benzyl (2R,3S,4R)-3-fluoro-4-hydroxypyrrolidine-2-carboxylate
  • Step 5 benzyl (2R,3S,4R)- 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3-fluoro-4- hydroxypyrrolidine-2-carboxylate
  • Step 6 (2R,3S,4R)- 1 -((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3-fluoro-4- hydroxypyrrolidine-2-carboxylic acid
  • Step 7 tert-butyl ((S)-1-((2R,3S,4R)-3-fluoro-4-hydroxy-2-(methylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl- 1 -oxobutan-2-yl)carbamate (2R,3R,4S)-1 -(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3-fluoro-4-hydroxypyrrolidine2- carboxylic acid (1 10.0 mg, 303.5 pmol) was dissolved in DMF (3.3 mL) and added DIPEA (1 1121 mg, 159 pL, 910.6 pmol), methanamine (23.57 mg, 379.4 pL, 2.00 molar, 758.8 pmol), and HATU (230.8 mg,
  • Step 1 methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate
  • NBS (1 .00 g, 5.645 mmol) was added to a mixture of methyl 1 H-pyrazolo[4,3-b]pyridine-5-carboxylate (1 g, 5.6 mmol) in ACN (10 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. Na2S20s (aq.) (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate
  • CS2CO3 (2035.90 mg, 6.248 mmol) was added to a mixture of methyl 3-bromo-1 H-pyrazolo[4,3- b]pyridine-5-carboxylate (800 mg, 3.124 mmol) and oxan-4-yl methanesulfonate (563.06 mg, 3.124 mmol) in DMF (8 mL). The resulting mixture was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 4 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1 ,5-naphthy ridi n- 1 -y l]-N-methy I- 1 -(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxamide
  • NMI (47.21 mg, 0.576 mmol) and methylamine (5.95 mg, 0.192 mmol) was added to a stirred solution of methyl 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1 ,5-naphthyridin-1 -yi]-1 -(oxan-4-yl)pyrazolo[4,3- b]pyridine-5-carboxylate (88.9 mg, 0.192 mmol) in ACN (1.5 mL). TCFH (107.55 mg, 0.384 mmol) was added to the reaction and the resulting mixture was stirred for 1 h at room temperature under air atmosphere.
  • Step 1 (E)-2-(6-bromo-3-chloropyridin-2-yl)-N,N-dimethylethen-1 -amine
  • Step 4 N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)- 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazolo[4,3-c]pyridin- 3-amine
  • XPhos Pd G3 (279.30 mg, 0.330 mmol) was added to a stirred solution of 6-bromo-3-chloro-2- (difluoromethyl)pyridine (400 mg, 1 .650 mmol), K3PO4 (700.40 mg, 3.300 mmol) and 1 -(oxan-4- yl)pyrazolo[4,3-c]pyridin-3-amine (360.09 mg, 1 .650 mmol) in dioxane (5 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3).
  • Step 5 N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6, 7-tetrahydro- 1 H- pyrazolo[4,3-c]pyridin-3-amine
  • Pentamethylcyclopentadienylrhodium(lll) chloride dimer (47.19 mg, 0.076 mmol) was added to a stirred solution of N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazolo[4,3- c]pyridin-3-amine (290 mg, 0.764 mmol) in TEA (2.8 mL) and formic acid (2 mL). The resulting mixture was stirred for 1 h at room temperature. The mixture was basified to pH 8 with saturated NaHCCh (aq.) and extracted with CH2CI2 (30 mL x 3).
  • Step 6 1-(3-((5-chloro-6-(difluoromethyl)pyridin-2-yl)amino)-1-(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7- tetrahydro-5H-pyrazolo[4, 3-c]pyridin-5-yl)ethan- 1 -one
  • Acetic anhydride (42.56 mg, 0.417 mmol) was added to a stirred mixture of N-(5-chloro-6- (difluoromethyl)pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3- amine (160 mg, 0.417 mmol) and TEA (126.55 mg, 1 .251 mmol) in DCM (3 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 7 methyl 3-[6-chloro-7-(difluoromethoxy)-3,4-dihydro-2H- 1 ,5-naphthyridin-1 -yl]-1 -(oxan-4-yl)- 4H,6H, 7H-pyrazolo[4, 3-c]pyridine-5-carboxylate
  • Step 1 methyl 5-amino-2-chloropyridine-3-carboxylate 4-(pyridin-4-yl) pyridine (39.06 mg, 0.230 mmol) was added to a stirred solution of methyl 2-chloro-5- nitropyridine-3-carboxylate (10 g, 46.172 mmol) and (dihydroxyboranyl)boronic acid (12.41 g, 138.26 mmol) in DMF (100 mL). The resulting mixture was stirred for 5 min at room temperature. The resulting mixture was diluted with saturated water (1 L) and extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4.
  • Step 2 methyl 5-amino-6-bromo-2-chloropyridine-3-carboxylate
  • NBS (5.82 g, 32.690 mmol) was added to a solution of methyl 5-amino-2-chloropyridine-3-carboxylate (6 g, 32.690 mmol) in MeCN (65 mL) at 0 °C. The resulting mixture was stirred for 1 h at room temperature.
