WO2023049723A1 - Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins - Google Patents
Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins Download PDFInfo
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- WO2023049723A1 WO2023049723A1 PCT/US2022/076749 US2022076749W WO2023049723A1 WO 2023049723 A1 WO2023049723 A1 WO 2023049723A1 US 2022076749 W US2022076749 W US 2022076749W WO 2023049723 A1 WO2023049723 A1 WO 2023049723A1
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- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- OCPNDBAWFUIPFR-UHFFFAOYSA-N tert-butyl 3-phenylmorpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOCC1C1=CC=CC=C1 OCPNDBAWFUIPFR-UHFFFAOYSA-N 0.000 description 1
- LPCZUBQFSBAHID-UHFFFAOYSA-N tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C=1C=C2CN(C(=O)OC(C)(C)C)CCC2=CC=1B1OC(C)(C)C(C)(C)O1 LPCZUBQFSBAHID-UHFFFAOYSA-N 0.000 description 1
- VPGSXEIYGTTXOE-UHFFFAOYSA-N tert-butyl N-[1-[8-(5-carbamoyl-2-methylpyrazol-3-yl)-5-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methylamino]imidazo[1,2-c]pyrimidin-2-yl]ethyl]carbamate Chemical compound C(N)(=O)C1=NN(C(=C1)C=1C=2N(C(=NC=1)NCC1=C(C=CC3=C1CCO3)F)C=C(N=2)C(C)NC(OC(C)(C)C)=O)C VPGSXEIYGTTXOE-UHFFFAOYSA-N 0.000 description 1
- FPJOPPJXKZEKBE-GUUQVPQOSA-N tert-butyl N-[dideuterio-(2,3-dideuterio-5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]carbamate Chemical compound FC=1C=CC2=C(C(C(O2)[2H])[2H])C=1C([2H])([2H])NC(OC(C)(C)C)=O FPJOPPJXKZEKBE-GUUQVPQOSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- GUNCFVCHRNIIBC-UHFFFAOYSA-N tributyl-(2-cyclopropylpyrazol-3-yl)stannane Chemical compound C(CCC)[Sn](C=1N(N=CC=1)C1CC1)(CCCC)CCCC GUNCFVCHRNIIBC-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present disclosure relates to compounds that inhibit the Polycomb Repressive Complex 2 (PRC2).
- PRC2 Polycomb Repressive Complex 2
- the present disclosure relates to compounds, pharmaceutical compositions comprising the compounds and methods for use therefor in treating blood disorders, including sickle cell disease and thalassemia.
- the Polycomb Repressive Complex 2 is a multiprotein complex that contributes to the epigenetic silencing of target genes to regulate development and homeostasis.
- the PRC2 complex is comprised of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12).
- EED is a critical regulator of PRC2 in the silencing of expression of genes and gene clusters involved in development including but not limited to fetal orthologues (i.e. gamma globin), Hox genes, X chromosome inactivation, etc.
- EED provides a pharmacologic target for the treatment of diseases or disorders to impact transcription of specific target genes in blood and other tissues.
- a method of treating a blood disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
- Z is O or S
- X is O, CR 11 , CR n OH, or C(R n )2, wherein: when X is O, is a single bond; when X is C(R n )2’ is a single bond; when X is CR n OH, is a single bond; or when X is CR 11 , is a double bond;
- R 1 is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R 4 ;
- R 2 is -C(R 5a R 5b )R 7 or heteroaryl
- R 3 is C1-C3 alkyl or halogen; each R 4 is independently cyano, halogen, alkoxy, hydroxyl, hydroxyalkyl, -P(O)(OCi-C3 alkyl)2, - COOR 11 , aralkyl, heteroalkyl, haloalkyl, -Y 2 -haloalkyl; -YLCi-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -YLheterocyclyl, -L-N(R n )2, -O-L-N(R n )2, - C(CF3)N(R n )2, -Y 1 -N(R 11 )2 or -Y 2 -N(R n )2 wherein the ring of the -L-cycloalkyl, -
- L is a bond or C1-C4 alkylene
- Y 1 is a bond, -C(O)-, or -NHC(O)-;
- Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-;
- R 5a and R 5b are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R 5a or R 5b is hydrogen;
- R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;
- R 7 is -NR 8a R 8b wherein R 8a and R 8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R 10 ; or
- R 7 is -OR 8a or -N(R 8a )2 wherein each R 8a is independently hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl; each R 9 is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R n )2, Ci-Ce alkyl or -YLheterocyclyl, wherein the -Y 1 -heterocyclyl is optionally substituted with one or more R 10 ; each R 10 is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 11 is independently hydrogen or C1-C3 alkyl; and n is 1 or 2.
- a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is selected from Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopen
- ALL Acute lymphoblast
- a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is sickle cell disease.
- a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is thalassemia.
- the thalassemia is alpha thalassemia.
- the thalassemia is beta thalassemia.
- chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
- an “alkyl” moiety generally refers to a monovalent radical (e.g.
- a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.”
- alkyl a divalent radical
- aryl a divalent moiety that is required and is stated as being “aryl”
- All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
- Polycomb Repressive Complex 2 or “PRC2 complex” refers to a mammalian multiprotein complex comprising three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12) and two additional non- essential subunits, AEBP2, and RbAp48.
- EZH2 enhancer of zeste homolog 2
- EED embryonic ectoderm development protein
- SUZ12 suppressor of zeste 12
- EED refers to the embryonic ectoderm development protein subunit of the PRC2 complex.
- EZH2 or “EZH2 enzyme” refers to a mammalian histone methyltransferase, which is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), and functions to silence target genes by tri -methylating lysine 27 of histone H3 (H3K27me3).
- PRC2 Polycomb Repressive Complex 2
- a “PRC2 inhibitor” refers to compounds of the present disclosure that are represented by formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the PRC2 complex. While not wanting to be bound by any theory, we theorize that the inhibitors of the present disclosure may inhibit PRC2 enzymatic activity by binding to EED to prevent assembly of the PRC2 complex on histone H3 tails thereby inhibiting its activity.
- a “PRC2-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having an activating EZH2 mutation and/or aberrant expression of PRC2.
- a non-limiting example of an PRC2 -associated disease or disorder is a PRC2-associated blood disorder.
- amino refers to -NH2.
- acetyl refers to “-C(O)CH3.
- acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.
- alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn and C12 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
- alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
- alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
- alkylene is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
- alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
- alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
- alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
- alkoxy refers to -OCi-Ce alkyl.
- cycloalkyl as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
- “cycloalkyl” includes C3, C4, C5, Ce, C7, Cs, C9, C10, Cn and C12 cyclic hydrocarbon groups.
- Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
- heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NR X , wherein R x is hydrogen or C1-C3 alkyl.
- heteroalkyl groups include methoxymethyl, methoxy ethyl and methoxypropyl.
- aryl is a Ce-Cw aromatic moiety comprising one to three aromatic rings.
- aryl includes Ce, C10, C13, and C14 cyclic hydrocarbon groups.
- An exemplary aryl group is a Ce-Cio aryl group.
- Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
- An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety.
- An exemplary aralkyl group is -(Ci-C6)alkyl(C6 -Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
- a “heterocyclyl” or “heterocyclic” group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 5 , O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons.
- heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4- piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
- -L-heterocyclyl refers to a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C3 - C4 alkylene.
- heteroaryl refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 1471 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S.
- “Heteroaryl” also includes fused multicyclic (e.g. , bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.
- heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][l,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3
- a “-L-heteroaryl,” “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to another group via an alkylene linker.
- heteroalkyl groups comprise a Ci- C ( , alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
- heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
- arylene is an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
- halogen or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.
- haloalkyl refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen.
- exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluoromethyl.
- hydroxyalkyl refers to an alkyl chain, as defined herein, wherein at least on hydrogen of the alkyl chain has been replaced by hydroxyl.
- an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of PRC2 complex.
- a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of PRC2 complex. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- treatment means any manner in which the symptoms or pathology of a condition, disorder or disease in a subject are ameliorated or otherwise beneficially altered.
- amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting, or transient, that can be attributed to or associated with administration of the composition.
- a method of treating a blood disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond;
- Z is O or S
- X is O, CR 11 , CR n OH, or C(R n )2, wherein: when X is O, is a single bond; when X is C(R n )2, is a single bond; when X is CR n OH, is a single bond; or when X is CR 11 , is a double bond;
- R 1 is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R 4 ;
- R 2 is -C(R 5a R 5b )R 7 or heteroaryl
- R 3 is alkyl or halogen; each R 4 is independently cyano, halogen, alkoxy, hydroxyl, hydroxyalkyl, -P(O)(OCi -C3 alkyl)2, -
- L is a bond or C1-C4 alkylene
- Y 1 is a bond, -C(O)-, or -NHC(O)-;
- Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-;
- R 5a and R 5b are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R 5a or R 5b is hydrogen;
- R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;
- R 7 is -NR 8a R 8b wherein R 8a and R 8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R 10 ; or
- R 7 is -OR 8a or -N(R 8a )2 wherein each R 8a is independently hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl; each R 9 is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R n )2, Ci-Ce alkyl or -Y'-hctcrocyclyl.
- each R 10 is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 11 is independently hydrogen or C1-C3 alkyl; and n is 1 or 2.
- Z is O.
- X is C(R n )2 and is a single bond.
- Z is O or S.
- X is O, CR 11 , CR n OH or C(R n )2, wherein when X is O, is a single bond; when X is C(R n )2, is a single bond; when X is CR n OH, is a single bond; or when X is CR 11 , is a double bond.
- n is one. In one embodiment, n is two.
- Z is O, X is O, n is one and is a single bond. In another embodiment, Z is O, X is CR11 and is a double bond. In one embodiment, Z is O, X is C(R11)2, n is one, and is a single bond. In one embodiment, Z is O, X is CR11OH, n is one, and is a single bond. In another embodiment, Z is O, X is C(R11)2, n is two, and is a single bond. In yet another embodiment, Z is S, X is C(R11)2, n is one, and is a single bond.
- R1 is aryl, which is optionally substituted with one or more R4.
- the aryl is phenyl, which is optionally substituted with one or more R4.
- the one or more R4 are each independently halogen, hydroxyl, haloalkyl, -COOR11, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-N(R11)2, -O-L-N(R11)2, -
- R4 is -Y1-C1-C6 alkyl and Y1 is a bond and the Cl - C6 alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
- R4 is -L-N(R11)2 and L is methylene or ethylene and each R11 is hydrogen, each R11 is methyl or one R11 is methyl and one R11 is hydrogen.
- the aryl is substituted with a single R4 group. In one embodiment, the aryl is substituted with two R4 groups. In one embodiment, the aryl is substituted with three R4 groups.
- Exemplary aryl R4 groups include halogen, hydroxyl, haloalkyl, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-N(R11)2, -Y1-N(R11)2, -Y2-N(R11)2, -Y2-haloalkyl, -L-heterocyclyl, or -Y l-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl, or -Y l-heterocyclyl is optionally substituted with one or more R9.
- R1 is phenyl substituted with -Y2-C1-C6 alkyl.
- Y2 is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl.
- R1 is phenyl substituted with the -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the Cl- C6 alkyl is methyl.
- R1 is phenyl, which is disubstituted with methyl and -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the Cl- C6 alkyl is methyl.
- R1 is phenyl substituted one R4, wherein R4 is a cyano group.
- R1 is phenyl substituted one R4, wherein R4 is -L-heteroaryl. In certain embodiments, the -L-heteroaryl is tetrazolyl. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is -P(O)(OC1 -C3 alkyl)2. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is -COOR11. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is - O-L-N(R11)2. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is aralkyl.
- R1 is phenyl substituted with at least one R4, wherein R4 is -L-N(R11)2.
- L is a bond.
- L is methylene.
- each R11 is independently hydrogen.
- each R11 is independently Cl- C3 alkyl.
- each C1-C3 alkyl is methyl.
- one R11 is C1-C3 alkyl and the other is hydrogen.
- the one C1-C3 alkyl is methyl.
- R1 is phenyl substituted with -L-N(R11)2 and further substituted with one or more halogen and/or C1-C6 alkyl.
- R1 is phenyl substituted with one R4, wherein R4 is -Y1-N(R11)2.
- R4 is -Y1-N(R11)2.
- Y1 is -C(O)- and each R11 is C1-C3 alkyl.
- each C1-C3 alkyl is methyl.
- Y 1 is -C(O)- and each R11 is hydrogen.
- Y 1 is -C(O)- and one R11 is C1-C3 alkyl and the other is hydrogen.
- the one C1-C3 alkyl is methyl.
- R1 is phenyl substituted with -Yl- N(R11)2 and further substituted with one or more halogen and/or C1-C6 alkyl.
- R1 is phenyl substituted with -Y2-haloalkyl, wherein Y2 is -S- or -SO2- and the haloalkyl is trifluoromethyl.
- R1 is phenyl substituted with at least one -L- heterocyclyl or -Yl-heterocyclyl, each heterocyclyl optionally substituted with one or more R9.
- R1 is phenyl substituted with one R4, wherein R4 is -Yl-heterocyclyl optionally substituted with one or more R9.
- Y 1 is -C(O)- and the heterocyclyl is piperazinyl optionally substituted with C1-C3 alkyl.
- the R4 group is -L-heterocyclyl optionally substituted with one or more R9.
- L is methylene and the heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl -piperazinyl.
- L is methylene and the heterocyclyl is azetinidyl, pyrrolidinyl, piperidinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R9.
- Exemplary R9 groups include oxo, halogen, hydroxyalkyl and C1-C3 alkyl.
- R1 is phenyl substituted with -Yl- heterocyclyl optionally substituted with one or more 97.
- Y 1 is -C(O)- and the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl, each optionally further substituted with one or more halogen.
- R1 is phenyl substituted with -L-heteroaryl optionally substituted with one or more R9.
- the -L-heteroaryl is tetrazolyl.
- R1 is phenyl substituted with -P(O)(OC1-C3 alkyl)2. In another embodiment, R1 is phenyl substituted with -COOR11. In one embodiment, R1 is phenyl substituted with hydroxyalkyl, -O-L-N(R11)2 or aralkyl.
- R1 is heteroaryl, which is optionally substituted with one or more R4.
- R1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R4.
- the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each of which is optionally substituted with one or more R4.
- the heteroaryl is substituted with a single R4 group. In one embodiment, the heteroaryl is substituted with two R4 groups. In one embodiment, the heteroaryl is substituted with three R4 groups.
- Exemplary heteroaryl R4 groups include amino, cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y2-haloalkyl -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Yl-heterocyclyl, -L-N(R11)2, or -Y1-N(R11)2, wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and -Yl-heterocyclyl is
- R9 is amino, hydroxyl, cyano, alkoxy, or halogen.
- R7 is C1-C3 alkyl.
- R9 is halogen, wherein the halogen is fluorine or chlorine.
- R9 is alkoxy, wherein the alkoxy is methoxy or ethoxy.
- R9 is cycloalkyl, wherein the cycloalkyl is cyclopropyl.
- R1 is heteroaryl and each R4 is independently hydroxyalkyl, heteroalkyl or haloalkyl.
- the hydroxyalkyl is hydroxymethyl, hydroxyethyl or 2-methyl, 2-hydroxypropyl.
- the heteroalkyl is methoxymethyl or methoxyethyl.
- the haloalkyl is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.
- R1 is heteroaryl and R4 is -Y1-C1-C6 alkyl, wherein Y1 is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl.
- R4 is -Y1-C1-C6 alkyl, wherein Y1 is a -C(O)- and the C1-C6 alkyl is methyl, ethyl or isopropyl.