  • Step 3 methyl 5-amino-2-chloro-6-[(1 E)-3-ethoxy-3-oxoprop-1 -en-1 -yl]pyridine-3-carboxylate CS2CO3 (12.27 g, 37.666 mmol) was added to a stirred solution of methyl 5-amino-6-bromo-2- chloropyridine-3-carboxylate (5 g, 18.833 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)prop-2-enoate (3.83 g, 16.950 mmol) in dioxane (60 mL) and H2O (15 mL) followed by the addition of Pd(dppf)Cl2-CH2Cl2 (1 .38 g, 1 .883 mmol).
  • Step 4 methyl 5-amino-2-chloro-6-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylate
  • PtC>2 (3.19 g, 14.501 mmol) was added to a solution of methyl 5-amino-2-chloro-6-[(1 E)-3-ethoxy-3- oxoprop-1 -en-1 -yl]pyridine-3-carboxylate (4 g, 14.501 mmol) in MeOH (40 mL). The resulting mixture was stirred for 1 h at room temperature under 10 atm of hydrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with MeOH (100 mL x 3), and the filtrate was concentrated under reduced pressure.
  • Step 5 methyl 2-chloro-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate
  • DPPA (2.91 g, 10.590 mmol) was added to a stirred solution of 2-chloro-6-oxo-7,8-dihydro-5H-1 ,5- naphthyridine-3-carboxylic acid (1 .6 g, 7.060 mmol) and EtsN (2.14 g, 21 .180 mmol) in t-BuOH (15 mL). The resulting mixture was stirred for 3 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4.
  • Step 8 tert-butyl N-(2-chloro-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate Borane-tetrahydrofuran complex (1 M in THF) (6 mL, 0.067 mmol) was added dropwise to a stirred solution of tert-butyl N-(2-chloro-6-oxo-7,8-dihydro-5H-1 ,5-naphthyridin-3-yl)carbamate (1.1 g, 3.694 mmol) in THF (6 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere.
  • Step 9 tert-butyl N- ⁇ 2-chloro-5-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-7,8-dihydro-6H- 1,5-naphthyridin- 3-yl ⁇ carbamate
  • Step 10 2-chloro-5-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-7,8-dihydro-6H-1,5-naphthyridin-3-amine HCI in 1 ,4-dioxane(4.0 M) (4 mL) was added dropwise to a solution of tert-butyl N- ⁇ 2-chloro-5-[1 -(oxan-4- yl)pyrazolo[4,3-c]pyridin-3-yl]-7,8-dihydro-6H-1 ,5-naphthyridin-3-yl ⁇ carbamate (620 mg, 1.278 mmol) in DCM (4 mL).
  • Step 11 2-chloro-N, N-dimethyl-5-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-7,8-dihydro-6H- 1,5- naphthyridin-3-amine
  • Step 12 2-chloro-N, N-dimethyl-5-[ 1 -(oxan-4-yl) -4H,5H,6H, 7H-pyrazolo[4, 3-c]pyridin-3-yl]- 7, 8-dihydro-6H- 1 ,5-naphthyridin-3-amine
  • Step 13 methyl 3-[6-chloro-7-(dimethylamino)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1-(oxan-4-yl)- 4H,6H, 7H-pyrazolo[4, 3-c]pyridine-5-carboxylate
  • Step 1 methyl 2-[(5-fluoro-3-nitropyridin-2-yl)oxyJacetate
  • Step 2 7- fluoro- 1 H, 3H-pyrido[2, 3-b][1,4 ]oxazin-2-one
  • Step 3 7-fluoro-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazine Borane-tetrahydrofuran complex (1 .0 M in THF) (40 mL) was added to a stirred solution of 7-fluoro- 1 H,3H-pyrido[2,3-b][1 ,4]oxazin-2-one (4 g, 23.792 mmol) in THF (40 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of MeOH (40mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature.
  • Step 4 6-chloro-7-fluoro- 1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazine
  • NCS (3.03 g, 22.706 mmol) was added to a stirred solution of 7-fluoro-1 H,2H,3H-pyrido[2,3- b][1 ,4]oxazine (3.5 g, 22.706 mmol) in DMF (50 mL). The resulting mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NazCCh (aq.) (800 mL) and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (800 mL x 2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 1 tert-butyl (S)-(1 -(4-(4-bromo-3-fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl)ethyl)carbamate
  • AcOK (1961 .56 mg, 19.986 mmol) was added to a stirred mixture of tert-butyl N-[(1 S)-1 -(4- bromophenyl)ethyl]carbamate (2 g, 6.662 mmol) and 4-bromo-3-fluoro-1 -methylpyrazole (131 1 .75 mg, 7.328 mmol) and in DMF (20 mL).
  • Step 2 tert-butyl (S)-(1 -(4-(3-fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl)ethyl)carbamate
  • Step 3 (S)-1 -(4-(3-fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl)ethan-1 -amine 2,2,2-trifluoroacetate Trifluoroacetic acid (3.00 mL) was added to a stirred solution of tert-butyl (S)-(1 -(4-(3-fluoro-1 -methyl-1 H- pyrazol-5-yl)phenyl)ethyl)carbamate (600 mg, 1 .879 mmol) in DCM (3 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the desired intermediate (835 mg, crude) as a yellow oil that was used in the next step directly without further purification.