- Y 1 is -NHC(O)- and the C1-C6 alkyl portion is methyl.
- R1 is heteroaryl and R4 is -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the C1-C6 alkyl is methyl.
- R4 is -Y2-C1-C6 alkyl, wherein Y2 is -S- and the C1-C6 alkyl is methyl.
- R1 is heteroaryl and R4 is -Yl-heterocyclyl, which is optionally substituted with one or more R9.
- Y 1 is a bond.
- Y1 is -C(O)-.
- Y 1 is a bond and the heterocyclyl is azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl.
- R9 is C1-C3 alkyl. In one embodiment, R9 is halogen.
- the heteroaryl is substituted with at least one R4 that is -L-heterocyclyl, which is optionally substituted with one or more R9.
- L is ethylene and the heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl.
- L is methylene and the heterocyclyl is azetinidyl, pyrrolidinyl, piperidinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R9.
- the R9 is independently -L-N(R11)2, hydroxyl, cyano, alkoxy, or halogen.
- R9 is C1-C3 alkyl.
- R7 is halogen, wherein the halogen is fluorine or chlorine.
- R9 is alkoxy, wherein the alkoxy is methoxy or ethoxy.
- R9 is cycloalkyl, wherein the cycloalkyl is cyclopropyl.
- R9 is -L- N(R11)2.
- L is a bond.
- L is methylene.
- each Rll is independently hydrogen.
- each Rll is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R11 is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl.
- R1 is heteroaryl and R4 is -L-N(R11)2.
- L is a bond.
- L is methylene, ethylene, or propylene.
- each R11 is independently C1-C3 alkyl.
- each C1-C3 alkyl is methyl.
- one R11 is C1-C3 alkyl and the other is hydrogen.
- the one Cl- C3 alkyl is methyl.
- each R11 is independently hydrogen.
- R1 is heteroaryl and R4 is -L-heteroaryl, which is optionally substituted with one or more R9.
- L is a bond.
- L is C1-C3 alkylene.
- the C1-C3 alkylene is methylene.
- the heteroaryl of the -L-heteroaryl is pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl or pyridazinyl.
- the heteroaryl of the -L-heteroaryl is pyridyl.
- R1 is heteroaryl which is substituted with two R4 groups independently selected from two -Y1-C1-C6 alkyl groups; -Y1-C1-C6 alkyl and alkoxy; -Yl- CI-C6 alkyl and cycloalkyl; -Y1-C1-C6 alkyl and haloalkyl; -Y1-C1-C6 alkyl and amino; two alkoxy groups; alkoxy and halogen; alkoxy and cyano; and amino and haloalkyl.
- R4 is - Y1-C1-C6 alkyl, wherein each Y1 is a bond and each C1-C6 alkyl is methyl, ethyl or isopropyl.
- the cycloalkyl is cyclopropyl.
- the alkoxy is methoxy.
- the halogen is fluorine or chlorine.
- the haloalkyl is trifluoromethyl or trifluoroethyl.
- R1 is -L-heterocyclyl optionally substituted with one or more R4.
- L is a bond and the heterocyclyl is tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.
- L is a methylene and the heterocyclyl is azetidinyl, pyrrolidinyl or 3X2-azabicyclo[3.1.0]hexanyl.
- the heterocyclyl is substituted with one or more R4 selected from oxo, halogen, alkoxy, hydroxyl and -Y1-C1-C6 alkyl, wherein Y is a bond or -C(O)-.
- R2 is -C(R5aR5b)R7.
- R5a is hydrogen and R5b is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl.
- R5a is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl and R5b is hydrogen.
- R7 is -OR8a.
- R8a is hydrogen or C1-C3 alkyl.
- R7 is -NR8aR8b.
- R8a and R8b are each hydrogen.
- R8a is hydrogen and R7b is C1-C3 alkyl, halosulfonylalkyl, cycloalkyl or aralkyl.
- R7 is -NR8aR8b, wherein R8a and R8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R10.
- the 4-8 membered saturated or partially saturated heterocyclyl is azetidinyl or 3-hydroxy-azetidinyl.
- R2 is heteroaryl.
- the heteroaryl is tetrazolyl, oxazolyl, or oxadiazolyl.
- n is zero. In one embodiment, n is one and R3 is halogen. In certain embodiments, the halogen is fluorine or chlorine. In one embodiment, the halogen is fluorine. [0082] In one embodiment, R6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl. In certain embodiments, R6 is hydrogen. In other embodiments, R6 is methyl, ethyl, or propyl.
- the cyclyl portion of R4 group is substituted with one R9 group.
- R9 is oxo, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R11)2 or C1-C3 alkyl.
- R9 is C1-C3 alkyl, wherein the C1-C3 alkyl is methyl, ethyl or isopropyl.
- R9 is halogen, wherein the halogen is fluorine or chlorine.
- R9 is oxo.
- the cyclyl portion of R4 group is substituted with two R9 groups.
- the two R9 groups are each halogen, wherein each halogen is fluorine.
- the compound is: PHARMACEUTICAL COMPOSITIONS
- the disclosure provides pharmaceutical compositions comprising a PRC2 inhibitor according to the disclosure and a pharmaceutically acceptable carrier, excipient, or diluent for use in the treatment of a blood disorder in a subject.
- Compounds of the disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
- compounds of the disclosure are administered intravenously in a hospital setting.
- administration may preferably be by the oral route.
- compositions according to the disclosure may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
- diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
- the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
- salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
- examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
- inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
- organic acids such as acetic acid, oxalic acid, tartaric acid, succin
- the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
- R is hydrogen, alkyl, or benzyl
- Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsul
- the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount without causing serious toxic effects in the subject treated.
- a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day.
- a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
- the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
- compositions comprising compounds of the present disclosure may be used in the methods described herein.
- a method of treating a blood disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as disclosed herein.
- a method of treating a blood disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as disclosed herein, wherein the blood disorder is selected from Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Id
- the blood disorder is sickle cell disease.
- the blood disorder is thalassemia.
- the thalassemia is alpha thalassemia.
- the thalassemia is beta thalassemia.
- any of the methods disclosed herein wherein the method results in induction of fetal hemoglobin expression in erythroid cells.
- any of the methods disclosed herein wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein.
- any of the methods disclosed herein wherein the method results in increased levels of fetal hemoglobin protein in the subject.
- the concentration and route of administration to the subject will vary depending on the blood disorder to be treated.
- the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
- Other anti- neoplastic compounds e.g., chemotherapy
- other treatments such as radiation or surgical intervention
- the degree of mono- and dimethylation of histone H3K27 may be monitored in the subject using well known methods, including those described in Example A below, to access the effectiveness of treatment, along with other prognostic or biological factors, and dosages may be adjusted accordingly by the attending medical practitioner.
- the compounds disclosed herein may be prepared using methods described in United States Patent No. 11,091,495 and/or PCT Application Publication No. WO 2020/247475, the contents of which are incorporated by reference herein for that purpose.
- the compounds disclosed herein may also be prepared using methods known to those having ordinary skill in the art and commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.
- R 2 -ester substituted imidazo[l,2-c]pyrimidine A is coupled to R 3 optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C.
- a boronic acid derivative (Y)-R 1 D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R 2 ester is converted to the alcohol via a reducing agent such as lithium aluminum hydride to generate intermediate alcohol E.
- the alcohol E is converted to the corresponding aldehyde F via oxidation using a suitable oxidant, e.g., Dess-Martin periodinane, which is then converted to the secondary alcohol by treatment with an organometallic reagent such as a Grignard reagent to form title compound alcohol G.
- a suitable oxidant e.g., Dess-Martin periodinane
- an organometallic reagent such as a Grignard reagent
- R 2 -cyano substituted imidazo[l,2-c]pyrimidine H is coupled to R 3 optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate I.
- a boronic acid derivative (Y)-R 1 D is coupled via a Suzuki reaction with halogen substituted Intermediate I in the presence of a suitable base, e.g., sodium carbonate, and the R 2 cyano is converted to the amine via a metal-mediated hydrogenation using hydrogen gas and a suitable metal such as Raney nickel to form title compound amine J.
- Intermediate F can undergo a reductive amination reaction with an R 8a R 8b optionally substituted Intermediate amine K using an appropriate reducing agent such as sodium triacetoxyborohydride, to form the title compound L.
- an organometallic reagent such as an alkyl magnesium halide undergoes nucleophilic addition to R 2 -cyano imidazo[l,2-c]pyrimidine I to give the R 11 substituted amine intermediate M.
- the resultant amine M is protected with an appropriate protecting group, e.g. tert-butyloxycarbonyl to give Intermediate N.
- the Intermediate N can then be coupled with a boronic acid derivative (Y)-R 1 D via a Suzuki reaction in the presence of a suitable base, such as sodium carbonate, and the protecting group removed from the resultant product via treatment with a strong acid, e.g. TFA to give the desired title compound O.
- An exemplary Intermediate A, Intermediate A-l may be used to synthesize compounds of formula (I).
- a mixture of 6-amino-5 -bromo- lH-pyrimidin-2 -one (2.00 g, 10.5 mmol, 1.00 equiv) and ethyl 3-bromo-2-oxo-propanoate (3.12 g, 16.0 mmol, 2.00 mb, 1.52 equiv) in DMF (20.0 mb) was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo to give a residue.
- a second exemplary Intermediate A, Intermediate A-2 also may be used to synthesize compounds of formula (I).
- ethyl 8-bromo-5-oxo-6H-imidazo[ l,2-c]pyrimidine-2- carboxylate (3.00 g, 10.2 mmol, 1.00 equiv) in MeOH (60.0 mb) was added NaOH (1 M, 30.5 mb, 3.00 equiv).
- the resultant mixture was stirred at 60 °C for 1 h. Subsequently, the reaction mixture was concentrated and the pH was adjusted to 4 with IM aq HC1 at which time a precipitate formed.
- Intermediate A-2 may be prepared on a large scale as follows:
- An exemplary Intermediate B, Intermediate B-l may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, and is a single bond.
- reaction mixture was diluted with petroleum ether (100 mL) and washed with brine (50.0 mL x 4), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
- the crude material was purified by column chromatography (petroleum ether) to afford l-bromo-3-(2,2- diethoxyethoxy)benzene (17.0 g, 48.2 mmol, 83.4% yield, 82.0% purity) as a light yellow oil.
- a second exemplary Intermediate B, Intermediate B-2 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR 11 , is a double bond and one R 3 is fluorine.
- a third exemplary Intermediate B, Intermediate B-3 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is chlorine.
- benzofuran-4-carboxylic acid 900 mg, 5.55 mmol, 1 equiv
- MeOH 9.00 mb
- palladium on activated carbon 20.0 mg, 555 pmol, 10.0 wt %, 0.10 equiv
- the vessel was evacuated and purged with hydrogen several times.
- the mixture was stirred at 25 °C for 12 h under hydrogen (50.0 psi).
- the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 2,3-dihydrobenzofuran-4-carboxylic acid (750 mg, 3.66 mmol, 65.9% yield, 80.0% purity) as a white solid.
- a fourth exemplary Intermediate B, Intermediate B-4 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- Z is O
- n is one
- X is C(R n )2
- R 3 is fluorine.
- the reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (500 ml *5), and concentrated at reduced pressure to provide a residue.
- Intermediate B-4 may be prepared on a large scale as follows:
- the fdter cake was dissolved in water (200 mL) and the pH was adjusted to 9 with sat.aq. K2CO3 at 0 °C prior to extraction with DCM (200 mL x 4).
- the combined organic phase was washed with brine (200 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to afford (5 -fluoro-2, 3 -dihydrobenzo furan-4-yl)methanamine (50.0 g, 299 mmol, 79.9% yield) as a brown oil.
- a fifth exemplary Intermediate B, Intermediate B-5 may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- a sixth exemplary Intermediate B, Intermediate B-6 may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R n )2, is a single bond and one R 3 is fluorine.
- a seventh exemplary Intermediate B, Intermediate B-7 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n ) 2 , is a single bond, one R 3 is fluorine and two methylene hydrogens are replaced with deuteriums.
- An eighth exemplary Intermediate B, Intermediate B-8 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond, one R 3 is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.
- a ninth exemplary Intermediate B, Intermediate B-9 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, is a single bond, and one R 3 is fluorine.
- An exemplary Intermediate C, Intermediate C-l may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- a second exemplary Intermediate C, Intermediate C-2 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR 11 , is a double bond and one R 3 is fluorine.
- a third exemplary Intermediate C, Intermediate C-3 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, and is a single bond.
- ethyl 8-bromo- 5-chloro-imidazo[l,2-c] pyrimidine -2 -carboxylate 103 mg, 328 pmol, 1.00 equiv
- l,3-benzodioxol-4- ylmethanamine 54.6 mg, 361 pmol, 1.10 equiv
- DIEA 42.4 mg, 328 pmol, 57.2 uL, 1.00 equiv.
- a fourth exemplary Intermediate C, Intermediate C-4 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is chlorine.
- ethyl 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2 -carboxylate 230 mg, 755 pmol, 1.00 equiv
- (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine 118 mg, 642 pmol, 0.850 equiv
- DIEA 195 mg, 1.51 mmol, 263 pL, 2.00 equiv
- Another Intermediate C may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R n )2, and is a single bond.
- ethyl 8-bromo-5- chloro-imidazo[ 1, 2-c]pyrimidine-2 -carboxylate 250 mg, 802 pmol, 1.00 eq.
- DMF 3.00 mL
- DIPEA 207 mg, 1.60 mmol, 279 pL, 2.00 eq.
- chroman-5-ylmethanamine (170 mg, 1.04 mmol, 1.30 eq.
- Intermediate C-4B may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- a fifth exemplary Intermediate C, Intermediate C-5 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- Intermediate C-5 may be prepared as follows:
- a sixth exemplary Intermediate C, Intermediate C-6 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond and one R 3 is fluorine.
- the mixture was diluted with water (3.00 mb) and extracted with ethyl acetate (2.00 mb x 3). The combined organic layers were washed with brine (2.00 mb x 3). dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to provide a residue.
- a seventh exemplary Intermediate C, Intermediate C-7 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond, one R 3 is fluorine and two methylene hydrogens are replaced with deuteriums.
- An eighth exemplary Intermediate C, Intermediate C-8 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R n )2, is a single bond, one R 3 is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.
- a ninth exemplary Intermediate C, Intermediate C-9 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, is a single bond, and one R 3 is fluorine.
- the aqueous phase was extracted with ethyl acetate (3.00 mL x 2).
- the combined organic phase was washed with brine (3.00 mL x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluorobenzo[d][I,3]dioxol-4- yl)methyl)amino)imidazo[I,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 128 pmol, 82.5% yield) as a yellow solid.
- An exemplary Intermediate D, Intermediate D-l may be used to synthesize compounds of formula I wherein R 1 is a disubstituted heteroaryl.
- the crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to afford a mixture of l-isopropyl-3 -methyl -4- (4, 4, 5, 5- tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) and I -isopropyl-5 -methyl -4-(4, 4,5,5- tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil.
- a second exemplary Intermediate D, Intermediate D-2 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
- a third exemplary Intermediate D, Intermediate D-3 may be used to synthesize compounds of formula I or formula II wherein R 1 is heteroaryl substituted with two R 4 substituents.
- a fourth exemplary Intermediate D, Intermediate D-4 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
- a mixture of sodium (111 mg, 4.82 mmol, 1.00 equiv) in methanol (772 mg, 24.1 mmol, 975. pL, 5.00 equiv) was stirred at 25 °C for 0.5 h.
- To this solution was added 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) and the mixture was stirred at 25 °C for 2 h.
- the reaction was quenched upon the addition of water (5 mb).