  • LCMS (ESI) m/z [M+H]+ 220.15.
  • Step 4 (S)-1 -(4-(3,4-dif luoro-1 -methyl-1 H-pyrazol-5-yl)phenyl)ethan-1 -amine 1 -ChloroMethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1269.14 mg, 3.582 mmol) was added to a stirred solution of (S)-1 -(4-(3-fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl)ethan-1 -amine 2,2,2- trifluoroacetate (796 mg, 2.388 mmol) in MeCN (10 mL).
  • Step 1 (S,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide
  • Titanium(4 + ) ion tetrakis(ethanolate) (12.33 g, 54.048 mmol) was added to a stirred solution of 4-bromo- benzaldehyde (5 g, 27.024 mmol) and (S)-2-methylpropane-2-sulfinamide (3.28 g, 27.024 mmol) in THF (60 ml_).
  • the resulting mixture was stirred for 20 min at 70°C.
  • the resulting mixture was diluted with ethyl acetate (100 mL). The reaction was quenched with brine (100 mL) at room temperature.
  • Step 2 (S)-N-[(1 R)-1-(4-bromophenyl)-2,2-difluoroethyl]-2-methylpropane-2-sulfinamide t-BuOK (5.84 g, 52.047 mmol) was added to a stirred solution of (S,E)-N-(4-bromobenzylidene)-2- methylpropane-2-sulfinamide (5 g, 17.349 mmol) and (difluoromethyl)trimethylsilane (6.46 g, 52.047 mmol) in THF (100 mL). The resulting mixture was stirred for 2 h at -78°C under nitrogen atmosphere.
  • Step 3 (S)-N-[(1R)-2, 2-di fluoro- 1 -[4- (2-methylpyrazol-3-yl)phenyl]ethyl]-2-methylpropane-2-sulfinamide XPhos Pd G3 (328.40 mg, 0.388 mmol) was added to a stirred solution (S)-N-[(1 R)-1 -(4-bromophenyl)-
  • Step 5 tert-butyl N-[(2S)-1-[(2S,4R)-2- ⁇ [(1R)-2,2-difluoro-1-[4-(2-methylpyrazol-3- yl)phenyl]ethyl]carbamoyl ⁇ -4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate TCFH (820.08 mg, 2.922 mmol) was added to a stirred solution of (2S,4R)-1 -[(2S)-2-[(tert- butoxycarbonyl)amino]-3,3-dimethylbuta noyl]-4-hydroxypyrrolidine-2-carboxylic acid (603.98 mg, 1 .753 mmol), (1 R)-2,2-difluoro-1 -[4-(2-methylpyrazol-3-yl)phenyl]ethanamine hydrochloride (400 mg, 1.461 mmol
  • Step 6 (2S,4R)-1-[(2S) -2-amino-3, 3-dimethylbutanoyl]-N-[ ( 1 R) -2, 2-di fluoro- 1 -[4- (2-methylpyr azol-3- yl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide
  • Step 1 5-chloro-3-fluoro-4-methoxypyridin-2-amine 4-(chioromethyl)-1 -fiuoro-1 ,4-diazabicyclo [2.2.2]octane-1 ,4-diium; bis(tetrafluoroboranuide) (1.12 g, 3.153 mmol) was added to a stirred solution of 5-chloro-4-methoxypyridin-2-amine (1 g, 6.306 mmol) in CHCh (6 mL) and H2O (6 mL). The resulting mixture was stirred overnight at 15 °C. The resulting mixture was diluted with water (150 mL) and extracted with DCM (170 mL x 3).
  • Step 2 5-chloro-3-fluoro-4-methoxy-N-[ 1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine
  • XantPhos Pd G4 (136.25 mg, 0.142 mmol) was added to a stirred solution of 5-chloro-3-fluoro-4- methoxypyridin-2-amine (250 mg, 1 .416 mmol), 3-bromo-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridine (319.56 mg, 1 .133 mmol), XantPhos (163.84 mg, 0.283 mmol) and CS2CO3 (1383.87 mg, 4.248 mmol) in dioxane (6 mL).
  • Step 3 5-chloro-3-fluoro-4-methoxy-N-methyl-N-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine NaH (39.38 mg, 1 .642 mmol) was added to a solution of 5-chloro-3-fluoro-4-methoxy-N-[1 -(oxan-4- yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine (310 mg, 0.821 mmol) in DMF (4 mL) in portions at 0 °C. The resulting mixture was stirred for 0.5 h at room temperature.
  • Step 4 5-chloro-3-fluoro-4-methoxy-N-methyl-N-[1-(oxan-4-yl)-4H,5H,6H, 7H-pyrazolo[4,3-c]pyridin-3- yl]pyridin-2-amine
  • Pentamethylcyclopentadienylrhodium(lll) chloride dimer (47.32 mg, 0.077 mmol) was added to a stirred solution of 5-chloro-3-fluoro-4-methoxy-N-methyl-N-[1 -(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2- amine (150 mg, 0.383 mmol) and 1 -methyl-1 H-imidazole (79.71 mg, 0.972 mmol) in TEA (2.8 mL) and FA (2 mL). The resulting mixture was stirred for 1 h at room temperature.
  • Step 5 3-[(5-chloro-3-fluoro-4-methoxypyridin-2-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)-4H,6H, 7H- pyrazolo[4,3-c]pyridine-5-carboxamide
  • N-methylimidazole-1 -carboxamide (90.09 mg, 0.720 mmol) was added to a stirred solution of 5-chloro-3- fluoro-4-methoxy-N-methyl-N-[1 -(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine (190 mg, 0.480 mmol) and TEA (145.71 mg, 1 .440 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (40 mL) and extracted with DCM (50 mL x 3).
  • Step 1 2-bromo-5-chloro-4-(oxetan-3-yloxy)pyridine
  • Step 2 5-chloro-N-[ 1 -(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-4-(oxetan-3-yloxy)pyridin-2-amine
  • XantPhos 104.35 mg, 0.180 mmol
  • t-BuONa 519.95 mg, 5.409 mmol
  • 2-bromo-5-chloro-4-(oxetan-3-yloxy)pyridine (477 mg, 1 .803 mmol) and 1 -(oxan-4-yl)pyra zolo[4,3-c]pyridin-3-amine (393.61 mg, 1 .803 mmol) in toluene (10 mL).
  • Step 3 5-chloro-N-methyl-N-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-4-(oxetan-3-yloxy) pyridin-2-amine NaH (89.58 mg, 3.732 mmol, 60% purity) was added to a stirred solution of 5-chloro-N-[1 -(oxan-4- yl)pyrazolo[4,3-c]pyridin-3-yl]-4-(oxetan-3-yloxy)pyridin-2-amine (500 mg, 1 .244 mmol) in DMF (5 mL) in portions at 0°C under nitrogen atmosphere.
  • Step 4 5-chloro-N-methyl-N-[1-(oxan-4-yl)-4H,5H,6H, 7H-pyrazolo[4,3-c]pyridin-3-yl]-4-(oxe tan-3- yloxy)pyridin-2-amine
  • Step 5 3- ⁇ [5-chloro-4-(oxetan-3-yloxy)pyridin-2-yl](methyl)amino ⁇ -N-methyl- 1 -(oxan-4-yl)- 4H,6H, 7H- pyrazolo[4,3-c]pyridine-5-carboxamide
  • TEA (1 .716 mmol) was added to a solution of 5-chloro-N-methyl-N-[1 -(oxan-4-yl)- 4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-4-(oxe tan-3-yloxy)pyridin-2-amine (120 mg, 0.286 mmol) and N-methylimidazole-1 -carboxamide (143.04 mg, 1 .144 mmol) in DCM (2.5 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL x 3).
  • Step 1 tert-butyl (1 r,3r)-3-(methanesulfonyloxy)cyclobutane-1 -carboxylate
  • Step 2 tert-butyl (1 s,3s)-3- ⁇ 3-bromopyrazolo[4,3-c]pyridin-1 -yl ⁇ cyclobutane-1 -carboxylate K2CO3 (1 .55 g, 1 1 .186 mmol) was added to a stirred solution of tert-butyl (1 r,3r)-3- (methanesulfonyloxy)cyclobutane-l -carboxylate (1 g, 3.995 mmol) and 3-bromo-1 H-pyrazolo[4,3- c]pyridine (506.31 mg, 2.557 mmol) in DMF (15 mL).
  • Step 3 tert-butyl (1s,3s)-3- ⁇ 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H- 1,5-naphthyridin-1- yl]pyrazolo[4,3-c]pyridin-1-yl ⁇ cyclobutane-1 -carboxylate
  • XantPhos Pd G4 (109.29 mg, 0.114 mmol) was added to a stirred solution of tert-butyl (1s,3s)-3- ⁇ 3- bromopyrazolo[4,3-c]pyridin-1 -yl ⁇ cyclobutane-1 -carboxylate (400 mg, 1.136 mmol), 2-chloro-3- (difluoromethyl)-5,6,7,8-tetrahydro-1 ,5-naphthyridine hydrochloride (289.68 mg, 1.136 mmol), XantPhos (131.42 mg,
  • Step 4 tert-butyl (1s,3s)-3- ⁇ 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H- 1 ,5-naphthyridin-1 -yl]- 4H,5H, 6H, 7H-pyrazolo[4, 3-c]pyridin- 1 -yljcyclobutane- 1 -carboxylate
  • Pentamethylcyclo pentadienylrhodium(lll) chloride dimer (73.17 mg, 0.118 mmol) was added to a stirred solution of tert-butyl (1 s,3s)-3- ⁇ 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1 , 5-naphthy ridi n- 1 - yl]pyrazolo[4,3-c]pyridin-1 -yl)cyclobutane-1 -carboxylate (290 mg, 0.592 mmol) and KI (196.51 mg, 1.184 mmol) in TEA (2.8 mL) and FA (2 mL).