- a fifth exemplary Intermediate D, Intermediate D-5 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
- R 1 is heteroaryl substituted with two R 4 substituents.
- a sixth exemplary Intermediate D, Intermediate D-6 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
- R 1 is aryl substituted with two R 4 substituents.
- NaSMe 869 mg, 5.29 mmol, 1.00 equiv. The mixture was stirred at 50 °C for 12 h.
- reaction mixture was diluted with ethyl acetate (50.0 mL) and the organic layer was washed with brine (40.0 mL x 3), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford l-bromo-2 - methyl-4- methylsulfanyl -benzene (900 mg, crude) as a light yellow oil.
- a seventh exemplary Intermediate D, Intermediate D-7 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with an R 4 substituent.
- R 1 is aryl substituted with an R 4 substituent.
- pyrrolidine (1.79 g, 25.1 mmol, 2.10 mb, 5.00 equiv) in methanol (16.0 mb) was added NaBPhCN (347 mg, 5.53 mmol, 1.10 equiv). The mixture was stirred at 20 °C for 24 h.
- An eighth exemplary Intermediate D, Intermediate D-8 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
- R 1 is heteroaryl substituted with two R 4 substituents.
- n- butyllithium 2.50 M, 1.80 mb, 1.00 equiv
- z-PrMgCl 2.50 M, 1.12 mb, 0.500 equiv
- reaction mixture was quenched by the addition of satd aq ammonium chloride (20.0 mL) at 20 °C and was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-chloro-2- methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.00 g, 3.71 mmol, 82.5% yield) as a gray solid, which used for the next step without further purification.
- a ninth exemplary Intermediate D, Intermediate D-9 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with three R 4 substituents.
- a tenth exemplary Intermediate D, Intermediate D-10 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
- An eleventh exemplary Intermediate D, Intermediate D-l 1 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with three R 4 substituents.
- R 1 is heteroaryl substituted with three R 4 substituents.
- (2.S')-2-mcthyloxiranc (392 mg, 6.75 mmol, 473 pL, 15.0 equiv) was added cesium carbonate (29.3 mg, 90.1 pmol, 0.20 equiv).
- a twelfth exemplary Intermediate D, Intermediate D-12 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
- R 1 is aryl substituted with two R 4 substituents.
- DIEA 490 mg, 3.79 mmol, 660 pL, 3.00 equiv
- '. '-dimcthylaminc 2.00 M in THF, 1.27 mL, 2.00 equiv
- DMF 3.00 mL
- a thirteenth exemplary Intermediate D, Intermediate D-13 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
- a fourteenth exemplary Intermediate D, Intermediate D-14, may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with one R 4 substituent.
- R 1 is aryl substituted with one R 4 substituent.
- ammonia 7 N in MeOH, 224 pL, 1.57 mmol, 2.00 equiv.
- the reaction mixture was stirred at 25 °C for 30 min.
- the mixture was concentrated in vacuo to provide a residue that was poured into water (10.0 mL).
- a fifteenth exemplary Intermediate D, Intermediate D-15 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued heteroaryl.
- 2-methoxyethanol (236 mg, 3.10 mmol, 245 pL, 1.50 equiv) in tetrahydrofiiran (2.00 mL) was added portionwise sodium hydride (99.3 mg, 60.0%, 2.48 mmol, 1.20 equiv) at 0 °C.
- the mixture was stirred at this temperature for 45 min followed by the dropwise addition of 5 -bromo-2 -chloro-pyrimidine (400 mg, 2.07 mmol, 1.00 equiv) at room temperature.
- a sixteenth exemplary Intermediate D, Intermediate D-16 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued heteroaryl.
- R 1 is a disubstitued heteroaryl.
- 5-bromo-4-methyl-pyridine-2-carbaldehyde 500 mg, 2.50 mmol, 1.00 equiv
- p-toluenesulfonic acid 47.6 mg, 250 pmol. 0.10 equiv.
- the mixture was stirred at 110 °C for 12 h and was subsequently concentrated in vacuo to give a residue.
- a seventeenth exemplary Intermediate D, Intermediate D-17, may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued bicyclic heteroaryl.
- a mixture of paraformaldehyde (350 mg, 3.63 mmol, 2.20 equiv) in methanol (1.00 mL) was stirred at 60 °C for 1 h and then cooled to 40 °C.
- To the mixture was added AcOH (1 drop) and 6-bromo-l, 2,3,4- tetrahydroisoquinoline (350 mg, 1.65 mmol, 1.00 equiv) followed by NaCNBH; (114 mg, 1.82 mmol, 1.1 equiv).
- An eighteenth exemplary Intermediate D, Intermediate D-18, may be used to synthesize compounds of formula I, wherein R 1 is a N-protected bicyclic heteroaryl.
- R 1 is a N-protected bicyclic heteroaryl.
- BOC2O 617 mg, 2.83 mmol, 1.50 equiv
- dimethylaminopyridine 46.1 mg, 377 pmol, 0.20 equiv.
- the mixture was stirred at 25 °C for 3 h and was subsequently filtered and concentrated in vacuo to give a residue.
- a nineteenth exemplary Intermediate D, Intermediate D-19 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued aryl.
- a mixture of paraformaldehyde (133 mg, 4.42 mmol, 122 pL, 10.0 equiv) and methyl alcohol (1.00 mb) was stirred at 60 °C for 1 h and then cooled to 0 °C.
- acetic acid 52.5 mg, 874 pmol, 0.05 mb, 1.98 equiv
- 2- (4-bromophenyl)pyrrolidine 100 mg, 442 pmol. 1.00 equiv).
- a twentieth exemplary Intermediate D, Intermediate D-20 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstituted aryl.
- a twenty first exemplary Intermediate D, Intermediate D-21 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued heteroaryl.
- R 1 is a monosubstitued heteroaryl.
- methanol 13.0 mL
- NaBH 4 300 mg, 7.93 mmol, 2.07 equiv
- a twenty second exemplary Intermediate D, Intermediate D-22 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued aryl.
- R 1 is a monosubstitued aryl.
- 2-(4- bromophenyl)ethanamine 200 mg, 1.0 mmol, 155 pL, 1.00 equiv
- formalin 300 mg, 9.99 mmol, 275 pL, 10.0 equiv
- HCOOH 5.00 mL
- a twenty third exemplary Intermediate D, Intermediate D-23 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued aryl.
- Diethyl phosphite (97.6 mg, 707 pmol, 91.2 pL, 1.00 equiv) in tetrahydrofuran (2.00 mb) was added Pd(OAc)2 (4.76 mg, 21.2 pmol, 0.03 equiv), potassium acetate (9.02 mg, 91.9 pmol, 0.13 equiv), DPPF (23.5 mg, 42.4 pmol, 0.06 equiv) and triethylamine (107 mg, 1.06 mmol, 147 pL, 1.50 equiv).
- a twenty fourth exemplary Intermediate D, Intermediate D-24, may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued aryl.
- 2-(4-bromo-3 -methyl - phenyl)pyrrolidine 500 mg, 2.08 mmol, 1.00 equiv
- dichloromethane 5.00 mb
- BOC2O 1.05 g, 4.79 mmol, 1.10 mL, 2.30 equiv
- dimethylaminopyridine 25.4 mg, 208 pmol, 0.10 equiv.
- the mixture was stirred at 25 °C for 1 h and was subsequently filtered and concentrated under reduced pressure to give a residue.
- reaction mixture was fdtered and concentrated under reduced pressure to give a residue.
- a twenty fifth exemplary Intermediate D, Intermediate D-25 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued aryl.
- R 1 is a disubstitued aryl.
- TsOHTLO 194200 mg, 1.00 mmol, 0.10 equiv
- ethylene glycol 1.25 g, 20.1 mmol, 1.12 mL, 2.00 equiv
- a twenty sixth exemplary Intermediate D, Intermediate D-26 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued heteroaryl.