  • Step 5 methyl 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H- 1 ,5-naphthyridin-1 -yl]-1 -[(1 s,3s)-3-(tert- butoxycarbonyl)cyclobutyl]-4H, 6H, 7H-pyrazolo[4, 3-c]pyridine-5-carboxylate
  • Step 6 (1s,3s)-3- ⁇ 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H- 1 ,5-naphthyridin- 1-yl]-5- (methoxycarbonyl)-4H,6H, 7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ cyclobutane-1 -carboxylic acid
  • TFA 0.5 mL
  • Step 7 methyl 3-[6-chloro- 7-(difluoromethyl)-3,4-dihydro-2H- 1 ,5-naphthyridin- 1 -yl]- 1 -[( 1 s,3s)-3- (methylcarbamoyl)cyclobutyl]-4H, 6H, 7H-pyrazolo[4, 3-c]pyridine-5-carboxylate
  • HATU (276.03 mg, 0.726 mmol) was added to a stirred solution of (1 s,3s)-3- ⁇ 3-[6-chloro-7- (difluoromethyl)-3,4-dihydro-2H-1 ,5-naphthyridin-1 -yl]-5-(methoxycarbonyl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-1 -yl]cyclobutane-1 -carboxylic acid (180 mg, 0.363 mmol), methanamine, hydrochloride (24.51 mg, 0.363 mmol) and DIEA (140.74 mg, 1 .089 mmol) in DMF (3 mL).
  • Step 1 1-(difluoromethyl)-4-fluoropyrazole
  • Step 2 tert-butyl N-[(1S)-1- ⁇ 4-[2-(difluoromethyl)-4-fluoropyrazol-3-yl]phenyl ⁇ ethyl]carbamate
  • Step 3 (1S)-1 - ⁇ 4-[2-(difluoromethyl)-4-fluoropyrazol-3-yl]phenyl ⁇ ethanamine
  • Step 4 tert-butyl N-[(2S)- 1 -[(2S,4R)-2- ⁇ [(1 S)- 1 - ⁇ 4-[2-(difluoromethyl)-4-fluoropyrazol-3-yl]p henyl ⁇ ethyl]carbamoyl ⁇ -4-hydroxypyrrolidin- 1 -yl]-3, 3-d i methyl- 1 -oxobutan-2-yl]carbamate
  • HATU (313.33 mg, 0.824 mmol) was added to a stirred solution of (1 S)-1 - ⁇ 4-[2-(difluoromethyl)-4- fluoropyrazol-3-yl]phenyl]ethanamine (200 mg, 0.687 mmol), (2S,4R)-1 -[(2S)-2-[(tert- butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (236.51 mg, 0.687 mmol) and DIEA (266.27 mg, 2.061 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 1 h.
  • Step 5 (2S.4R)- 1-((S)-2-amino-3.3-dimethylbutanoyl)-N-((S)-1-(4-( 1-(difluoromethyl)-4-fluoro- 1H-pyrazol- 5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 1 tert-butyl (R)-(1-(4-bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate 2-(tributyl-l A [5]-phosphanylidene)acetonitrile (3.43 g, 14.232 mmol) was added to a stirred solution of tertbutyl N-[(1 R)-1 -(4-bromophenyl)-2-hydroxyethyl]carbamate (3 g, 9.488 mmol) and phthalimide (1 .40 g, 9.488 mmol) in THF (40 mL).
  • Step 2 tert-butyl (R)-(2-amino-1-(4-brornophenyl)ethyl)carbamate
  • Step 3 tert-butyl (R)-(1-(4-bromophenyl)-2-(dimethylamino)ethyl)carbamate
  • Step 4 tert-butyl (R)-(2-(dimethylamino)-1 -(4-(4-fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl) ethylcarbamate Pd(0Ac)2 (26.49 mg, 0.118 mmol) and AcOK (231 .58 mg, 2.361 mmol) were added to a solution of tertbutyl (R)-(1 -(4-bromophenyl)-2-(dimethylamino)ethyl)carbamate (270 mg, 0.787 mmol) and 4-fluoro-1 - methylpyrazole (118.10 mg, 1.181 mmol) in DMF (4 mL).
  • Step 5 [(2R)-2-amino-2-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethyl]dimethylamine hydrochloride HCI in 1 ,4-dioxane(4.0 M) (0.5 mL) was added to a solution of tert-butyl (R)-(2-(dimethylamino)-1-(4-(4- fluoro-1 -methyl-1 H-pyrazol-5-yl)phenyl) ethylcarbamate (68 mg, 0.188 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford the title compound (68 mg, crude) as a white solid that was used in the next step directly without further purification.
  • LCMS (ESI) m/z [M+H] + 299.14.
  • Step 6 tert-butyl ((S)-1-((2S,4R)-2-(((R)-2-(dimethylamino)-1-(4-(4-fluoro-1 -methyl-1 H-pyrazol-5- yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate
  • Step 7 (2S R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(1 R)-2-(dimethylamino)-1-[4-(4-fluoro-2- methylpyrazol-3-yl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide hydrochloride
  • Step 1 tert-butyl N-[(1 R)-1 -(4-bromophenyl)-2-(2-methoxyethoxy)ethyl]carbamate
  • Tetrabutylazanium chloride (878.95 mg, 3.163 mmol) was added to a stirred solution of tert-butyl N-[(1 R)- 1 -(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g, 3.163 mmol) and 2-bromoethyl methyl ether (2.197 g, 15.815 mmol) in DCM (5 mL) and NaOH (14.0 M) (5 mL). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3).
  • Step 2 tert-butyl N-[(1 R)-1-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]-2-(2-methoxyethoxy) ethylcarbamate
  • Pd(0Ac)2 (77.98 mg, 0.347 mmol) was added to a stirred solution of tert-butyl N-[(1 R)-1 -(4-bromophenyl)- 2-(2-methoxyethoxy)ethyl]carbamate (650 mg, 1 .737 mmol), 4-fluoro-1 -methylpyrazole (208.60 mg, 2.084 mmol) and AcOK (51 1 .33 mg, 5.21 1 mmol) in DMF (10 mL). The resulting mixture was stirred at 100°C for 4 h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3).
  • Step 3 5- ⁇ 4-[( 1R)- 1 -amino-2-(2-rnethoxyethoxy)ethyl]phenyl ⁇ -4-fluoro- 1 -methylpyrazole hydrochloride HCI (4.0 M in 1 ,4-dioxane) (1 mL) was added to a solution of tert-butyl N-[(1 R)-1 -[4-(4-fluoro-2- methylpyrazol-3-yl)phenyl]-2-(2-methoxyethoxy) ethylcarbamate (170 mg, 0.432 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford the crude product (165 mg, crude) as a light yellow solid that was used in the next step directly without further purification.
  • LCMS (ESI) m/z [M+H] + 330.13.
  • Step 4 tert-buty! N-[(2S)-1 -[(2S,4R)-2- ⁇ [(1 R)-1 -[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]-2- (2- methoxyethoxy)ethyl]carbamoyl ⁇ -4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbarriate HATU (291 .65 mg, 0.766 mmol) was added to a stirred solution of 5- ⁇ 4-[(1 R)-1 -amino-2-(2- methoxyethoxy)ethyl]phenyl ⁇ -4-fluoro-1 -methylpyrazole hydrochloride (150 mg, 0.51 1 mmol), (2S,4R)-1 - [(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-
  • Step 5 (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(1 R)-1-[4-(4-fluoro-2-methylpyr azol-3- yl)phenyl]-2-(2-methoxyethoxy)ethyl]-4-hydroxypyrrolidine-2-carboxamide hydrochloride
  • Step 1 tert-butyl 4-hydroxy-2-(oxan-4-yl)-5H,7H,8H-pyrido[4,3-d]pyrimidine-6-carboxylate
  • Step 2 tert-butyl 4-chloro-2-(oxan-4-yl)-5H,7H,8H-pyrido[4,3-d]pyrimidine-6-carboxylate
  • PPhs (1 .56 g, 5.962 mmol) was added to a stirred solution of tert-butyl 4-hydroxy-2-(oxan-4-yl)-5H,7H,8H- pyrido[4,3-d]pyrimidine-6-carboxylate (1 g, 2.981 mmol) in dioxane (20 mL) at room temperature under nitrogen atmosphere. After 30 min NCS (0.80 g, 5.962 mmol) was added and the resulting mixture was stirred at 70°C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3).
  • Step 4 6-chloro-7-(difluoromethyl)-1-[2-(oxan-4-yl)-5H,6H, 7H,8H-pyrido[4,3-d]pyrimidin-4-yl]-3,4-dihydro- 2H- 1,5-naphthyridine hydrochloride
  • CU(OAC)2 (2.56 g, 14.078 mmol) was added to a stirred mixture of 4-chloro-3-(difluoromethyl)aniline (1 g, 5.631 mmol), methylboronic acid (0.84 g, 14.078 mmol) and pyridine (1 .56 g, 19.709 mmol) in 1 ,4- dioxane (20 mL). The resulting mixture was stirred at 1 10°C for 16 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4.
  • Step 4 (S)-1 -(3-((4-chloro-3-(difluoromethyl)phenyl)(methyl)amino)-1 H-pyrazolo[4,3-c]pyridin-1 - yl)propan-2-ol
  • XantPhos Pd G4 (187.89 mg, 0.195 mmol) was added to a stirred solution of (S)-1 -(3-bromo-1 H- pyrazolo[4,3-c]pyridin-1 -yl)propan-2-ol (500 mg, 1 .952 mmol), 4-chloro-3-(difluoromethyl)-N-methylaniline (561.13 mg, 2.928 mmol), XantPhos (112.97 mg, 0.195 mmol) and Cs2CO3 (1272.22 mg, 3.904 mmol) in dioxane (10 mL). The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere.