- a twenty seventh exemplary Intermediate D, Intermediate D-27 may be used to synthesize compounds of formula I, wherein R 1 a monosubstitued bicyclic heteroaryl.
- a twenty eighth exemplary Intermediate D, Intermediate D-28 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued bicyclic heteroaryl.
- DMF disubstitued bicyclic heteroaryl.
- 6- (4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-l-one 270 mg, 989 pmol, 1.00 equiv
- a twenty ninth exemplary Intermediate D, Intermediate D-29 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued aryl.
- a mixture of 5-bromo-2- (bromomethyl)benzonitrile (100 mg, 364 pmol, 1.00 equiv), diisopropylethylamine (141 mg, 1.09 mmol, 190 pL, 3.00 equiv) and dimethylamine (2.00 M, 1.82 mL, 10.0 equiv) in dimethyl formamide (2.00 mL) was stirred at room temperature for 3 h.
- the reaction mixture was diluted with water 5.00 mL and extracted with ethyl acetate (5.00 mL x 3).
- a thirtieth exemplary Intermediate D, Intermediate D-30 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued heteroaryl.
- R 1 is a disubstitued heteroaryl.
- Ir(COD)2(OMe)2 5.00 mg, 7.54 pmol, 0.02 equiv
- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (68.5 mg, 535 pmol, 77.7 pL, 1.50 equiv) in w-pcntanc (0.50 mL) was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (5.00 mg, 18.6 pmol, 0.05 equiv) and the mixture was stirred at 25 °C for 20 minutes.
- a thirty first exemplary Intermediate D, Intermediate D-31 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued aryl, in which one substituent has two hydrogens replaced with deuteriums.
- R 1 is a disubstitued aryl, in which one substituent has two hydrogens replaced with deuteriums.
- the reaction mixture was cooled to 0 °C and diluted with THF (10.0 mL). The reaction was quenched upon the dropwise addition of deuterium oxide (0.24 mL), 15% NaOD solution in deuterium oxide (0.24 mL) at 0 °C, and finally deuterium oxide (0.72 mL). The mixture was stirred at room temperature for 10 min, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCf.
- a thirty second exemplary Intermediate D, Intermediate D-32 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued aryl.
- R 1 is a disubstitued aryl.
- a thirty third exemplary Intermediate D, Intermediate D-33 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued heteroaryl.
- R 1 is a monosubstitued heteroaryl.
- 1-cyclopropylpyrazole 200 mg, 1.85 mmol, 1.00 equiv was added and the reaction was stirred at -78°C for 1 h.
- Tributyl(chloro)stannane (602 mg, 1.85 mmol, 498 uL, 1.00 equiv) was added drop-wise and the reaction was stirred at -78 °C for another 30 min.
- the reaction mixture was partitioned between ethyl acetate (5.00 mL) and saturated ammonium chloride (5.00 mL).
- the organic phase was separated, washed with brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tributyl-(2-cyclopropylpyrazol-3-yl)stannane (1.00 g, crude) as a colorless oil which used for the next step without further purification.
- a thirty fourth exemplary Intermediate D, Intermediate D-44 may be used to synthesize compounds of formula I, wherein R 1 is a disubstitued heteroaryl.
- R 1 is a disubstitued heteroaryl.
- a thirty fifth exemplary Intermediate D, Intermediate D-35 may be used to synthesize compounds of formula I, wherein R 1 is a tri substituted heteroaryl.
- R 1 is a tri substituted heteroaryl.
- a thirty sixth exemplary Intermediate D, Intermediate D-36 may be used to synthesize compounds of formula I, wherein R 1 is a monosubstitued aryl.
- R 1 is a monosubstitued aryl.
- the reaction mixture was diluted with DCM (5.00 mL) and cooled to 0 °C, then quenched by addition water dropwise (0.30 mL) and 10% sodium hydroxide aqueous solution (0.30 mL), followed by water (0.90 mL).
- the suspension was dried with anhydrous Mg2SC>4, filtered, and the filtrate was concentrated under reduced pressure to give a residue.
- reaction mixture was quenched by addition water (0.01 mL) and 10 % sodium hydroxide solution (0.01 mL) at 0 °C, followed by water (0.03 mL), the mixture stirred at 25 °C for 10 min, then filtered and concentrated under reduced pressure to give a residue.
- reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (5.00 mL), extracted with ethyl acetate (5.00 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
- Step A To a solution of 1 -phenylpropane- 1,2-dione (1.00 g, 6.75 mmol, 909 pL, 1.00 eq.) in CHCI , (10.0 mL) was added Br2 (1.19 g, 7.42 mmol, 383 pL, 1.10 eq. dropwise at 75 °C, the mixture was stirred at 75 °C for 4 hr. The reaction mixture was diluted with DCM 50 mL and washed with brine (30 mL x 2), the separated organic phase was dried over sodium sulfate, fdtered, and concentrated in vacuo.
- Step B To a solution of 6-amino-5-bromopyrimidin-2(17/)-one (0.64 g, 3.30 mmol, 1.00 eq.) in AcOH (6.00 mL) was added 3 -bromo- 1 -phenylpropane- 1,2-dione (1.40 g, 4.62 mmol, 1.40 eq.), the mixture was stirred at 120 °C for 1 hr.
- Step C To a solution of 2-benzoyl-8-bromoimidazo[l,2-c]pyrimidin-5(677)-one (0.18 g, 388 pmol, 1.00 eq.) in POCL (5.00 mL) was added DIPEA (150 mg, 1.16 mmol, 203 pL, 3.00 eq.) dropwise at 0 °C, and the mixture was stirred at 120 °C for 12 hr.
- DIPEA 150 mg, 1.16 mmol, 203 pL, 3.00 eq.
- Step D To a solution of (8-bromo-5-chloroimidazo[l,2-c]pyrimidin-2-yl)(phenyl)methanone (45.0 mg, 133 pmol, 1.00 eq.) in DMF (3.00 mL) was added DIPEA (34.3 mg, 265 pmol, 46.2 pL, 2.00 eq.) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (28.01 mg, 159.16 pmol, 1.2 eq ). The mixture was stirred at 85 °C for 30 minutes, then diluted with water 20 mL and filtered.
- Step E A mixture of (8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(phenyl)methanone (60.0 mg, 128 pmol, 1.00 eq ), 1,3- dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (42.8 mg, 193 pmol, 1.5.0 eq.), NaHCCF (32.4 mg, 385 pmol, 15.0 pL, 3.00 eq.), Pd(dppf)C12 (14.1 mg, 19.3 pmol, 0.15 eq.) in dioxane (1.50 m ) and H2O (0.50 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 1 h
- Step F To a solution of (8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(phenyl)methanone (19.0 mg, 37.5 pmol, 1.00 eq.) in THF (2.00 mL) was added NaBlL (1.70 mg, 45.0 pmol, 1.20 eq.) at 0 °C, the mixture was stirred at 10 °C for 1 hr. The reaction mixture was quenched with water (0.1 mL) and concentrated in vacuo.
- Step A To a solution of (8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)methanol (1.50 g, 3.67 mmol, 1.00 eq.) in THF (15.0 mb) was added di-tert-butyl dicarbonate (2.00 g, 9.18 mmol, 2.11 mb, 2.50 eq.) and DMAP (44.9 mg, 367 pmol, 0.10 eq ), the reaction mixture was stirred at 80 °C for 1 hour.
- Step B To a solution of (2-(((tert-butoxycarbonyl)oxy)methyl)-8-(l,3-dimethyl-lH-pyrazol-5- yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (400 mg, 657 pmol, 1.00 eq.) in methanol (6.00 mb) was added potassium carbonate (182 mg, 1.31 mmol, 2.00 eq.), the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give a residue.