  • Step 1 6-chloro ⁇ 5-fluoro-2-methoxypyridin-3-amine NCS (563.68 mg, 4.221 mmol) was added in portions to a stirred solution of 5-fluoro-2-methoxypyridin-3- amine (600 mg, 4.221 mmol) in DMF (5 mL) at 0°C. The resulting mixture was stirred at 60°C for 1 h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 6-chloro-5-fluoro-2-methoxy-N-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-3-amine
  • XantPhos Pd G4 (218.01 mg, 0.227 mmol) was added to a stirred solution of 6-chloro-5-fluoro-2- methoxypyridin-3-amine (400 mg, 2.265 mmol), 3-bromo-1 -(oxan-4-yl)pyrazolo[4,3-c]pyridine (639.12 mg, 2.265 mmol), t-BuONa (0.65 g, 6.727 mmol) and XantPhos (131 .08 mg, 0.227 mmol) in dioxane (5 mL).
  • Step 3 6-chloro-5-fluoro-2-methoxy-N-methyl-N-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-3-amine NaH (142.92 mg, 3.573 mmol, 60%) was added in portions to a stirred solution of 6-chloro-5-fluoro-2- methoxy-N-[1 -(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-3-amine (450 mg, 1 .191 mmol) in DMF (5 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min.
  • Step 4 6-chloro-5-fluoro-2-methoxy-N-methyl-N-[ 1 -(oxan-4-yl)-4H, 5H, 6H, 7H-pyrazolo[4, 3-c]pyridin-3- yl]pyridin-3-amine
  • Step 5 3-[(6-chloro-5-fluoro-2-methylpyridin-3-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)-4H,6H, 7H- pyrazolo[4,3-c]pyridine-5-carboxamide
  • Step 1 3-iodo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine
  • CS2CO3 (17.95 g, 55.098 mmol) was added to solution of 3-iodo-1 H-pyrazolo[4,3-c]pyridine (4.5 g, 18.366 mmol) and oxan-4-yl methanesulfonate (4.63 g, 25.712 mmol) in DMF (90 mL). The resulting mixture was stirred for 1 h at 120°C. The resulting mixture was diluted with water (900 mL) and extracted with EtOAc (900 mL x 3). The combined organic layers were washed with saturated brine (300 mL x 3) and dried over anhydrous Na2SC , filtered and concentrated to give a crude product.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XB-C18 50*250 mm, 10 pm; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN ; Flow rate: 100 mL/min; Gradient: 10 % B to 40 % B in 30 min; Wave Length: 220 nm/ 254 nm; RT1 (min): 26) to afford the title compound (3.92 g) as an off-white solid.
  • XantPhos Pd G4 (43.86 mg, 0.046 mmol) was added to a stirred solution of 3-iodo-1 -(oxan-4- yl)pyrazolo[4,3-c]pyridine (150 mg, 0.456 mmol), 6-chloro-N-methylpyridazin-3-amine (65.43 mg, 0.456 mmol), XantPhos (52.74 mg, 0.091 mmol) and CS2CO3 (445.46 mg, 1.368 mmol) in toluene (3 mL). The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere.
  • Step 3 6-chloro-N-methyl-N-[1-(oxan-4-yl)-4H,5H,6H, 7H-pyrazolo[4,3-c]pyridin-3-yl]pyridazin-3-amine (Cp*RhCl2)2 (26.89 mg, 0.044 mmol) was added to a stirred solution of 6-chloro-N-methyl-N-[1 -(oxan-4- yl)pyrazolo[4,3-c]pyridin-3-yl]pyridazin-3-amine (150 mg, 0.435 mmol) in EtsN (2.8 mL) and formic acid (2 mL). The resulting mixture was stirred at room temperature for 1 h.
  • Step 4 methyl 3-[(6-chloropyridazin-3-yl)(methyl)amino]-1-(oxan-4-yl)-4H,6H, 7H-pyrazolo[4,3-c]pyridine- 5-carboxylate
  • EtsN (195.81 mg, 1 .935 mmol) was added to a stirred solution of bis(2,5-dioxopyrrolidin-1 -yl) carbonate (128.88 mg, 0.503 mmol) and methanol (18.60 mg, 0.581 mmol) in MeCN (3 mL). The resulting mixture was stirred at room temperature for 15min.
  • Step 1 4-[(1 S)-1 -[(tert-butoxycarbonyl)amino]ethyl]phenylboronic acid
  • Pd(dppf)Cl2CH2Cl2 (272.04 mg, 0.333 mmol) was added to a stirred solution of tert-butyl N-[(1 S)-1 -(4- bromophenyl)ethyl]carbamate (500 mg, 1 .666 mmol), 2-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,5- dimethyl-1 ,3,2-dioxaborinane (564.36 mg, 2.499 mmol) and AcOK (326.93 mg, 3.332 mmol) in dioxane (6 mL). The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere.
  • Step 2 tert-butyl N-[( 1S)-1 -[4-(2-methylimidazol- 1 -yl)phenyl]ethyl]carbamate
  • CU(OAC)2 (180.87 mg, 0.996 mmol) was added to a stirred solution of 4-[(1 S)-1 -[(tert- butoxycarbonyl)amino]ethyl]phenylboronic acid (240 mg, 0.905 mmol), 2-methylimidazole (74.33 mg, 0.905 mmol), pyridine (157.54 mg, 1 .991 mmol) and TEA (100.77 mg, 0.996 mmol) in DCE (4 mL). The resulting mixture was stirred at 70°C for 1 h. The mixture was diluted with H2O (30 mL) and extracted with CH2CI2 (30 mL x 3).