- Step C To a solution of tert-butyl (8-(l,3-dimethyl-lH-pyrazol-5-yl)-2- (hydroxymethyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (80.0 mg, 157 pmol, 1.00 eq.) in THF (4.00 mb) was added sodium hydride (12.6 mg, 315 pmol, 60.0% purity, 2.00 eq.) at 0 °C, the reaction mixture was stirred at 0 °C for 30 minutes, then methyl iodide (44.7 mg, 315 pmol, 19.6 pL, 2.00 eq.) was added dropwise.
- Step D A solution of tert-butyl (8-( l.3-dimcthyl-IH-pyrazol-5-yl)-2- (methoxymethyl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)carbamate (71.0 mg, 128 pmol, 1.00 eq.) in TFA (0.30 mb) and DCM (1.00 mb) was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. (10.0 mb), extracted with DCM (5.00 mLx3).
- Step A A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (160 mg, 367 pmol, 1 eq.), sodium hydroxide (1 M, 1.10 mL, 3 eq.) in methanol (3.30 mL) was stirred at 55 °C for 30 minutes under N2 atmosphere.
- Step B A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylic acid (124 mg, 304.
- Step C A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (100 mg, 246. pmol, 1.00 eq.), TEA (484 mg, 4.79 mmol, 666 pL, 19.4 eq.) in THF (2.00 mL) was added TFAA (302 mg, 1.44 mmol, 200 pL, 5.84 eq.) at 0 °C, and then the mixture was stirred at 0-30 °C for 40 mins, under aN2 atmosphere.
- Step D A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (90.0 mg, 231 pmol, 1.00 eq.), 1,3-dimethyl-
- Step E To a solution of 8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (80.0 mg, 193 pmol, 1.00 eq.) in THF (2.00 m ) and NFk’FEO (14.0 M, 0.80 m , 58.0 eq.) was added Raney nickel (16.53 mg, 192.95 pmol, 1.00 eq.) under nitrogen.
- Step A To a solution of 8-bromo-5 -(((5 -fluoro-2,3 -dihydrobenzofuran -4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (3.50 g, 9.02 mmol, 1.00 eq.) in THF (10.0 mb) was added methyl magnesium bromide (3.00 M, 18.0 mb, 6.00 eq) dropwise at 0 °C.
- Step B To a solution of 2-(l-aminoethyl)-8-bromo-/V-((5-fluoro-2,3-dihydrobenzofiiran-4- yl)methyl)imidazo[l,2-c]pyrimidin-5-amine (3.00 g, 7.38 mmol, 1.00 eq.) and di-Z rt-but l dicarbonate (3.22 g, 14.8 mmol, 3.39 mL, 2.00 eq.) in THF (15.0 mL) was added TEA (2.24 g, 22.15 mmol, 3.08 mL, 3.00 eq.) and DMAP (90.2 mg, 738 pmol, 0.10 eq.).
- Step C To a solution of tert-butyl (l-(8-bromo-5-(((5-fhioro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (600 mg, 1.18 mmol, 1.00 eq.) and 1,3- dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (395 mg, 1.78 mmol, 1.50 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added sodium bicarbonate (199 mg, 2.37 mmol, 92.2 pL, 2.00 eq.) and Pd(dppf)C12 (86.7 mg, 118 pmol, 0.10 eq.) under nitrogen atmosphere.
- tert-butyl l-(
- Step B A mixture of 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (80.0 mg, 149 pmol, 1.00 eq) and Raney nickel (15.0 mg) in methanol (1.50 mb) and ammonium hydroxide (0.50 mb) was degassed and purged with H2 3 times, and then the mixture was stirred under H2 (15 psi) at 25 °C for 12 hours.
- reaction mixture was stirred at 40 °C for 2 hours, then the mixture was added sodium triacetoxyborohydride (44.0 mg, 207 pmol, 3.00 eq.) in one portion and stirred at 40 °C for 2 hours.
- the reaction mixture was fdtered and concentrated under reduced pressure to give a residue.
- reaction mixture diluted with ammonium chloride solution (20.0 mL) and the suspension was filtered, the filtrate was extracted with ethyl acetate (30.0 mL x 2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give residue.
- Step A A mixture of tert-butyl (l-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (70.0 mg, 138 pmol, 1.00 eq.), 4, 4,5,5- tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-l,3,2-dioxaborolane (81.9 mg, 276 pmol, 2.00 eq.), Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.10 eq.) and sodium bicarbonate (34.8 mg, 415 pmol, 16.1 pL, 3.00 eq.) in a mixture solvent of water (0.40 mL) and dioxane (2.00 mL) was degassed and purged with nitrogen for 3 times
- Step B A solution of tert-butyl (l-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (80.0 mg, 134 pmol, 1.00 eq.) in a mixture solvent of dichloromethane (3.00 mL) and trifluoroacetic acid (1.00 mL), the reaction mixture was stirred at 25 °C for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to give a residue.
- Step A A mixture of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole -3 -carboxylate (263 mg, 988 pmol, 2.00 eq.), tert-butyl (l-(8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (250 mg, 494 pmol, 1.00 eq.), bis(tri-tert-butylphosphine) palladium (0) (50.5 mg, 98.7 pmol, 0.20 eq.) and potassium carbonate (341 mg, 2.47 mmol, 5.00 eq.) in amixture solvent of dioxane (5.00 mL) and water (1.00 mL) was de
- Step B A mixture of methyl 5-(2-(l-((/ert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)- 1 -methyl- 1 H-py razolc-3 - carboxylate (250 mg, 402 pmol, 1.00 eq.) and sodium hydroxide (1.00 M in water, 1.21 mL, 3.00 eq.) in methanol (10.0 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 50 °C for 1 hour under a nitrogen atmosphere.
- Step C To a solution of 5-(2-(l-((tert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)- 1 -methyl- I H-py razolc-3 - carboxylic acid (230 mg, 417 pmol, 1.00 eq.) and ammonium chloride (66.9 mg, 1.25 mmol, 3.00 eq.) in DMF (3.00 mb) was added diisopropylethylamine (162 mg, 1.25 mmol, 218 pL, 3.00 eq.) and HATU (238 mg, 625 pmol, 1.50 eq.).
- Step D To a mixture of tert-butyl ( l-(8-(3-carbamoyl-l-mcthyl-IH-pyrazol-5-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, 218 pmol, 1.00 eq.) and triethylamine (441 mg, 4.36 mmol, 607 pL, 20.0 eq.) in anhydrous tetrahydrofuran (2.00 mb) was added trifluoroacetic anhydride (458 mg, 2.18 mmol, 303 pL, 10.0 eq.) at 0 °C, The resulting mixture was warmed to 25 °C and stirred for 30 minutes.
- Step E A solution of tert-butyl ( l-(8-(3-cyano-l-mcthyl-IH-pyrazol-5-yl)-5-(((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, 225 pmol, 1.00 eq.) in a mixture solvent of dichloromethane (1.50 mL) and trifluoroacetic acid (0.50 mL) was stirred at 25°C for 30 minutes. The reaction mixture was evaporated to give a residue.
- Step A To a solution of 8-bromo-5 -(((5 -fluoro-2, 3 -dihydrobenzofuran -4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (50.0 mg, 129 pmol, 1.00 eq.) in THF (1.00 mb) was added cyclopropyl magnesium bromide (0.50 M, 1.55 mb, 6.00 eq.) dropwise at 15 °C, the mixture was stirred at 25 °C for 5 hours, then the reaction mixture was cooled to -10 °C.
- Step B To a mixture of 2-(amino(cyclopropyl)methyl)-8-bromo-A-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine (61.0 mg, 116 pmol, 1.00 eq.) and TEA (35.1 mg, 347 pmol, 48.3 pL, 3.00 eq.) in THF (2.00 mb) was added di-tert-butyl dicarbonate (50.5 mg, 231 pmol, 53.1 pL, 2.00 eq.) and DMAP (1.41 mg, 11.6 pmol, 0.10 eq.) in one portion at 20 °C under a nitrogen atmosphere.
- reaction mixture was stirred at 20 °C for 3 hours.