  • Step 3 (1S)-1 -[4- (2-methylimidazol- 1 -yl)phenyl]ethanamine
  • Step 4 tert-butyl N-[(2S)-1 -[(2S,4R)-4-hydroxy-2- ⁇ [(1 S)-1 -[4-(2-methylimidazol-1 - yl)phenyl]ethyl]carbamoyl ⁇ pyrrolidin- 1 -yl]-3, 3-dimethyl- 1 -oxobutan-2-yl]carbamate HATU (464.73 mg, 1 .222 mmol) was added to a stirred solution of (1 S)-1 -[4-(2-methylimidazol-1 - yl)phenyl]ethanamine (123 mg, 0.61 1 mmol), (2S,4R)-1 -[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3- dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (210.47 mg, 0.611 mmol) and DIEA (236.95 mg,
  • Step 5 (2S, 4R)-1-[(2S) -2-amino-3, 3-dimethylbutanoyl]-4-hydroxy-N-[( 1S)-1 -[4-(2-methylimidazol- 1 - yl)phenyl]ethyl]pyrrolidine-2-carboxamide
  • Step 1 4-fluoro-1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole n-BuLi (0.55 mL, 2.997 mmol) was added to a solution of 4-fluoro-1 -methylpyrazole (5 g, 49.952 mmol) in THF (50 mL) at 0°C for 1 h under nitrogen atmosphere followed by the addition of 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (11.15 g, 59.942 mmol) dropwise at -78°C. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with sat.
  • Step 2 tert-butyl (S)-(1 -(6-(4-fluoro-1 -methyl-1 H-pyrazol-5-yl)pyridin-3-yl)ethyl)carbamate
  • XPhos Pd G3 (0.56 g, 0.664 mmol) was added to a stirred solution of tert-butyl N-[(1 S)-1 -(6-bromopyridin- 3-yl)ethyl]carbamate (2.00 g, 6.635 mmol), 4-fluoro-1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (4.5 g, 19.906 mmol) and CS2CO3 (6.49 g, 19.906 mmol) in dioxane (28 mL) and H2O (7 mL).
  • Step 3 (S)-1-(6-(4-fluoro-1 -methyl-1 H-pyrazol-5-yl)pyridin-3-yl)ethan-1 -amine hydrochloride
  • Step 4 tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(6-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3- yl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate TCFH (1 .83 g, 6.533 mmol) was added to a stirred solution of (2S,4R)-1 -[(2S)-2-[(tert- butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 4.355 mmol), 1 -methyl-1 H-imidazole (1 .07 g, 13.065 mmol) and (S)-1 -(6-(4-fluoro-1 -methyl-1 H-pyr
  • Step 5 (2S,4R)- 1 -((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)- 1 -(6-(4-fluoro-1 -methyl- 1 H-pyrazol-5- yl)pyridin-3-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride
  • Step 1 7-bromo-6-chloro-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine
  • NCS (5.46 g, 40.921 mmol) was added to a stirred solution of 7-bromo-2,3-dihydro-1 H-pyrido[2,3- b][1 ,4]oxazine (8 g, 37.201 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined and washed with brine (200 mL) and dried over anhydrous Na2SC>4, filtered and concentrated to give a crude product.
  • Step 2 tert-butyl 7-bromo-6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -carboxylate
  • EtsN (6.33 g, 62.529 mmol) was added to a stirred mixture of 7-bromo-6-chloro-2,3-dihydro-1 H- pyrido[2,3-b][1 ,4]oxazine (5.2 g, 20.843 mmol) and (Boc)2O (9.10 g, 41 .686 mmol) and DMAP (509.27 mg, 4.169 mmol) in DCM (60 mL). The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL x 2).
  • Step 3 tert-butyl 6-chloro-7-vinyl-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-1 -carboxylate
  • Pd(dppf)Cl2 (1 .63 g, 1 .995 mmol) was added to a stirred mixture of tert-butyl 7-bromo-6-chloro-2,3- dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-1 -carboxylate (4.65 g, 13.301 mmol), 2-ethenyl-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (2.05 g, 13.301 mmol) and K3PO4 (5.65 g, 26.602 mmol) in 1 ,4-dioxane (60 mL) and H2O (15 mL).
  • Step 4 tert-butyl 6-chloro-7-formyl-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-1 -carboxylate 2,6-lutidine (722.20 mg, 6.740 mmol) was added to a stirred mixture of tert-butyl 6-chloro-7-vinyl-2,3- dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-1 -carboxylate (1 g, 3.370 mmol), Potassium osmate(VI) dihydrate (124.16 mg, 0.337 mmol) and NalO (2883.10 mg, 13.480 mmol) in THF (10 ml_) and H2O (5 ml_).

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Abstract

La présente divulgation concerne des composés utiles pour le traitement de troubles liés à la CBP.
PCT/US2025/025477 2024-04-19 2025-04-18 Composés et leurs utilisations Pending WO2025222187A1 (fr)

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