- Water (3.00 mL) was added to the reaction mixture and then extracted with ethyl acetate (3.00 mL x 2).
- the combined organic phase was washed with brine (8.00 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated in vacuo.
- Step C tert-butyl ((8-bromo-5-(((5-fhioro-2,3-dihydrobenzofiiran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(cyclopropyl)methyl)carbamate (40.0 mg, 75.1 pmol, 1.00 eq ), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (20.0 mg, 90.2 pmol, 1.20 eq.), Pd(dppf)C12 (5.50 mg, 7.51 pmol, 0.10 eq.) and sodium bicarbonate (18.9 mg, 225 pmol, 8.77 pL, 3.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was degassed and then heated to 100 °C for
- Step D To a mixture of tert-butyl (cyclopropyl(8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)methyl)carbamate (20.0 mg, 36.5 pmol, 1.00 eq.) in DCM (0.50 mL) was added TFA (770 mg, 6.75 mmol, 0.50 mL, 185 eq.) in one portion at 20 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 2 hours.
- TFA 770 mg, 6.75 mmol, 0.50 mL, 185 eq.
- Step A To a solution of 8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (80.0 mg, 197 pmol, 1.00 eq.) and di-tert-butyl dicarbonate (47.3 mg, 217 pmol, 49.7 pL, 1.10 eq.) in THF (1.00 mb) was added DMAP (2.40 mg, 19.7 pmol, 0.10 eq.). The reaction mixture was stirred at 35 °C for 1 hour.
- Step B To a solution of tert-butyl (8-(l,3-dimethyl-lH-pyrazol-5-yl)-2-formylimidazo[l,2- c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (85.0 mg, 168 pmol, 1.00 eq.) and potassium carbonate (46.4 mg, 336 pmol, 2.00 eq.) in DMF (1.00 mb) was added trimethyl(trifhroromethyl)silane (191 mg, 1.34 mmol, 8.00 eq.) dropwise at 0 °C.
- Step C To a solution of tert-butyl (8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-2-(2.2.2-trifluoro-l- hydroxyethyl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (22.0 mg, 38.2 pmol, 1.00 eq.) in DCE (1.00 mb) was added manganese dioxide (6.60 mg, 76.3 pmol, 2.00 eq.). The mixture was stirred at 40 °C for 1 hour.
- Step D To a solution of tert-butyl (8-( l.3-dimcthyl-IT/-pyrazol-5-yl)-2-(2.2.2- trifluoroacetyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5-fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (12.0 mg, 20.9 pmol, 1.00 eq.) in THF (0.50 mL) was added ammonia (711 pg, 41.8 pmol, 2.00 eq.) and titanium isopropoxide (11.9 mg, 41.8 pmol, 12.3 pL, 2.00 eq.
- Step E To a solution of tert-butyl (2-( l-amino-2.2.2-trifluorocthyl)-8-( l.3-dimcthyl-l7/- pyrazol-5-yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (10.0 mg, 17.4 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.30 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated in vacuo to give a residue.
- Step A A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (250 mg, 644 pmol, 1.00 eq.), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (215 mg, 966 pmol, 1.50 eq.), Pd(dppf)C12 (47.1 mg, 64.4 pmol, 0.10 eq.) and sodium bicarbonate (162 mg, 1.93 mmol, 75.1 pL, 3.00 eq.) in dioxane (1.70 mL) and water (0.30 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 95 °C for 1 hour under a nitrogen atmosphere.
- Step B To a mixture of -( 1,3 -dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3 -dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (20.0 mg, 44.6 pmol, 1.00 eq.) and ammonium chloride (2.50 mg, 46.7 pmol, 1.05 eq.) in DMF (1.00 mL) was added sodium azide (3.00 mg, 46.1 pmol, 1.03 eq.). The reaction mixture was heated at 100 °C for 3 hours.
- reaction mixture was cooled and diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mLx 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- Step A A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (800 mg, 1.84 mmol, 1.00 eq ), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (612 mg, 2.76 mmol, 1.50 eq.), NaHCCh (463 mg, 5.51 mmol, 214 pL, 3.00 eq.) and Pd(dppf)C12 (134 mg, 184 pmol, 0.10 eq.) in water (1.60 mL) and dioxane (8.00 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 105 °C for 2 hours under a nitrogen
- Step B To a solution of ethyl 8-( 1,3 -dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (400 mg, 888 pmol, 1.00 eq.) in ethanol (4.00 mL) was added hydrazine hydrate (178 mg, 3.55 mmol, 173 pL, 4.00 eq.) at 25 °C. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue.
- Step C To a solution 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbohydrazide (50.0 mg, 97.4 pmol, 1.00 eq.) in triethoxymethane (2.00 mL) and DMSO (2.00 mL) was added ammonium chloride (20.8 mg, 390 pmol, 4.00 eq.), the reaction mixture was stirred at 130 °C for 1 hour.
- the compounds of the present disclosure may have one or more chiral center and, if so, are synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
- the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions, as well as methods described herein, e.g., EXAMPLES 11 and 12.
- compounds of the present disclosure may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the disclosure.
- the assay uses purified human, His-tagged PRC2 complex, including N-terminal His-tagged EZH2 enzyme, N-terminal Flag-tagged embryonic ectoderm development protein (EED), N-terminal His-tagged suppressor of zeste 12 (SUZ12), N-terminal His- tagged AEBP2, and N-terminal His-tagged RbAp48.
- EED embryonic ectoderm development protein
- SAM radiolabeled S-adenosyl methionine
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Abstract
La présente invention concerne des procédés de traitement d'un sujet ayant un trouble sanguin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule (I). L'invention concerne également de tels procédés dans lesquels le trouble sanguin est la drépanocytose, ou la thalassémie, notamment l'alpha-thalassémie et la bêta-thalassémie.
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WO2020190754A1 (fr) * | 2019-03-15 | 2020-09-24 | Fulcrum Therapeutics, Inc. | Dérivés d'azolopyridine macrocycliques utilisés en tant que modulateurs eed et prc2 |
WO2020247475A1 (fr) * | 2019-06-05 | 2020-12-10 | Mirati Therapeutics, Inc. | Dérivés d'imidazo [1,2-c]pyrimidine utilisés comme inhibiteurs de prc2 pour le traitement du cancer |
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WO2020190754A1 (fr) * | 2019-03-15 | 2020-09-24 | Fulcrum Therapeutics, Inc. | Dérivés d'azolopyridine macrocycliques utilisés en tant que modulateurs eed et prc2 |
WO2020247475A1 (fr) * | 2019-06-05 | 2020-12-10 | Mirati Therapeutics, Inc. | Dérivés d'imidazo [1,2-c]pyrimidine utilisés comme inhibiteurs de prc2 pour le traitement du cancer |
Non-Patent Citations (2)
Title |
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ANONYMOUS: "Fulcrum Therapeutics Presents Published Structure of Investigational Small Molecule FTX6058 at the American Chemical Society (ACS) Spring 2021 Virtual Conference", FULCRUM THERAPEUTICS, 9 April 2021 (2021-04-09), XP093059746, Retrieved from the Internet <URL:https://www.globenewswire.com/news-release/2021/04/09/2207657/0/en/Fulcrum-Therapeutics-Presents-Published-Structure-of-Investigational-Small-Molecule-FTX-6058-at-the-American-Chemical-Society-ACS-Spring-2021-Virtual-Conference.html> [retrieved on 20230630] * |
EFREMOV IVAN V, APPIAH KINGSLEY KOFI, CACACE ANGELA, DONG YANFEI, JOHNSTONE SHAWN D, KAZMIRSKI STEVEN, LI QINGYI, MOXHAM CHRISTOPH: "Discovery of clinical candidate FTX-6058: a potent, orally bioavailable upregulator of fetal hemoglobin for treatment of sickle cell disease", 2021 SPRING ACS NATIONAL MEETING, 16 April 2021 (2021-04-16) - 1 May 2021 (2021-05-01), XP055944715 * |
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